• History & Evolution
• Biosynthesis & dietary uptake
• EPA and the microbiome
• EPA and inflammation
• EPA and neurology
• EPA and oncology
• EPA and 5P medicine
• References

History & Evolution

1957: first isolated (Klenk, E. and Eberhagen, D., 1957) | 1964: EPA linked to prostaglandin production (Bergström, S. et al., 1964) | 1978: discovery of cardiovascular protective effects

Eicosapentaenoic acid (EPA) is a long-chain omega-3 polyunsaturated fatty acid (PUFA) and a precursor to many lipid signaling molecules involved in inflammation and cardiometabolic regulation. The name reflects its structure: “eicosa” refers to its 20 carbon atoms, while “pentaenoic” refers to five double bonds (Castro, L. et al., 2016).

EPA was first isolated from cod liver oil in 1957 by Klenk and Eberhagen (Klenk, E. and Eberhagen, D., 1957). At the time, lipid research focused on omega-6 fatty acids, particularly arachidonic acid (AA) and linoleic acid, as their roles in cholesterol metabolism and prostaglandin synthesis made them more compelling targets (Spector, A. and Kim, H., 2019). Although Bergström later showed that EPA could also be enzymatically converted into prostaglandin E3 (Bergström, S. et al., 1964), this pathway attracted little attention and interesting early findings on omega-3 fatty acids were largely overlooked.

This changed in 1978, when Dyerberg and Bang observed notably low rates of myocardial infarction among Greenland Eskimos, who typically followed a diet of marine lipids rich in EPA and docosahexaenoic acid (DHA) (Dyerberg, J. and Bang, O., 1978).

By the 1980s, epidemiological and clinical studies linked diets rich in marine omega-3 fatty acids to lower rates of cardiovascular disease, putting EPA at the heart of vascular biology. EPA has since been shown to have protective effects against wide-ranging diseases, including obesity, diabetes, chronic obstructive pulmonary disease and certain cancers (Watabe, S. et al., 2024).

EPA is found primarily in marine microalgae, fish and other marine animals, where it accumulates through the food chain.

Biosynthesis vs. dietary uptake

In humans, EPA comes mainly from the diet, particularly oily fish, seafood and fish-based supplements. However, this is not a reliable source. Fish do not produce EPA themselves but obtain it from algae, so their EPA content varies depending on their diet and environment (Watabe, S. et al., 2024). Concerns about sustainability and contamination of fish and fish-derived supplements have increased interest in alternative sources such as algal oils (Sousa, S. et al., 2024).

EPA can also be produced endogenously, but only in small amounts. It is synthesized from the essential fatty acid alpha-linolenic acid (ALA), found in foods such as flaxseed, walnuts and vegetable oils (Watabe, S. et al., 2024). This conversion takes place mainly in the liver through a series of enzymatic reactions. The process is quite inefficient: only 1-15% of ALA is converted to EPA, and this can be further reduced by alcohol consumption, smoking, inactivity and dietary factors (Sousa, S. et al., 2024).

As a result, endogenous synthesis does not make a significant contribution to circulating EPA and, for most people, dietary intake is the main source. Recommended daily intake is around 250-500 mg per day (together with downstream metabolite DHA), rising to 700-1000 mg for pregnant and lactating women (Sousa, S. et al., 2024).

Once in circulation, EPA is incorporated into cell membranes where it can be converted into lipid mediators, including prostaglandins, leukotrienes and resolvins (Igarashi, M. et al., 2013).

EPA and the microbiome

Research shows that EPA interacts with the gut microbiome, directly affecting bacterial growth, diversity and survival. As with other PUFAs, EPA has been shown in experimental settings to have an antibacterial effect against Gram-positive species such as Bacillus cereus and Staphylococcus aureus, which are both causes of infection (Le, PNT. and Desbois, A., 2017).

Studies report a decrease in the Firmicutes/Bacteroidetes ratio and increases in genera such as Bifidobacterium, Lachnospira, Roseburia and Lactobacillus (Amedei, A. et al., 2025). EPA has also been found to modulate levels of pro-inflammatory molecules and affect short-chain fatty acid (SCFA) concentrations (Fu, Y. et al., 2021). These effects are associated with improved cardiovascular risk profiles.

In turn, beneficial bacteria including Bifidobacterium, Lactobacillus and Akkermansia have been shown to influence EPA absorption and metabolism, indicating a two-way interaction between EPA and the gut microbiome (Amedei, A. et al., 2025).

EPA and inflammation

Inflammation is one of the main pathways through which EPA affects human health.
As a precursor to lipid signaling molecules, EPA influences how inflammatory mediators are produced. In cell membranes, it partly replaces omega-6 fatty acids such as arachidonic acid, changing the pool of fatty acids available for enzymatic conversion and leading to the production of eicosanoids that are generally less pro-inflammatory (Crupi, R. and Cuzzocrea, S., 2022). EPA is also converted into specialized pro-resolving mediators, such as resolvins, which help limit and resolve inflammation. More broadly, these changes in membrane composition influence cell signaling, gene expression and the production of cytokines, adhesion molecules and other inflammatory mediators (Calder, P., 2010).

These pathways are also influenced by the exposome. Environmental factors such as diet, pollutants and oxidative stress can alter fatty acid composition and downstream inflammatory signaling (Hinman, J. et al., 2025). Studies show that higher omega-3 status, including EPA levels, is associated with increased pro-resolving and reduced pro-inflammatory lipid mediator responses following exposures such as air pollution, highlighting EPA’s role in shaping inflammatory responses to environmental stressors (Chen, H. et al., 2025).

Clinically, this translates into measurable effects on disease-related inflammation. EPA has been shown to reduce pro-inflammatory cytokines and oxidative stress, improve endothelial function and support stabilization of atherosclerotic plaques, all of which are relevant to cardiovascular risk (Crupi, R. and Cuzzocrea, S., 2022). In inflammatory conditions such as rheumatoid arthritis, higher intakes of EPA (typically with DHA) are associated with reduced inflammatory activity, although relatively high and sustained doses are often required (Calder, P., 2010). A 2024 literature review found that EPA is linked to improved metabolic and inflammatory profiles in non-communicable diet-related conditions such as obesity, diabetes and cardiovascular disease (Banaszak, M. et al., 2024).

A 2021 study using targeted lipidomics linked EPA’s anti-inflammatory effects to improvements in depression (Borsini, A. et al., 2021). Using a “depression in a dish” model of human hippocampal cells, researchers showed that EPA-derived lipid mediators protected neurons from inflammation-related damage and supported neurogenesis. In patients with major depressive disorder, higher levels of these metabolites were associated with reduced symptom severity, suggesting a mechanistic link between EPA, inflammation and depression.

EPA and neurology

EPA has been studied in neurology because of its effect on synaptic function, neuroinflammation and neuronal survival. In a preclinical study, EPA was taken up by both neurons and glial cells (Kawashima, A. et al., 2010). This increased long-term potentiation in the hippocampus and activated intracellular signaling involving phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), while reducing markers of cell death. These findings suggest a potential role in protecting against neurodegeneration and support interest in EPA in conditions such as Alzheimer’s disease, Huntington’s disease and schizophrenia.

More recent work has looked at EPA in neurodevelopmental disorders and epilepsy, where inflammation, oxidative stress and synaptic dysfunction are recurring factors (Li, M. et al., 2025). Omega-3 fatty acids, including EPA, may help in attention deficit hyperactivity disorder (ADHD), autism spectrum disorder and Tourette syndrome, but the evidence is mixed and clinical effects are often modest. For example, in ADHD, some studies report improvement in attention or behavior from higher EPA doses, while others find no clear benefit. In epilepsy, EPA and other omega-3 fatty acids have been explored mainly as adjuncts rather than stand-alone treatments, with some studies reporting reduced inflammatory markers or seizure frequency.

Omics studies suggest that lipid dysregulation, including EPA, may contribute to neurological disease progression. For example, in a 2025 longitudinal metabolomic-lipidomic study of 767 people with multiple sclerosis, decreased serum EPA was associated with slower walking speed and reduced manual dexterity (Noroozi, R. et al., 2026).

A 2026 study found that after repetitive mild traumatic brain injury, EPA accumulates in the brain under baseline conditions but is then depleted during injury-related metabolic stress (Karakaya, E. et al., 2026). This was associated with impaired endothelial repair, reduced angiogenic signaling and vascular and cognitive decline.

These findings make EPA a metabolite of interest as a marker of and potential therapeutic target in neuroinflammatory and neurovascular processes.

EPA and oncology

The relationship between EPA and cancer is unclear. The metabolite has been shown to suppress proliferation in colon, pancreatic, breast, esophageal and other cancer cell lines (Mizoguchi, K. et al., 2014), and EPA-derived resolvins seem to have an anti-tumor effect (Kiyasu, Y. et al., 2024).

However, clinical studies show mixed results. In animal models, for example, fish oil has been shown to both suppress colorectal carcinogenesis and to promote colitis-associated cancer (Kiyasu, Y. et al., 2024).

Evidence in patients is also limited. Small studies in patients undergoing chemotherapy report changes in inflammatory markers and immune function with EPA (often combined with DHA) (Munhoz, J. et al., 2025). However, findings are inconsistent, and there is currently insufficient evidence to support routine use in cancer care.

EPA and 5P medicine

EPA’s links to diet, genetics and inflammation make it an interesting metabolite for the study of chronic, non-communicable diseases, which are a top priority in population health. In epidemiological research, circulating omega-3 fatty acids, including EPA, are used as objective biomarkers of dietary intake and have been associated with cardiovascular outcomes and mortality risk across large cohorts and meta-analyses (Jiang, H. et al., 2022).

Studies also show that EPA’s effects depend on both exposure (diet) and host biology (genetics), with implications for precision medicine. For example, in the seAFOod polyp prevention trial, EPA supplementation was found to reduce adenoma risk by around 50% in individuals with a specific FADS variant, while those without the allele saw no benefit (Sun, G. et al., 2024).

EPA also seems to play a role in aging, making it increasingly relevant as populations age and the burden of chronic disease grows (Hinman, J. et al., 2025). Studies show changes in PUFA profiles and inflammatory and oxidative stress markers across the lifespan (Aiello, A. et al., 2024). In long-lived women, a lower AA to EPA ratio was associated with higher antioxidant capacity (Hinman, J. et al., 2025).

References

Aiello, A. et al. (2024). Polyunsaturated fatty acid status and markers of oxidative stress and inflammation across the lifespan: A cross-sectional study in a cohort with long-lived individuals. Experimental Gerontology, 195, 112531. DOI: https://doi.org/10.1016/j.exger.2024.112531.

Amedei, A. et al. (2025). Potential and Future Therapeutic Applications of Eicosapentaenoic/Docosahexaenoic Acid and Probiotics in Chronic Low-Grade Inflammation. Biomedicines, 13(10), 2428. DOI: https://doi.org/10.3390/biomedicines13102428.

Banaszak, M. et al. (2024). Role of Omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic (DHA) as modulatory and anti-inflammatory agents in noncommunicable diet-related diseases – Reports from the last 10 years. Clinical Nutrition ESPEN, 63, 240-258. DOI: https://doi.org/10.1016/j.clnesp.2024.06.053.

Bergström, S. et al. (1964). The Enzymatic Conversion of Essential Fatty Acids into Prostaglandins: PROSTAGLANDINS AND RELATED FACTORS 34. Journal of Biological Chemistry, 239, PC4006-PC4008. DOI: https://doi.org/10.1016/S0021-9258(18)91234-2.

Borsini, A. et al. (2021). Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis. Molecular Psychiatry, 26, 6773–6788. DOI: https://doi.org/10.1038/s41380-021-01160-8.

Calder, P. (2010). Omega-3 Fatty Acids and Inflammatory Processes. Nutrients, 2(3), 355–374. DOI: https://doi.org/10.3390/nu2030355.

Castro, L. et al. (2016). Long-chain polyunsaturated fatty acid biosynthesis in chordates: Insights into the evolution of Fads and Elovl gene repertoire. Progress in Lipid Research, 62, 25-40. DOI: https://doi.org/10.1016/j.plipres.2016.01.001.

Chen, H. et al. (2025). Omega-3 Fatty Acid Intake and Oxylipin Production in Response to Short-Term Ambient Air Pollution Exposure in Healthy Adults. Toxics, 13(12), 1063. DOI: https://doi.org/10.3390/toxics13121063.

Crupi, R. and Cuzzocrea, S. (2022). Role of EPA in Inflammation: Mechanisms, Effects, and Clinical Relevance. Biomolecules, 12(2), 242. DOI: https://doi.org/10.3390/biom12020242.

Dyerberg, J. and Bang, O. (1978). Dietary fat and thrombosis. The Lancet, 311(8056), 152. DOI: https://doi.org/10.1016/S0140-6736(78)90448-8.

Fu, Y. et al. (2021). Associations among Dietary Omega-3 Polyunsaturated Fatty Acids, the Gut Microbiota, and Intestinal Immunity. Mediators Inflamm, 8879227. DOI: https://doi.org/10.1155/2021/8879227.

Hinman, J. et al. (2025). Effects of molecular interactions between the exposome and oxylipin metabolism on healthspan. Front. Physiol., 16, DOI: https://doi.org/10.3389/fphys.2025.1584195.

Igarashi, M. et al. (2013). Kinetics of eicosapentaenoic acid in brain, heart and liver of conscious rats fed a high n-3 PUFA containing diet. Prostaglandins Leukot Essent Fatty Acids, 89(6), 403–412. DOI: https://doi.org/10.1016/j.plefa.2013.09.004.

Jiang, H. et al. (2022). Omega-3 polyunsaturated fatty acid biomarkers and risk of type 2 diabetes, cardiovascular disease, cancer, and mortality. Clin Nutr, 41(8), 798-1807. DOI: https://doi.org/10.1016/j.clnu.2022.06.034.

Karakaya, E. et al. (2026). Eicosapentaenoic acid reprograms cerebrovascular metabolism and impairs repair after brain injury, with relevance to chronic traumatic encephalopathy. Cell Reports, 117135. DOI: https://doi.org/10.1016/j.celrep.2026.117135.

Kawashima, A. et al. (2010). Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells. J Nutr Biochem, 21(4), 268-77. DOI: https://doi.org/10.1016/j.jnutbio.2008.12.015. Epub 2009.

Kiyasu, Y. et al. (2024). EPA, DHA, and resolvin effects on cancer risk: the underexplored mechanisms. Prostaglandins Other Lipid Mediat, 174, 106854. DOI: https://doi.org/10.1016/j.prostaglandins.2024.106854.

Klenk, E. and Eberhagen, D. (1957). [Occurrence of delta5, 8, 11, 14, 17-n-eicosapentanoic acid in cod liver oil and its isolation] (Article in German). Hoppe Seylers Z Physiol Chem, 307(1), 42-8.

Le, PNT. and Desbois, A. (2017). Antibacterial Effect of Eicosapentaenoic Acid against Bacillus cereus and Staphylococcus aureus: Killing Kinetics, Selection for Resistance, and Potential Cellular Target. Mar Drugs, 15(11), 334. DOI: https://doi.org/10.3390/md15110334.

Li, M. et al. (2025). Omega-3 fatty acids: multi-target mechanisms and therapeutic applications in neurodevelopmental disorders and epilepsy. Front. Nutr. , 12, 1598588. DOI: https://doi.org/10.3389/fnut.2025.1598588.

Mizoguchi, K. et al. (2014). Induction of Apoptosis by Eicosapentaenoic Acid in Esophageal Squamous Cell Carcinoma. Anticancer Research December, 34(12), 7145-7149. PMID: 25503142.

Munhoz, J. et al. (2025). Perspective: Implications of Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation on the Immune System during Cancer Chemotherapy: Perspectives from Current Clinical Evidence. Advances in Nutrition, 16(8), 100464. DOI: https://doi.org/10.1016/j.advnut.2025.100464.

Noroozi, R. et al. (2026). Serum metabolomic-lipidomic signatures track long-term neurological performance in multiple sclerosis. Mol. Neurodegener. Adv., 2(1), DOI: https://doi.org/10.1186/s44477-025-00008-7.

Sousa, S. et al. (2024). Factors impacting the microbial production of eicosapentaenoic acid. Appl Microbiol Biotechnol, 108(1), 368. DOI: https://doi.org/10.1007/s00253-024-13209-z.

Spector, A. and Kim, H. (2019). Emergence of omega-3 fatty acids in biomedical research. Prostaglandins, Leukotrienes and Essential Fatty Acids, 140, 47-50. DOI: https://doi.org/10.1016/j.plefa.2018.11.017.

Sun, G. et al. (2024). Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial. Am J Clin Nutr, 120(2), 360-368. DOI: https://doi.org/10.1016/j.ajcnut.2024.06.004.

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• History & Evolution
• Biosynthesis & dietary uptake
• Dimethylglycine and cardiology
• Dimethylglycine and diabetes
• Dimethylglycine and neurology
• Dimethylglycine and immunity
• Dimethylglycine and oncology
• Dimethylglycine and 5P medicine
• References

History & Evolution

1943: discovery | 1950-1960: description as endurance enhancer | 1974: marketed as supplement

Dimethylglycine (DMG) was first described in 1943 (Cupp et al. 2003). It gained attention in the 1950s-1960s through studies conducted in the Soviet Union claiming improved oxygen use, reduced fatigue, and enhanced physical performance (Wolfsegger et al. 2021). This led to its widespread use among Russian athletes and cosmonauts. During this period, DMG was often incorrectly marketed as vitamin B15 or pangamic acid, in which it was sometimes included (Cupp et al. 2003).
DMG entered the U.S. supplement market in 1974, and similar performance claims appeared in American reports in 1975 (Wolfsegger et al. 2021). In 1982, the Food and Drug Administration (FDA) banned pangamic acid due to inconsistent composition and unsupported health benefits, but DMG itself remained legal (Cupp et al. 2003). Today, DMG is recognized not as a vitamin but as a natural metabolite in one carbon metabolism.

Biosynthesis vs. dietary uptake

DMG is a naturally occurring amino acid derivative present in the cells of all plants and animals. Small amounts are obtained through the diet, particularly from legumes, grains, and meat (Yao et al. 2022; Cupp et al. 2003). Dietary DMG that is not immediately metabolized in the liver enters the circulation and is delivered to peripheral tissues (Svingen et al. 2013)
In humans, most DMG arises from endogenous metabolism rather than direct dietary intake (Cupp et al. 2003). DMG is formed when choline is metabolized along the choline–betaine–glycine pathway. A key step in this path is the remethylation of homocysteine mainly in liver and kidney tissue: the enzyme betaine homocysteine methyltransferase (BHMT) transfers a methyl group from betaine to homocysteine, generating methionine and DMG (McGregor et al. 2001). Notably, DMG inhibits BHMT via negative a feedback loop (Svingen et al. 2013).
Once formed, DMG is rapidly oxidized in mitochondria by dimethylglycine dehydrogenase (DMGDH) to produce sarcosine, linking DMG metabolism directly to the folate dependent one carbon cycle (McAndrew et al. 2008). Under normal physiological conditions, circulating DMG levels remain low. A small fraction of unmetabolized DMG is excreted in urine (Svingen et al. 2013). Elevated DMG occurs when DMGDH function is impaired (McAndrew et al. 2008) or when BHMT activity is altered (McGregor et al. 2001).

Dimethylglycine and cardiology

Observational cohort studies consistently link plasma DMG levels with cardiovascular outcomes. In patients with recent acute coronary syndrome, higher baseline DMG was associated with increased risk of acute myocardial infarction, heart failure, and death over ~2.5 years (Lever et al. 2012). Similarly, in a large cohort with stable angina pectoris, DMG correlated with traditional coronary artery disease risk factors and independently predicted incident myocardial infarction during ~4.6 years of follow up (Svingen et al. 2013).
Furthermore, two cohorts of patients with suspected stable angina pectoris or acute myocardial infarction showed that elevated DMG was associated with higher all-cause and cardiovascular mortality, with stronger effects in acute myocardial infarction. DMG improved risk prediction in both groups (Svingen et al. 2015).
In pregnant women carrying fetuses with confirmed congenital heart disease, decreased maternal serum DMG emerged as a potential prenatal diagnostic marker (Xie et al. 2025). Mechanistically, high plasma DMG levels may be linked to the regulation of lipid and energy metabolism.
Experimental evidence suggests that activation of peroxisome proliferator activated receptor alpha (PPARα) reduces transcription of enzymes involved in DMG catabolism, potentially contributing to elevated circulating DMG concentrations (Svingen et al. 2015). However, the exact biological mechanisms underlying the observed associations between DMG and cardiovascular outcomes remain to be fully elucidated.

Dimethylglycine and diabetes

Observational human data indicate that low plasma DMG is associated with higher blood glucose. A genome-wide-association study identified a strong signal at the DMGDH locus that associated with lower DMG and higher insulin, HOMA IR and incident diabetes risk. This suggests that DMG deficiency may contribute to diabetes development and that DMGDH inhibition or DMG supplementation could be explored therapeutically (Magnusson et al. 2015). Additional metabolomics work shows DMG levels differ between normal glucose tolerance and impaired glucose regulation, positioning DMG as a risk associated marker in early dysglycemia (Liu et al. 2024).
Beyond these findings, maternal metabolic studies indicate that mothers carrying twins with low plasma DMG/betaine ratios have a decreased risk of gestational diabetes, suggesting that DMG-betaine balance may modulate glucose metabolism during pregnancy (Gong et al. 2021). Although all human evidence is observational and mechanistic or interventional studies are missing. The metabolic link becomes even clearer in the context of liver disease. The same ratio, this time assessed directly in hepatic tissue, proved highly relevant in a study of metabolic dysfunction associated steatotic liver disease (MASLD) in mice. The impaired DMG/betaine ratio was closely linked to disrupted one carbon remethylation (Pacana et al. 2015). These liver findings support the idea that altered DMG metabolism is part of a broader metabolic dysfunction relevant to both hepatic disease and diabetes.

Dimethylglycine and neurology

DMG supplements are often advertised as supporting cognitive function, mood, memory, or neurotransmitter synthesis, but scientific evidence for neurological benefits remains limited. Preclinical data show some promising mechanistic effects: in a BTBR mouse model of autism spectrum disorder (ASD), supplementation with DMG and B vitamins reduced ASD like behaviors, potentially through multifactor effects including decreased oxidative stress and inflammation, improved gut microbiota and gut permeability, altered body composition, reduced hepatic steatosis, and enhanced mitochondrial function in both liver and brain (Cimmino et al. 2025). However, these findings did not translate into clinical benefit. A double blind, placebo controlled trial in children with autism or pervasive developmental disorder reported no behavioral improvements in 33 of 37 participants receiving DMG (Kern et al. 2001). Similarly, a randomized, placebo controlled pilot study in patients with progressive multiple sclerosis found no effects of DMG on disability, fatigue, or cognitive and motor performance (Wolfsegger et al. 2021). Recent data strengthen the mechanistic rationale for DMG in neurodegeneration, particularly Alzheimer’s disease (AD). DMG was identified as the most effective of twelve metabolites in restoring catalase function, a key antioxidant enzyme impaired in AD, by preventing its aggregation, enhancing activity, stabilizing its native fold, and reducing amyloid like fibrils. Together, these effects suggest that DMG may help counter oxidative stress, a major driver of AD pathology (Devi et al. 2026). However, despite these mechanistic insights, human studies, including interventional trials or metabolomics guided supplementation studies, are still lacking, and no clinical evidence currently supports neurological benefits of DMG.

Dimethylglycine and immunity

DMG shows consistent immunomodulatory effects in animal studies, but human evidence remains limited. In a rabbit model, DMG supplementation markedly increased antibody titers to influenza and Salmonella typhi vaccines and enhanced lymphocyte proliferation, indicating stronger humoral and cellular immunity (Reap et al. 1990). A feline study also reported immunological shifts after DMG-containing supplementation, with reduced neutrophils and increased lymphocytes, possibly reflecting changes in B cell or NK cell activity (Shahril Agus et al. 2025). DMG may further influence immune tolerance: in a rat model of recurrent implantation failure, reduced DMG was linked to lower Treg cell levels and impaired endometrial receptivity, whereas supplementation helped restore immune balance (Liu et al. 2026).
In humans, only one small double blind trial from 1981 showed increased antibody responses and higher leukocyte inhibition factor activity after DMG intake, suggesting enhanced immunity (Graber et al. 1981). However, this finding has never been replicated, and no modern clinical trials confirm immune boosting effects. Thus, while animal data are supportive, evidence in humans remains preliminary and inconclusive.

Dimethylglycine and oncology

Evidence on an influence of DMG in cancer studies is mixed and appears highly context dependent. Large cohort studies report no association between circulating DMG levels and cancer risk, including two nested case-control studies on pancreatic cancer in Asian populations (Huang et al. 2017) and colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (Nitter et al. 2014). In contrast, DMG is elevated in several tumor related settings. Urinary DMG was significantly increased in hepatocellular carcinoma (HCC) in a West African cohort and correlated with clinical stage, suggesting potential utility for surveillance (Ladep et al. 2014). Higher DMG has also been detected in esophageal tumor margins (Jianyong et al. 2017) and in fecal samples of colorectal cancer patients (Lin et al. 2016). One population study in individuals with hypertension reported a positive association between serum DMG and overall cancer risk (Zhang et al. 2023).
These divergent findings may reflect differences in population characteristics, disease stage, or sample types. Mechanistically, DMG participates in one carbon metabolism, supporting amino acid and nucleotide synthesis and cellular methylation reactions. When primary dietary methyl donors (choline, methionine, creatine) are insufficient, DMG can act as a secondary methyl donor. Because dysregulated methylation is a hallmark of cancer, shifts in DMG availability may influence tumor biology, although causal evidence is still limited (Zhang et al. 2023).

Dimethylglycine and 5P medicine

DMG is a molecular entry point into individualized, systems-oriented healthcare aligning with the principles of 5P medicine. Altered DMG levels have been linked to cardiometabolic risk and conditions such as myocardial infarction, diabetes (Magnusson et al. 2015), and metabolic dysfunction-associated liver disease (Pacana et al. 2015). Hence, DMG is positioned as potential early predictive marker even though causal evidence is still missing. Disease specific and matrix dependent patterns, like elevated urinary DMG in hepatocellular carcinoma (Ladep et al. 2014), increased fecal DMG in colorectal cancer (Lin et al. 2016), or reduced maternal DMG in pregnancies with congenital heart disease (Xie et al. 2025), highlight its relevance for more precise diagnostics or stratification. Because DMG metabolism is shaped by nutrition (Yao et al. 2022; Cupp et al. 2003), liver and kidney function (McGregor et al. 2001), genetics (McAndrew et al. 2008), and microbiome (Cimmino et al. 2025; Liu et al. 2024; Wang et al. 2022), individual interpretation is essential. Overall, DMG reflects interconnected pathways such as methylation, mitochondrial function, and cardiometabolic regulation, making it a valuable indicator of metabolic stress and early dysregulation.

References

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Liu, F.-T. et al.: Endometrial microbiota-dimethylglycine-Treg cell axis affects endometrial receptivity in recurrent implantation failure (2026) Science China. Life sciences | https://doi.org/10.1007/s11427-025-3138-x.

Liu, Y. et al.: Changes in Isoleucine, Sarcosine, and Dimethylglycine During OGTT as Risk Factors for Diabetes (2024) The Journal of Clinical Endocrinology & Metabolism | https://doi.org/10.1210/clinem/dgae018.

Magnusson, M. et al.: Dimethylglycine Deficiency and the Development of Diabetes (2015) Diabetes | https://doi.org/10.2337/db14-1863.

McAndrew, R.P. et al.: Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R (2008) Journal of inherited metabolic disease | https://doi.org/10.1007/s10545-008-0999-2.

McGregor, D.O. et al.: Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations (2001) Kidney International | https://doi.org/10.1046/j.1523-1755.2001.00743.x.

Nitter, M. et al.: Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) (2014) Annals of oncology : official journal of the European Society for Medical Oncology | https://doi.org/10.1093/annonc/mdu185.

Pacana, T. et al.: Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease (2015) PLOS ONE | https://doi.org/10.1371/journal.pone.0136822.

Reap, E.A. et al.: Stimulation of the immune response by dimethylglycine, a nontoxic metabolite (1990) The Journal of laboratory and clinical medicine | PMID: 1691258.

Shahril Agus, S.A. et al.: Effect of N, N-Dimethylglycine (DMG) Supplementation on Haematological Parameters and Frequency of CD4+ and CD8+ T Cells in Cats Post-vaccination (2025) Pertanika Journal of Tropical Agricultural Science | https://doi.org/10.47836/pjtas.48.3.12.

Svingen, G.F.T. et al.: Plasma dimethylglycine and risk of incident acute myocardial infarction in patients with stable angina pectoris (2013) Arteriosclerosis, thrombosis, and vascular biology | https://doi.org/10.1161/ATVBAHA.113.301714.

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• History & Evolution
• Biosynthesis & dietary uptake
• Fructose and the microbiome
• Fructose and cardiometabolism
• Fructose and neurology
• Fructose and oncology
• Fructose and 5P medicine
• References

History & Evolution

1847: isolation | 1880s: stereochemistry | 1956: clinics | 1970s: industry | 2004: health concerns

Fructose entered the world of chemistry in 1847, when Augustin Pierre Dubrunfaut isolated it from sucrose (Rödel 1974). For decades it was also called levulose because its solution rotates plane polarized light to the left. In the 1880s-1890s, Emil Fischer revolutionized carbohydrate science by mapping relationships among glucose, fructose, and mannose and introducing Fischer projections, which fixed the stereochemical language we still use (Horton 2013). A clinical turn came in 1956-1963, when physicians characterized hereditary fructose intolerance (HFI), a recessive disorder of aldolase B, and explained the syndrome’s biochemistry (Chambers et al. 1956). The role of fructose in the food industry became prominent in the early 1970s after work on glucose isomerase brought about commercial high fructose corn syrup (HFCS) (Horton 2013). In 2004, after decades of increasing intake of HFCS sweetened beverages, their link with U.S. obesity trends was brought to light (Bray et al. 2004), catalyzing an enduring debate about the ethics of adding fructose and other sweeteners to our foods.

When it does make it into our plates and glasses, fructose has advantageous properties compared to glucose: it is generally ~1.2 to 1.7 times sweeter than sucrose (Fontvieille et al. 1989), thus requiring less fructose for the same sensation. However, this advantage is most pronounced in cold matrices. Classic psychophysical work shows fructose’s relative sweetness climbs at low temperatures and drops when heated (Green et al. 2015). The mechanistic study of the fate of fructose in the body further added fuel to the polemic, with the discovery that fructose is a substrate for hepatic lipogenesis.

Biosynthesis vs. dietary uptake

Fructose is a naturally occurring monosaccharide that can be produced endogenously in humans via the polyol pathway, where glucose is converted to sorbitol and then to fructose (Delannoy et al. 2025). In diet, fructose is abundant in fruits, honey, and some vegetables and is specifically present in processed foods as part of sucrose or in the form of HFCS (Flores Monar et al. 2025).
After ingestion, fructose is absorbed in the small intestine primarily via facilitated diffusion through the GLUT5 transporter located on the apical membrane of enterocytes (Taylor et al. 2021). Once inside the enterocyte, fructose is transported across the basolateral membrane into the portal circulation by GLUT2 (Jung et al. 2022). From the portal vein, fructose is delivered mainly to the liver, which serves as the central site of fructose metabolism.

Within the liver, fructose undergoes rapid phosphorylation by ketohexokinase (KHK) to form fructose-1-phosphate (F1P) (Flores Monar et al. 2025; Jung et al. 2022). Consequently, fructose-1-phosphate is cleaved by aldolase B into dihydroxyacetone phosphate (DHAP) and glyceraldehyde, intermediates which enter glycolysis or gluconeogenesis. A substantial fraction of these metabolites is directed toward de novo lipogenesis, contributing to triglyceride synthesis. A low flux of intermediates is directed towards the hexosamine biosynthetic pathway, supporting the formation of sugar nucleotides required for proper protein glycosylation. This essential regulatory process controls protein folding, receptor signaling and immune function (Paneque et al. 2023).

Unlike glucose, fructose metabolism does not stimulate insulin secretion or leptin production, which has implications for energy homeostasis and lipid accumulation (Taylor et al. 2021; Flores Monar et al. 2025). Under normal physiological conditions, almost all absorbed fructose is processed during first-pass metabolism, so urinary excretion is negligible (Macdonald et al. 1978; Jung et al. 2022). However, in cases of fructose malabsorption or hereditary fructose intolerance, unmetabolized fructose may appear in urine and cause gastrointestinal symptoms (Simões et al. 2025; Febbraio et al. 2021).

Fructose and the microbiome

When the small intestine’s first-pass capacity to absorb fructose is exceeded, particularly with high loads of free fructose from HFCS-sweetened foods and beverages, unabsorbed fructose reaches the distal gut and becomes directly available to the microbiota (Jung et al. 2022; Febbraio et al. 2021). Chronic high free-fructose intake shifts microbial communities toward simple-sugar-degrading bacteria and away from key fiber-degrading taxa (Simões et al. 2025). By contrast, fructose in whole fruits is delivered within a fiber-rich matrix that slows its arrival in the distal gut and supports saccharolytic commensal bacteria (Simões et al. 2025; Febbraio et al. 2021). Microbial fermentation of unabsorbed fructose generates gases typical of malabsorption and produces short-chain fatty acids (SCFAs) (Febbraio et al. 2021; Simões et al. 2025). Among SCFAs, acetate is particularly relevant because it enters the portal circulation and serves as a substrate for hepatic acetyl-CoA, thereby fueling de novo lipogenesis and linking microbial activity to liver fat accumulation.

In contrast, butyrate generally exerts anti-inflammatory and barrier-supporting effects in the colon. High-fructose diets also shift microbial metabolism toward cardiometabolic risk-associated metabolites such as trimethylamine N-oxide (TMAO) in mice (Jung et al. 2022).
In the same luminal environment, unabsorbed fructose can non-enzymatically be combined to dietary peptides and incretins through fructosylation. These fructose-derived advanced glycation end products (FruAGE) activate receptors for advanced glycation end products (RAGE) and amplify inflammatory signaling locally and systemically (DeChristopher 2024). As dysbiosis progresses, SCFA imbalance and microbial activity reduce gut barrier integrity, leading to a “leaky gut” with increased permeability. Translocated lipopolysaccharide (LPS) and other microbial components then reach the liver, activate toll-like receptor (TLR) 4 on Kupffer cells, trigger tumor-necrosis factor (TNF)-driven inflammatory cascades, and propagate hepatic injury and metabolic dysfunction (Febbraio et al. 2021; Simões et al. 2025). Together, these processes link chronic high fructose exposure, microbial dysbiosis, impaired barrier function, and immune activation to a broad spectrum of metabolic and inflammatory diseases across the gut-organ axis.

Fructose and cardiometabolism

Over the past four decades, HFCS in processed foods and beverages has markedly increased dietary fructose exposure beyond normal physiological handling. This change parallels rising rates of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease, implicating industrial sweeteners as important contributors to cardiometabolic risk (Febbraio et al. 2021; DeChristopher 2024; Jung et al. 2022). Unlike fructose in whole fruits and honey, HFCS provides large amounts of free fructose in liquid form, bypassing the fiber matrix that normally slows absorption (Flores Monar et al. 2025; Jung et al. 2022). When intake is high, small-intestinal first-pass clearance saturates and excess fructose reaches the liver in substantial amounts (Jung et al. 2022; Febbraio et al. 2021).
In the liver, KHK-driven fructose phosphorylation bypasses phosphofructokinase and rapidly generates fructose-1-phosphate. This unregulated flux promotes lipogenesis while depleting adenosine-triphosphate (ATP) and trapping inorganic phosphate, activating adenosine-monophosphate (AMP) deaminase (AMPD) and increasing uric acid production. Elevated uric acid together with reactive oxygen species has been shown to promote endothelial dysfunction, inflammation and a pro-steatotic, pro-inflammatory hepatic milieu in animal models (Febbraio et al. 2021; Jung et al. 2022; Flores Monar et al. 2025). At the same time, fructose weakly stimulates insulin and satiety hormones such as glucagon-like peptide (GLP)-1, lessening satiation and fostering increased energy intake and positive energy balance (Flores Monar et al. 2025).

These mechanisms collectively drive hepatic steatosis, dyslipidemia and insulin resistance, core features of metabolic syndrome (DeChristopher 2024; Febbraio et al. 2021). Epidemiological data further link chronic high-fructose intake to hypertension, hyperuricemia and elevated cardiovascular risk independently of body mass index (Febbraio et al. 2021; Jung et al. 2022; DeChristopher 2024). Although the relative contribution of HFCS versus sucrose remains debated (Feinman et al. 2013) decades of excessive fructose consumption, particularly from sugar-sweetened beverages, represent a key factor in the growing burden of cardiometabolic disease (DeChristopher 2024; Flores Monar et al. 2025; Jung et al. 2022).

Fructose and neurology

In the hypothalamus of mice, chronic fructose exposure alters energy sensing and shifts neuropeptide signaling toward orexigenic, or appetite-stimulating pathways, thus directly linking high-fructose intake to positive energy balance and the metabolic changes in humans described above (Payant et al. 2021). The developing brain is especially vulnerable: in mice, early-life high-fructose diets impair microglial phagocytic activity, and reduce clearance of synapses and apoptotic neurons disrupts circuit refinement, leading to lasting deficits in learning and emotional regulation (Zelenka 2025). In the mature rodent brain, the hippocampus emerges as a key target of fructose-induced injury, with early mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired neuronal insulin signaling. Some changes persist after dietary normalization and result in long-term memory impairment (Flores Monar et al. 2025; DeChristopher 2024).

Within this framework, Alzheimer’s disease (AD) has been hypothesized to be driven, at least in part, by overactivation of cerebral fructose metabolism, largely through endogenous fructose production via the polyol pathway. In neuronal models, fructose metabolism via KHK C causes energy depletion and uric acid generation, leading to mitochondrial oxidative stress, impaired mitophagy, reduced oxidative phosphorylation, cerebral glucose hypometabolism, and insulin resistance. Chronic energy failure promotes uric acid-driven neuroinflammation via NF-κB and TLR4 in rodents and humans (Shao et al. 2016). Disruption of plasticity-related pathways causes synaptic dysfunction in rodents. Amyloid/tau pathology might come secondary to oxidative stress and impaired protein repair also in humans. These processes might ultimately lead to neuronal dysfunction (Johnson et al. 2020).

High sugar and high-fructose intake, high glycemic load, excess salt, alcohol, obesity, diabetes, aging, and traumatic brain injury may all enhance endogenous fructose production by inducing aldose reductase and fructokinase in the brain. Consistently, the levels of sorbitol and fructose, as well as the activity of AMPD2 and production of ammonia are all increased in the brains of patients with AD. In both animal and human studies, high sugar intake was linked to cognitive decline, hippocampal inflammation, and reduced brain volume (Johnson et al. 2020; Flores Monar et al. 2025).

Fructose and oncology

High fructose intake has been associated with an increased risk of several cancers, with particularly strong epidemiological links to pancreatic cancer. Many tumor types overexpress the fructose transporter GLUT5, and elevated GLUT5 together with KHK expression indicates active fructose utilization by cancer cells (Jung et al. 2022; Febbraio et al. 2021). At the level of host tissues and the tumor microenvironment, fructose acts prominently along the gut-liver axis. Mouse models revealed that dietary fructose enhances epithelial cell survival and drives villus elongation in the intestine. The expanded absorptive surface area leads to increasing nutrient uptake and adiposity in the context of a Western diet (Taylor et al. 2021; Febbraio et al. 2021).
In the liver, fructose-induced fibrosis and inflammation promote an immunosuppressive milieu that weakens CD8⁺ T cell-mediated immunosurveillance and favors hepatocellular carcinoma development (Febbraio et al. 2021).

Fructose can also drive tumor growth through cell non-autonomous fructolysis in animal models: KHK-C-expressing hepatocytes convert fructose into circulating lysophosphatidylcholines (LPCs) that are taken up by cancer cells to support phosphatidylcholine synthesis and membrane biogenesis, with fructose supplementation enhancing tumor growth even without overt weight gain or insulin resistance (Fowle-Grider et al. 2024). In parallel, many cancers undergo intrinsic metabolic reprogramming to exploit fructose. Under glucose-poor, fructose-rich conditions, cancer cells can use fructose as an alternative carbon source to sustain central carbon metabolism, de novo lipid and nucleic acid synthesis, and the Warburg effect, with aberrant fructose utilization activating oncogenic mechanistic target of rapamycin complex (mTORC) 1 signaling and suppressing anti-tumor immunity (Ting 2024; Zhao et al. 2025). Different tumors deploy these pathways in distinct ways, for example, pancreatic cancer channels fructose primarily into nucleotide synthesis via the non-oxidative pentose phosphate pathway, whereas hepatocellular carcinoma may rely on acetate derived from microbial fructose metabolism. Inhibition of fructose metabolism in such fructose-adapted cancer cells reduces malignancy (Ting 2024).

Fructose and 5P medicine

High intake of HFCS over long periods is a major, yet modifiable, risk factor for metabolic, neurological, and oncological conditions (Febbraio et al. 2021; Jung et al. 2022; DeChristopher 2024). Because diet is a central driver, fructose is an instructive example of how individuals can participate in shaping their health. Fructose from whole fruits, delivered with fiber and antioxidants, shows neutral or beneficial effects on metabolic biomarkers, whereas fructose from sugar-sweetened beverages and juices correlates with higher inflammatory markers, dyslipidemia, and intrahepatic fat (DeChristopher 2024; Jung et al. 2022). Experimental data indicate that HFCS-like, fructose-rich sweeteners induce reward-related and metabolic disturbances at lower exposure than sucrose, suggesting stronger reinforcing and pathological effects when fructose/glucose ratios are very high (DeChristopher 2024; Levy et al. 2015). Nonetheless, the most robust strategy for obesity, diabetes, and metabolic syndrome remains a general reduction of total carbohydrate intake, not merely swapping fructose for glucose (Feinman et al. 2013).

When symptoms are present precision medicine gains importance. In inflammatory bowel disease and fructose malabsorption, several strategies improve gastrointestinal symptoms and breath hydrogen in clinical studies. These include fructose-restricted and low-FODMAP diets, microbiota-directed therapies (probiotics, fecal microbiota transplantation), and oral xylose isomerase, which converts fructose to glucose (Simões et al. 2025). Regarding the gut-liver axis, KHK inhibitors, which are tested in clinical trials, lower de novo lipogenesis and improve metabolic markers (Jung et al. 2022). Epidemiological data also suggests that targeting brain KHK C or AMPD2, together with uric acid-lowering strategies, could enable to reduce the risk of dementia in the population (Johnson et al. 2020).

References

Bray, G.A. et al.: Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity (2004) The American Journal of Clinical Nutrition | https://doi.org/10.1093/ajcn/79.4.537.

Chambers, R.A. et al.: Idiosyncrasy to fructose (1956) Lancet (London, England) | https://doi.org/10.1016/S0140-6736(56)92196-1.

DeChristopher, L.R.: 40 years of adding more fructose to high fructose corn syrup than is safe, through the lens of malabsorption and altered gut health-gateways to chronic disease (2024) Nutrition Journal | https://doi.org/10.1186/s12937-024-00919-3.

Delannoy, P. et al.: Aldose reductase, fructose and fat production in the liver (2025) Biochemical Journal | https://doi.org/10.1042/BCJ20240748.

Febbraio, M.A. et al.: “Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis (2021) Cell Metabolism | https://doi.org/10.1016/j.cmet.2021.09.004.

Feinman, R.D. et al.: Fructose in perspective (2013) Nutrition & Metabolism | https://doi.org/10.1186/1743-7075-10-45.

Flores Monar, G.V. et al.: Mindful Eating: A Deep Insight Into Fructose Metabolism and Its Effects on Appetite Regulation and Brain Function (2025) Journal of Nutrition and Metabolism | https://doi.org/10.1155/jnme/5571686.

Fontvieille, A.M. et al.: Relative sweetness of fructose compared with sucrose in healthy and diabetic subjects (1989) Diabetes care | https://doi.org/10.2337/diacare.12.7.481.

Fowle-Grider, R. et al.: Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer (2024) Nature | https://doi.org/10.1038/s41586-024-08258-3.

Green, B.G. et al.: Temperature Affects Human Sweet Taste via At Least Two Mechanisms (2015) Chemical senses | https://doi.org/10.1093/chemse/bjv021.

Horton, D.: Carbohydrate Nomenclature | https://doi.org/10.1007/978-3-642-16712-6_67.

Johnson, R.J. et al.: Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease (2020) Frontiers in Aging Neuroscience | https://doi.org/10.3389/fnagi.2020.560865.

Jung, S. et al.: Dietary Fructose and Fructose-Induced Pathologies (2022) Annual Review of Nutrition | https://doi.org/10.1146/annurev-nutr-062220-025831.

Levy, A. et al.: Fructose:glucose ratios–a study of sugar self-administration and associated neural and physiological responses in the rat (2015) Nutrients | https://doi.org/10.3390/nu7053869.

Macdonald, I. et al.: Some effects, in man, of varying the load of glucose, sucrose, fructose, or sorbitol on various metabolites in blood (1978) The American Journal of Clinical Nutrition | https://doi.org/10.1093/ajcn/31.8.1305.

Paneque, A. et al.: The Hexosamine Biosynthesis Pathway: Regulation and Function (2023) Genes | https://doi.org/10.3390/genes14040933.

Payant, M.A. et al.: Neural mechanisms underlying the role of fructose in overfeeding (2021) Neuroscience and biobehavioral reviews | https://doi.org/10.1016/j.neubiorev.2021.06.034.

Rödel, W.: J. S. Fruton: Molecules and Life – Historical Essays on the Interplay of Chemistry and Biology. 579 Seiten. Wiley‐Interscience, New York, London, Sydney, Toronto 1972. Preis: 8,95 £ (1974) Food / Nahrung | https://doi.org/10.1002/food.19740180423.

Shao, X. et al.: Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans (2016) The Journal of neuroscience: the official journal of the Society for Neuroscience | https://doi.org/10.1523/JNEUROSCI.1480-16.2016.

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• History & Evolution
• Biosynthesis & dietary uptake
• Homovanillic acid and the microbiome
• Homovanillic acid and neurology
• Homovanillic acid and oncology
• Homovanillic acid and 5P medicine
• References

History & Evolution

1950s: discovery | 1963: detected in brain and cerebrospinal fluid (Andén, N. et al., 1963) | 1985: metabolic pathway identified (Westerink, B., 1985)

Homovanillic acid (HVA) is a monocarboxylic acid best known for its role as a major dopamine metabolite. The name “homovanillic” refers to the compound’s relationship to vanillic acid, a similar phenolic acid, with the prefix homo- indicating the addition of a methylene group (–CH2–) between the aromatic ring and the carboxyl group.

Interest in HVA began in the 1950s and 60s, when early chromatography studies detected HVA in the urine of mammals and identified it as a marker of dopamine turnover in the brain (Armstrong, M. et al., 1956) (Williams, C. et al., 1960). In 1963, Andén et al. showed that HVA was present in the brain and cerebrospinal fluid (CSF), and introduced a fluorometric method for its detection (Andén, N. et al., 1963). Following the dopamine thread, researchers in the following decades focused on the associations between HVA, dopamine and neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, depression and, more recently, neuroblastoma. Current research is directed at improving HVA’s diagnostic and prognostic utility as a biomarker in these conditions and refining techniques for its detection in different bodily fluids.

Although primarily found in humans and other mammals, as a phenolic compound HVA is also detectable in some bacteria and plants (Marhuenda-Muñoz, M. et al., 2019). It has been identified in beer, suggesting it can be produced during the fermentation process by microorganisms (Montanari, L. et al., 1999).

Biosynthesis vs. dietary uptake

HVA forms in the body as the final breakdown product of dopamine, through a two-step enzymatic process (Buleandră, M. et al., 2025). First, monoamine oxidase (MAO) breaks down dopamine into 3,4-dihydroxyphenylacetic acid (DOPAC) in dopaminergic neurons in the brain. Then, catechol-O-methyltransferase (COMT) methylates DOPAC and converts it to HVA. An alternative pathway involves COMT acting on dopamine to form 3-methoxytyramine, which MAO then breaks down to form HVA. HVA can also be biosynthesized from homovanillin through the action of the enzyme aldehyde dehydrogenase.

HVA enters the circulation from both the brain and peripheral tissues such as the lungs, liver and skeletal muscle, and is mainly excreted via the kidneys (Lambert, G. et al., 1993).

Clinically, HVA can be measured in urine, plasma and CSF. Because of the distance between site of production and site of measurement, all three matrices can be vulnerable to confounding factors (Amin, F. et al., 1992). In healthy adults, CSF concentrations typically fall in the range of hundreds of nanomoles per liter (Blennow, K. et al., 1993). Reference ranges for urinary HVA are between 0.8 to 35.0 µmol/mmol of creatinine (Newcastle Hospital). Plasma HVA has a half-life of around one hour, and may be affected by diet for several hours (Köhnke, M. et al., 2003). Fasting plasma levels vary by sex and age, and differences between females and males hold regardless of menopause and hormone treatments in transgender patients (Giltay, E. et al., 2005).

HVA may also form through dietary and microbial pathways. Dietary flavonols commonly found in tomatoes, onions, and tea, can lead to significantly elevated levels of urinary HVA (Combet, E. et al., 2011). Likewise, the microbial digestion of hydroxytyrosol (found in olive oil) can also lead to elevated levels of HVA in humans (Tuck, K. et al., 2002).

Homovanillic acid and the microbiome

Research shows links between HVA and gut microbiota. Zhao et al. found that gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, were depleted in patients with depression (Zhao, M. et al, 2024). Using metabolomics, they showed that B. longum could directly produce HVA in the gut with the substrates of mouse fodder and tyrosine. R. intestinalis promoted the growth of B. longum, in turn increasing HVA levels in the gut. R. faecis and Eubacterium rectale were also strongly correlated with HVA levels.

Another recent metabolomics study by Gątarek et al. investigated the relationship between gut-derived metabolites, including HVA, and Parkinson’s disease (Gątarek, P. et al., 2025). Here, urinary metabolite profiles indicated elevated levels of HVA and succinic acid , and reduced levels of trimethylamine N-oxide in PD patients compared to controls. These findings highlight how altered gut microbiota may influence HVA levels and in turn affect host dopamine catabolism.

Homovanillic acid and neurology

As an indicator of dopaminergic activity, HVA has long been studied as a marker in neurological and psychiatric diseases in which dopamine plays a role. In PD, HVA shows different patterns depending on the biological matrix analyzed. While urinary HVA may increase in PD patients compared to controls, CSF HVA levels are significantly lower in patients with PD, particularly those with akinesia, indicating reduced dopaminergic activity (Davidson, D. et al., 1977). HVA concentration increases with levodopa therapy, though this is not always associated with clinical improvement (Jiménez-Jiménez, F. et al., 2014).

Altered HVA has also been described in mood and cognitive disorders. CSF HVA levels are reduced in dementia with Lewy bodies and Alzheimer’s disease, compared to healthy subjects (Morimoto, S. et al., 2017). In a mouse model, administering HVA was found to improve symptoms of depression by inhibiting synaptic autophagy (Zhao, M. et al, 2024).

Autism spectrum disorder (ASD) has been linked to elevated urinary HVA using metabolomics (Gevi, F. et al., 2020). Higher HVA concentrations have also been associated with greater symptom severity, including agitation, stereotyped behaviors and reduced spontaneous activity (Kaluzna-Czaplinska, J. et al., 2010). Supplementation with vitamin B6, which has been found to be lacking in children with ASD, appears to reduce both HVA concentrations and neurological symptoms (Gątarek, P. et al., 2025). HVA has also been studied in relation to attention-deficit/hyperactivity disorder (ADHD), though findings are inconclusive (Predescu, E. et al., 2024).

In schizophrenia, plasma and CSF HVA often track with symptom severity, but the relationship is complicated. A 2021 review notes that lower CSF HVA often correlates with more severe symptoms and a poorer prognosis (Gasnier, M. et al., 2021). Other work indicates a positive correlation between HVA concentrations and symptom severity (Mazure, C. et al., 1991). Antipsychotic treatment typically causes an initial increase in HVA, followed by a gradual decrease (Gasnier, M. et al., 2021).

Homovanillic acid and oncology

HVA is a marker of catecholamine-secreting tumors, such as neuroblastoma, pheochromocytoma and other neural crest tumors. These tumors secrete excess catecholamines like dopamine, which is then broken down into HVA. Therefore, HVA levels can be a useful indicator of the tumor’s activity. Elevated urinary HVA and vanillylmandelic acid (VMA) are detected in children with neuroblastoma, making them standard tools for diagnosis, monitoring, and prognosis (Sadilkova, K. et al., 2013). A low VMA to HVA ratio is associated with more aggressive disease (Zambrano, E. and Reyes-Múgica, M., 2002).

Infant screening programs based on HVA/VMA were introduced in Japan and elsewhere in the 1980s, but later abandoned after large trials showed no survival benefit and significant overdiagnosis (Tajiri, T. et al., 2009).

While HVA remains clinically relevant in the diagnosis of neuroblastoma, a scoring system using urinary 3-methoxytyramine sulfate (3-MTS) and vanillactic acid has recently been found to be more sensitive than one based on HVA and VMA (Amano, H. et al., 2024).

Homovanillic acid and 5P medicine

HVA’s relationship to host behavior, genetics and microbial activity makes it highly relevant to 5P medicine. As a marker of dopaminergic function and treatment efficacy, HVA may help to refine and personalize different treatment strategies for patients. Advances in metabolomics now allow rapid, high-sensitivity quantification of HVA and vanillylmandelic acid in urine, streamlining diagnostic processes for a whole range of conditions (Pandya, V. and Frank, E., 2022).

At the population level, genome-wide association studies (GWAS) have identified genetic and epidemiological patterns of HVA (Luykx, J. et al., 2014). Multiomics studies are providing further insights, for example, into the causal genetic relationship between HVA and conditions such as eating disorders and schizophrenia (Wen, J. et al., 2025).

Outside the clinic, HVA also plays a role in public health. HVA and related metabolites are used in wastewater-based epidemiology, where their excretion rates correlate with catchment size and provide population-wide biomarkers for exposure and health monitoring (Pandopulos, A. et al., 2021).

References

Amano, H. et al. (2024). Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations. Cancer Sci, 115(5), 1634–1645 | https://doi.org/10.1111/cas.16116.

Amin, F. et al. (1992). Homovanillic Acid Measurement in Clinical Research: A Review of Methodology. Schizophrenia Bulletin, 18(1), 123-48 | https://doi.org/10.1093/schbul/18.1.123.

Andén, N. et al. (1963). On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sciences, 2(7), 448-458 | https://doi.org/10.1016/0024-3205(63)90132-2.

Armstrong, M. et al. (1956). The Phenolic Acids of Human Urine: Paper Chromatography of Phenolic Acids. J Biol Chem, 218(1), 293-303 | https://doi.org/10.1016/S0021-9258(18)65893-4.

Blennow, K. et al. (1993). Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18-88 years of age. Eur Neuropsychopharmacol, 3(1), 55-61 | https://doi.org/10.1016/0924-977x(93)90295-w.

Buleandră, M. et al. (2025). Electrochemical Study and Determination of Homovanillic Acid, the Final Metabolite of Dopamine, Using an Unmodified Disposable Electrode. Molecules, 30(2), 369 | https://doi.org/10.3390/molecules30020369.

Combet, E. et al. (2011). Dietary flavonols contribute to false-positive elevation of homovanillic acid, a marker of catecholamine-secreting tumors. Clinica Chimica Acta, 412(1-2), 165-169 | https://doi.org/10.1016/j.cca.2010.09.037.

Davidson, D. et al. (1977). CSF studies on the relationship between dopamine and 5-hydroxytryptamine in Parkinsonism and other movement disorders. J Neurol Neurosurg Psychiatry, 40(12), 1136–1141 | https://doi.org/10.1136/jnnp.40.12.1136.

Gątarek, P. et al. (2025). The Determination of Trimethylamine N-Oxide and Organic Acids Connected with Gut Microbiota in the Urine of Parkinson’s Disease Patients: A Pilot Study. Int J Mol Sci, 26(10), 4575 | https://doi.org/10.3390/ijms26104575.

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Gevi, F. et al. (2020). A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1866(10), 165859 | https://doi.org/10.1016/j.bbadis.2020.165859.

Giltay, E. et al. (2005). The sex difference of plasma homovanillic acid is unaffected by cross-sex hormone administration in transsexual subjects. Journal of Endocrinology, 187(1) | https://doi.org/10.1677/joe.1.06307.

Jiménez-Jiménez, F. et al. (2014). Cerebrospinal fluid biochemical studies in patients with Parkinson’s disease: toward a potential search for biomarkers for this disease. Frontiers in Cellular Neuroscience, 8 | https://doi.org/10.3389/fncel.2014.00369.

Köhnke, M. et al. (2003). Plasma Homovanillic Acid: A Significant Association with Alcoholism is Independent of a Functional Polymorphism of the Human Catechol-O-Methyltransferase Gene. Neuropsychopharmacology, 28, 1004–1010 | https://doi.org/10.1038/sj.npp.1300107. Retrieved from Neuropsychopharmacology volume 28, pages1004–1010 (2003).

Kaluzna-Czaplinska, J. et al. (2010). Determination of homovanillic acid and vanillylmandelic acid in urine of autistic children by gas chromatography/mass spectrometry. Medical Science Monitor, 16(9), CR445-50.

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• History & Evolution
• Biosynthesis & dietary uptake
• p-cresol glucuronide and nephrology
• p-cresol glucuronide and cardiometabolic disease
• p-cresol glucuronide and neurology
• p-cresol glucuronide and cancer
• p-cresol glucuronide and 5P medicine
• References

History & Evolution

Early 1990s: first studies on p-cresol

p-cresol glucuronide is a modified form of the gut-microbial metabolite p-cresol, synthesized in the liver to promote excretion through the urine. p-cresol is derived from bacterial proteolytic fermentation of tyrosine (Diether et al. 2019). Early uremia research often (mis)attributed circulating toxicity to unconjugated p-cresol, but improved analytics overturned this view. The current paradigm is that gut-derived p-cresol is rapidly conjugated across the colonic mucosa and in the liver, yielding chiefly p-cresol sulfate (pCS) and a smaller pool of p-cresol glucuronide (pCG), with free p-cresol usually undetectable (Soulage et al. 2022). The notion of unconjugated p-cresol as a uremic toxin is a “historical artefact” (Soulage et al. 2022) arising from acid or heat deproteinization that hydrolyzed conjugates during sample preparation.

Because research centered on pCS, pCG received comparatively little attention. A practical reason is that authentic pCG only became readily available as a commercial reference standard in the late 2000s (Koppe et al. 2017), slowing targeted quantification and mechanistic work until vendors supplied it. Despite higher total concentrations of pCS, differing albumin affinities leave pCS and pCG with comparably sized free fractions in serum (Liabeuf et al. 2013). Over time, pCG has moved from an overlooked “detox conjugate” to a recognized and valuable measure linking microbiome and host health.

Biosynthesis vs. dietary uptake

There appears to be no significant dietary pCG intake. However, diet shapes pCG levels indirectly by modulating colonic proteolysis. More total protein and aromatic amino acids increase substrate load, while fiber (Salmean et al. 2015), resistant starch (Snelson et al. 2024), and certain prebiotics (Meijers et al. 2010) steer carbon toward short-chain fatty acids (SCFA) and away from tyrosine fermentation (Snelson et al. 2024).

In the gut, tyrosine is first converted to 4-hydroxyphenylacetic acid and then decarboxylated to p-cresol, after which p-cresol crosses the mucosa and enters the portal circulation. During first-pass metabolism in the colon and the liver, phase II enzymes rapidly conjugate p-cresol: sulfotransferases yield pCS (Rong et al. 2021; Stachulski et al. 2023) and UDP-glucuronosyltransferases (UGTs) yield pCG (Rong et al. 2020). In the bloodstream, renal organic anion transporters OAT1/3 take up pCG and pCS for tubular secretion, leading to excretion through the urine. When kidney function or transporter capacity is reduced, both conjugates accumulate systemically (Wu et al. 2017), supporting their classification as uremic toxins.

p-cresol glucuronide and nephrology

In nephrology, pCG is clinically relevant: as glomerular filtration and tubular secretory capacity fall, pCG accumulates in serum, reaching even higher levels in hemodialysis (Peters et al. 2023; Liabeuf et al. 2013). Accordingly, pCG is considered a microbiome-derived uremic toxin linking gut ecology with renal outcomes.

Chronic kidney disease (CKD) reduces gut microbial diversity and induces compositional shifts (Peters et al. 2023). In a prospective cohort, pCG associated with greater estimated glomerular filtration rate (eGFR) loss over six years, showing that higher pCG tracks kidney decline (Peters et al. 2023). Furthermore, total and free pCG in serum rise with CKD severity, and higher pCG predicts overall and cardiovascular mortality, with risk prediction similar to pCS (Liabeuf et al. 2013). Beyond reflecting burden, pCG can perturb proximal tubular phenotype, inducing epithelial–mesenchymal transition markers, transporter dysregulation, and cellular stress in human renal proximal tubular cells. Notably, pCS did not affect cellular stress in the same system (Mutsaers et al. 2015).

Together, these lines of evidence support ongoing evaluation of pCG as a diagnostic and prognostic biomarker across CKD stages (Choudhary et al. 2025).

p-cresol glucuronide and cardiometabolic disease

Compared with its sulfate counterpart and the parent phenol, pCG appears less cytotoxic across human kidney, liver, and blood cell models; a pattern consistent with glucuronidation serving primarily as detoxification (Zhu et al. 2021; Bertarini et al. 2025). Nevertheless, its cardiometabolic relevance remains unsettled, with context-dependent findings that do not point uniformly toward a role as toxin or detoxicant.

In a prospective analysis in CKD patients, the total p-cresol burden (pCS + pCG) in serum associated with mortality and cardiovascular disease (CVD). Importantly the conjugation pattern mattered: a lower pCS/pCG ratio, so a relative shift toward glucuronidation, was independently associated with higher risks of mortality and CVD (Poesen et al. 2016). At the same time, metabolic effects diverged between conjugates, since in mouse and cellular models, pCG did not induce insulin resistance, whereas pCS did (Koppe et al. 2017). In liver models, the parent compound p-cresol induced pronounced oxidative stress, glutathione depletion, and necrotic cell death. In contrast, pCG showed minimal cytotoxicity in hepatocytes and behaved as a detoxification product rather than a toxin, making it unlikely to mediate the hepatic toxic effects attributed to p-cresol (Zhu et al. 2021).

Diet–microbiome evidence links pCG to hypertension and diabetes biology. In diabetic mice, uremic toxins, including pCG, were elevated in plasma. Resistant starch supplementation lowered pCG, strengthened the intestinal barrier and dampened renal inflammation as indicated by fewer neutrophils and lower complement activation. Finally, resistant starch reduced albuminuria, supporting a renoprotective effect of pCG in diabetes (Snelson et al. 2024).

In humans, low fiber intake associated with higher circulating pCG and higher blood pressure. In a randomized trial, SCFA-enriched fiber reduced both plasma pCG and blood pressure, consistent with a microbiota-mediated shift toward reduced tyrosine fermentation (Xu et al. 2025).

p-cresol glucuronide and neurology

As a host–microbe co-metabolite, pCG sits on the gut–brain axis. Although glucuronides are often considered inert (Bertarini et al. 2025), converging evidence suggests that pCG can be biologically active at the cerebral endothelium. In mice, pCG strengthened blood–brain barrier (BBB) integrity and reshaped the whole-brain transcriptome (Stachulski et al. 2023; Bertarini et al. 2025).

In human brain microvascular endothelial cells, pCG alone had little effect but prevented LPS-induced barrier permeability when co-applied, acting as a functional antagonist at toll-like receptor 4 (TLR4) (Stachulski et al. 2023). These findings support a context-dependent, neuroprotective role against pro-inflammatory stimuli under physiological conditions (Bertarini et al. 2025).

Population data are bidirectional: higher urinary p-cresol, pCS, and pCG have been reported in autistic children (Bertarini et al. 2025; Gabriele et al. 2014), whereas in children with CKD, pCG did not associate with neurological outcomes (Ebrahimi et al. 2025). In Parkinson’s disease cohorts, serum pCG was elevated alongside p-cresol and pCS in patients (Paul et al. 2023) and plasma pCG positively correlated with motor symptom severity (Chen et al. 2023). Evidences from Alzheimer’s disease (AD) research showed higher pCG levels in patients together with adverse brain aging and cognitive decline (Gordon et al. 2024).

p-cresol glucuronide and cancer

Metabolomics has contributed to placing pCG on the oncology map, not as a causal driver, but rather as a non-invasive urinary biomarker. In renal cell carcinoma, an independent validation cohort confirmed higher urinary pCG at diagnosis and still elevated one year post-nephrectomy (Oto et al. 2025). In colorectal cancer, urinary profiles of pCG across disease and recovery windows after surgery showed upregulation in disease stage 3-4 and downregulation in stage 0-2, suggesting stage-linked pCG variation (Fu et al. 2024; Liesenfeld et al. 2015). Similarly, a prospective study of bladder cancer (BC) patients validated urinary pCG as a diagnostic biomarker, and notably within non-muscle-invasive BC (NMIBC), as a staging biomarker (Oto et al. 2022).

p-cresol glucuronide and 5P medicine

Biomarkers predict treatment response, monitor progression, stratify risk, and enable precision care, serving several aims of 5P medicine. In blood, pCG levels rise with declining renal function and pCG has been suggested as diagnostic and prognostic marker across CKD stages (Choudhary et al. 2025).

Owing to its excretion fate, pCG is also a relevant marker in urine, a compelling non-invasive matrix for predictive and diagnostic applications in oncology (Liesenfeld et al. 2015; Oto et al. 2022). Urine reflects renal excretion, including short-term changes induced by diet or drugs, more rapidly than blood.

As a biomarker, pCG is also actionable. Diet and microbiome interventions, especially fermentable fibers/resistant starch, can lower circulating pCG levels (Snelson et al. 2024; Xu et al. 2025), supporting the preventive, predictive and participatory pillars of 5P medicine. Especially in combination with other uremic toxins like indoxyl sulfate or p-cresol sulfate , pCG can sharpen risk predictions, clarify mechanisms, and improve precision healthcare.

References

Bertarini, L. et al.: Para-Cresol and the Brain: Emerging Role in Neurodevelopmental and Neurodegenerative Disorders and Therapeutic Perspectives (2025) ACS pharmacology & translational science | https://doi.org/10.1021/acsptsci.5c00289.

Chen, S.-J. et al.: Plasma metabolites of aromatic amino acids associate with clinical severity and gut microbiota of Parkinson’s disease (2023) npj Parkinson’s Disease | https://doi.org/10.1038/s41531-023-00612-y.

Choudhary, B.B. et al.: Novel molecular biomarkers in kidney diseases: bridging the gap between early detection and clinical implementation (2025) Journal of Pharmacy and Pharmacology | https://doi.org/10.1093/jpp/rgaf096.

Diether, N.E. et al.: Microbial Fermentation of Dietary Protein: An Important Factor in Diet⁻Microbe⁻Host Interaction (2019) Microorganisms | https://doi.org/10.3390/microorganisms7010019.

Ebrahimi, M. et al.: Investigation of a targeted panel of gut microbiome-derived toxins in children with chronic kidney disease (2025) Pediatric Nephrology | https://doi.org/10.1007/s00467-024-06580-6.

Fu, C. et al.: The Potential of Metabolomics in Colorectal Cancer Prognosis (2024) Metabolites | https://doi.org/10.3390/metabo14120708.

Gabriele, S. et al.: Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study (2014) Biomarkers | https://doi.org/10.3109/1354750X.2014.936911.

Gordon, S. et al.: Metabolites and MRI-Derived Markers of AD/ADRD Risk in a Puerto Rican Cohort (2024) Research square | https://doi.org/10.21203/rs.3.rs-3941791/v1.

Koppe, L. et al.: p-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance (2017) Nephrology Dialysis Transplantation | https://doi.org/10.1093/ndt/gfx089.

Liabeuf, S. et al.: Does p-cresylglucuronide have the same impact on mortality as other protein-bound uremic toxins? (2013) PLoS ONE | https://doi.org/10.1371/journal.pone.0067168.

Liesenfeld, D.B. et al.: Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare) (2015) Metabolomics | https://doi.org/10.1007/s11306-014-0758-3.

Meijers, B.K.I. et al.: p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin (2010) Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association – European Renal Association | https://doi.org/10.1093/ndt/gfp414.

Mutsaers, H.A.M. et al.: Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology (2015) Toxicology in vitro : an international journal published in association with BIBRA | https://doi.org/10.1016/j.tiv.2015.07.020.

Oto, J. et al.: LC-MS metabolomics of urine reveals distinct profiles for non-muscle-invasive and muscle-invasive bladder cancer (2022) World Journal of Urology | https://doi.org/10.1007/s00345-022-04136-7.

Oto, J. et al.: Validation of urine p-cresol glucuronide as renal cell carcinoma non-invasive biomarker (2025) Journal of Proteomics | https://doi.org/10.1016/j.jprot.2024.105357.

Paul, K.C. et al.: Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease (2023) Molecular Neurodegeneration | https://doi.org/10.1186/s13024-023-00694-5.

Peters, B.A. et al.: Association of the gut microbiome with kidney function and damage in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (2023) Gut Microbes | https://doi.org/10.1080/19490976.2023.2186685.

Poesen, R. et al.: Metabolism, Protein Binding, and Renal Clearance of Microbiota-Derived p-Cresol in Patients with CKD (2016) Clinical journal of the American Society of Nephrology : CJASN | https://doi.org/10.2215/CJN.00160116.

Rong, Y. et al.: Characterizations of Human UDP-Glucuronosyltransferase Enzymes in the Conjugation of p-Cresol (2020) Toxicological Sciences | https://doi.org/10.1093/toxsci/kfaa072.

Rong, Y. et al.: Characterization of human sulfotransferases catalyzing the formation of p-cresol sulfate and identification of mefenamic acid as a potent metabolism inhibitor and potential therapeutic agent for detoxification (2021) Toxicology and applied pharmacology | https://doi.org/10.1016/j.taap.2021.115553.

Salmean, Y.A. et al.: Fiber supplementation lowers plasma p-cresol in chronic kidney disease patients (2015) Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation | https://doi.org/10.1053/j.jrn.2014.09.002.

Snelson, M. et al.: Dietary resistant starch enhances immune health of the kidney in diabetes via promoting microbially-derived metabolites and dampening neutrophil recruitment (2024) Nutrition & Diabetes | https://doi.org/10.1038/s41387-024-00305-2.

Soulage, C.O. et al.: The very last dance of unconjugated p-cresol… historical artefact of uraemic research (2022) Nephrology Dialysis Transplantation | https://doi.org/10.1093/ndt/gfab325.

Stachulski, A.V. et al.: A host-gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo (2023) Tissue Barriers | https://doi.org/10.1080/21688370.2022.2073175.

Wu, W. et al.: Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes (2017) Scientific Reports | https://doi.org/10.1038/s41598-017-04949-2.

Xu, C. et al.: Lack of dietary fibre increases gut microbiome-derived uremic toxins that contribute to increased blood pressure (2025) medRxiv | https://doi.org/10.1101/2025.09.16.25335853.

Zhu, S. et al.: Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation (2021) Pharmaceutics | https://doi.org/10.3390/pharmaceutics13060857.

• History & Evolution
• Biosynthesis & dietary uptake
• cAMP and cell signaling
• cAMP and neurology
• cAMP and oncology
• cAMP and 5P medicine
• References

History & Evolution

1957 – 1958: discovery of role as second messenger | 1971: Nobel Prize

Earl Sutherland and colleagues identified cyclic adenosine monophosphate (cAMP) as a second messenger that relays hormone signals inside cells. This work earned Sutherland the Nobel Prize in Physiology or Medicine in 1971 (Kresge et al. 2005). Over the next decades, cAMP emerged as a universal signaling molecule, coordinating metabolism, gene expression, cardiac contractility, neurotransmission, and immune responses across tissues and species (Patra et al. 2023). Remarkably, cAMP levels can rise and fall within seconds, allowing cells to respond dynamically to external stimuli (Jiang et al. 2007). In humans, everyday substances like caffeine modulate cAMP signaling by subtly amplifying the molecule’s effects on alertness and metabolism (Barcelos et al. 2020). Its influence also extends beyond multicellular organisms: bacteria use cAMP to regulate their nutrient uptake (You et al. 2013), while in social amoebae such as Dictyostelium discoideum, cAMP acts as a “social molecule”, guiding collective movement and aggregation (Brimson et al. 2025).

Biosynthesis vs. dietary uptake

There is no indication that cAMP is absorbed from the diet. In contrast, cAMP is synthetized from ATP by adenylyl cyclase (AC), a plasma membrane-bound intracellular enzyme. The activity of AC is sensitive to numerous stimuli, including hormones and neurotransmitters, through the action of a G-protein-coupled receptor (GPCR), comprising several regulatory subunits; e.g. the stimulatory Gαs subunit, and the inhibitory Gαi subunit (Yadav et al. 2025). Activated AC converts adenosine triphosphate (ATP) into cAMP, which functions as a second messenger to drive downstream signaling. After the signal is transduced, cAMP signaling is terminated primarily by phosphodiesterases (PDE) that hydrolyze it to 5’-adenosine monophosphate (AMP), a form that lacks signaling activity (Patra et al. 2023). Although cAMP is primarily expected within cells, it is also quantifiable in blood, urine (Piec et al. 2017), saliva (Henkin et al. 2007) and cerebrospinal fluid (Oeckl et al. 2012).

cAMP and cell signalling

cAMP is a ubiquitous second messenger that translates extracellular cues into precise cellular actions. Its principal effector is protein kinase A (PKA): cAMP binding activates PKA, which phosphorylates serine/threonine residues on target proteins. A classic example is phosphorylation of the cAMP response element-binding protein (CREB), which regulates gene transcription (Patra et al. 2023). cAMP also engages exchange protein directly activated by cAMP (EPAC) (Rooij et al. 1998), influencing cell adhesion, cell-cell junctions, exocytosis/secretion, cell differentiation and proliferation, gene expression, apoptosis, and cardiac hypertrophy (Wang et al. 2017). Beyond enzymes, cAMP modulates ion flux by acting on cyclic nucleotide-gated (CNG) channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Patra et al. 2023).

Because cAMP is used by many pathways, cells must control their signals in both time and space to preserve specificity. Spatial control comes from compartmentalization into multiprotein “signalosomes.” A-kinase anchoring proteins (AKAPs) tether PKA with selected effectors, phosphodiesterases (PDEs), and phosphatases to build microdomains or even smaller nanodomains at defined cellular sites. Within these domains, PKA phosphorylation activates nearby PDEs, which locally degrade cAMP and close a negative-feedback loop that terminates the signal (Yadav et al. 2025). Compartmentalization can be further reinforced by liquid-liquid phase separation (LLPS), the spontaneous condensation of biomolecules into reversible, membrane-less droplets. LLPS is governed by features such as intrinsically disordered regions and multivalency, by post-translational modifications, ligand/metabolite binding, local concentration, and the physicochemical environment (Folkmanaite et al. 2025). The quick assembly and disassembly of condensates at specific sites enables highly dynamic organization of signaling molecules. The spatial reach of a cAMP signal is ultimately set by phosphatase localization and activity, which define the functional boundary for PKA phosphorylation. Temporally, phosphatases reverse PKA phosphorylation to reset targets and limit the duration of cAMP effects (Conca et al. 2025).

cAMP and and oncology

The role of cAMP in cancer is intricate and often paradoxical. Its effects depend on genetic background, tumor type and stage, and microenvironmental influences. In many settings, increased cAMP-PKA/EPAC signaling promotes tumor growth, invasion, and therapy resistance (Zhang et al. 2024). Genetic alterations such as activating guanine nucleotide-binding protein alpha stimulating (GNAS) mutations or PKA fusion proteins (DNAJB1–PRKACA) drive persistent activation of this axis in gastrointestinal (Behmanesh et al. 2025) and liver cancers (Ahmed et al. 2022). PKA can regulate cytoskeletal dynamics (Howe 2004) and stress responses (Zhang et al. 2020). EPAC1 enhances adhesion, migration, glycolytic reprogramming, and metastasis in multiple cancer types. At the same time, EPAC activation has been shown to suppress migration in certain models (Zhang et al. 2024).

Downstream effector CREB integrates the signals at the transcriptional level and functions mainly as a tumor promoter (Ahmed et al. 2022). Its overexpression and hyperactivation are common in both solid and hematological malignancies, where it supports proliferation, angiogenesis, survival, and therapy resistance. High CREB activity is linked to poor prognosis and metastasis, and inhibition of CREB has been shown to reduce tumor growth and restore treatment sensitivity (Zhang et al. 2020).

The tumor microenvironment (TME) plays a decisive role in shaping cAMP responses. Low pH, a hallmark of the TME, stimulates proton-sensitive GPCRs that drive cAMP accumulation. Cancer-associated fibroblasts and immune cells can further modulate cAMP signaling through cytokine and growth factor release, while neuronal inputs via sympathetic and parasympathetic fibers add another regulatory layer. Together, these interactions promote angiogenesis, invasion, and immune evasion, including suppression of NK cell activity (Zhang et al. 2024).

cAMP and neurology

In the nervous system cAMP shapes how neurons grow, connect, and adapt. Boosting cAMP promotes neuronal survival and axon regrowth after spinal cord injury and shapes the activity of glial cells that support repair in the central nervous system (CNS) (Boczek et al. 2019; Zhou et al. 2022).

cAMP is also essential for synaptic plasticity and circuit excitability. Globally, it enhances presynaptic neurotransmitter release, while locally it adjusts inhibitory synapses, striking a balance that allows efficient encoding of learning and memory (Lee 2015). In astrocytes, cAMP triggers glycogen breakdown and the astrocyte-neuron lactate shuttle, fueling neurons during high demand. This lactate not only supports excitability and long-term potentiation but also feeds back to regulate noradrenaline release, linking metabolism and neuromodulation. Antidepressants and monoamines further elevate astrocytic cAMP, leading to CREB-driven production of neurotrophic factors which support plasticity, neuroprotection, and mood regulation. Importantly, the timing and duration of cAMP signals matter: acute bursts and chronic elevations can produce opposite effects on astrocytic functions (Zhou et al. 2019).

Disruptions in cAMP signaling are recognized as a common thread across neurodevelopmental and neurodegenerative disorders. Variants in PKA or PDE4D disrupt synaptic signaling and have been linked to autism, Fragile X syndrome, and Alzheimer’s disease (Bhattacharya et al. 2025). Even sleep loss lowers hippocampal cAMP and weakens memory. Promisingly, new PDE4D inhibitors are being developed to restore cAMP balance and improve cognition (Bhattacharya et al. 2025).

Beyond the nervous system itself, cAMP-PKA signaling is now emerging as a key mediator of gut-brain communication. Microbial metabolites can tune host cAMP activity, activating vagal pathways and modulating immune and endocrine responses. In turn, altered cAMP signaling feeds back on microbiota composition, creating a reciprocal network that influences neurodevelopment, neurotransmitter control, and behavioral traits. This bidirectional regulation has direct relevance for amyloid-β aggregation, mitochondrial function, and microglial activation (Deng et al. 2025).

cAMP in immunity and inflammation

In the immune system, cAMP regulates both innate and adaptive cell activities and serves as a central checkpoint in inflammation. Elevating cAMP signaling typically produces anti-inflammatory effects, while reduced cAMP activity favors immune activation. In phagocytes such as monocytes, macrophages, and neutrophils, cAMP dampens the release of pro-inflammatory cytokines and chemokines, restrains phagocytosis, and limits intracellular killing, thereby shaping the intensity of the inflammatory response (Raker et al. 2016).

cAMP is also a key mediator of resolution. It coordinates crosstalk with specialized pro-resolving mediators, regulates granulocyte recruitment, and fine-tunes apoptosis and clearance of dying cells. Importantly, cAMP drives macrophage polarization toward anti-inflammatory phenotypes, a hallmark of inflammation resolution (Tavares et al. 2020). When dysregulated, these processes contribute to chronic disease states; for instance, altered cAMP signaling influences both the onset and progression of ulcerative colitis (Cheng et al. 2024).

cAMP and 5P medicine

Modulation of cAMP pathways offers a powerful entry point for biomarker-driven interventions, directly aligning with the principles of 5P medicine. In oncology, expression of phosphodiesterase 4D (PDE4D) and corresponding protein abundance have been identified as a predictive biomarker of chemotherapy response in hypopharyngeal cancer, underscoring the value of cAMP turnover in treatment stratification (Kawata-Shimamura et al. 2022). In neurodevelopmental disease, the selective PDE4D inhibitor BPN14770 (zatolmilast) has shown clinical benefit in Fragile X syndrome (Berry-Kravis, Gurney 2020). Chronic inflammatory diseases also illustrate this principle: in chronic obstructive pulmonary disease, inhibition of PDE4 superfamily members is integrated into precision strategies where biomarker data guide treatment decisions in defined patient subgroups (Bolger 2023). Together, these findings highlight how targeting cAMP signaling can move beyond experimental insight toward practical applications in precision and personalized therapeutics.

References

Ahmed, M. B. et al.: cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach (2022) Cells | https://doi.org/10.3390/cells11132020.

Barcelos, R. P. et al.: Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance (2020) Nutrition research (New York, N.Y.) | https://doi.org/10.1016/j.nutres.2020.05.005.

Berry-Kravis et al.: Positive Results Reported in Phase II Fragile X Clinical Trial of PDE4D Inhibitor Zatolmilast from Tetra Therapeutics (2020) | https://www.fraxa.org/positive-results-reported-in-phase-ii-fragile-x-clinical-trial-of-pde4d-inhibitor-from-tetra-therapeutics/

Behmanesh, M. A. et al.: Unraveling the link between GNAS R201 mutation and colorectal cancer (2025) Scientific Reports | https://doi.org/10.1038/s41598-025-17399-y.

Bhattacharya, A. et al.: The promise of cyclic AMP modulation to restore cognitive function in neurodevelopmental disorders (2025) Current Opinion in Neurobiology | https://doi.org/10.1016/j.conb.2024.102966.

Boczek, T. et al.: Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment (2019) Journal of Neuroscience | https://doi.org/10.1523/JNEUROSCI.2752-18.2019.

Bolger, G. B.: Therapeutic Targets and Precision Medicine in COPD: Inflammation, Ion Channels, Both, or Neither? (2023) International Journal of Molecular Sciences | https://doi.org/10.3390/ijms242417363.

Brimson, C. A. et al.: Collective oscillatory signaling in Dictyostelium discoideum acts as a developmental timer initiated by weak coupling of a noisy pulsatile signal (2025) Developmental cell | https://doi.org/10.1016/j.devcel.2024.11.016.

Cheng, H. et al.: Cyclic adenosine 3′, 5′-monophosphate (cAMP) signaling is a crucial therapeutic target for ulcerative colitis (2024) Life Sciences | https://doi.org/10.1016/j.lfs.2024.122901.

Conca, F. et al.: Phosphatases Control the Duration and Range of cAMP/PKA Microdomains (2025) Function (Oxford, England) | https://doi.org/10.1093/function/zqaf007.

Deng, F. et al.: Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases (2025) Neural Regeneration Research | https://doi.org/10.4103/NRR.NRR-D-24-00607.

Folkmanaite, M. et al.: Compartmentalisation in cAMP signalling: A phase separation perspective (2025) British Journal of Pharmacology | https://doi.org/10.1111/bph.70145.

Henkin, R. I. et al.: cAMP and cGMP in human parotid saliva: relationships to taste and smell dysfunction, gender, and age (2007) The American Journal of the Medical Sciences | https://doi.org/10.1097/MAJ.0b013e3180de4d97.

Howe, A. K.: Regulation of actin-based cell migration by cAMP/PKA (2004) Biochimica et biophysica acta | https://doi.org/10.1016/j.bbamcr.2004.03.005.

Jiang, L. I. et al.: Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway (2007) The Journal of biological chemistry | https://doi.org/10.1074/jbc.M609695200.

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Oeckl, P. et al.: Simultaneous LC-MS/MS analysis of the biomarkers cAMP and cGMP in plasma, CSF and brain tissue (2012) Journal of Neuroscience Methods | https://doi.org/10.1016/j.jneumeth.2011.09.032.

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Piec, I. et al.: A LC-MS/MS method for the diagnostic measurement of cAMP in plasma and urine (2017) | https://ueaeprints.uea.ac.uk/id/eprint/65479/.

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Zhou, G. et al.: Multifaceted Roles of cAMP Signaling in the Repair Process of Spinal Cord Injury and Related Combination Treatments (2022) Frontiers in Molecular Neuroscience | https://doi.org/10.3389/fnmol.2022.808510.

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• History & Evolution
• Biosynthesis & dietary uptake
• Bilirubin and the microbiome
• Bilirubin and neurology
• Bilirubin and oncology
• Bilirubin and 5P medicine
• References

History & Evolution

1847: discovery | 1930: first synthesis of heme | 1960s: detoxification pathway elucidated
As early as 400BCE, Hippocratic physicians described yellowing skin as a sign of liver disease – a symptom we now know to be caused by bilirubin (Berk et al. 1977). In 1847, Rudolf Virchow identified the compound responsible for jaundice, as a blood breakdown product, coining the name from bilis (Latin: bile) and rubin (Latin: red) (Lightner 2013).

In the 1930s, chemist Hans Fischer demonstrated that bilirubin originated from the porphyrin ring of hemoglobin (Hopper et al. 2021; Berk et al. 1977). Later developments in chromatographic and spectrophotometric techniques allowed researchers to separate and quantify conjugated and unconjugated bilirubin, greatly advancing clinical diagnostics (Blanckaert et al. 1976; Heirwegh et al. 1989). Understanding of heme catabolism and bilirubin production increased further in the 1960s, when specific enzymatic reactions were identified (Hopper et al. 2021).

More recently, bilirubin has emerged as more than a waste product. Research points to antioxidant and signaling properties with potential cytoprotective effects. For example, patients with Gilbert’s syndrome, a mild hereditary unconjugated hyperbilirubinemia, show lower cardiovascular and metabolic disease risk (Fevery 2008).

Biosynthesis vs. dietary uptake

Approximately 80% of bilirubin is derived from hemoglobin catabolism in bone marrow. The remaining 20% originates from the turnover of various heme-containing proteins, primarily in the liver and muscle tissues. This occurs predominantly within the mononuclear phagocyte system, especially in splenic macrophages, hepatic Kupffer cells and bone marrow monocytes (Fevery 2008; Kalakonda et al. 2022).

Heme oxygenase cleaves heme, releasing chelated iron, carbon monoxide and biliverdin (Kalakonda et al. 2022). Biliverdin reductase then rapidly reduces the biliverdin to form bilirubin, a hydrophobic, orange-yellow pigment (Kalakonda et al. 2022). Due to its poor solubility in water, unconjugated bilirubin binds tightly to serum albumin, which facilitates its transport in the bloodstream, prevents renal filtration and protects tissues from bilirubin’s potentially toxic accumulation. Under normal conditions, virtually no free bilirubin is detectable in plasma (Fevery 2008; Kalakonda et al. 2022).

In the liver, bilirubin dissociates from albumin and enters hepatocytes where it is conjugated with one or two molecules of glucuronic acid by UDP-glucuronosyltransferase 1A1 (UGT1A1). This rate-limiting reaction renders bilirubin water-soluble and marks a key detoxification step in heme metabolism (Kalakonda et al. 2022).

Only conjugated bilirubin can be actively secreted into bile, where it forms micelles with bile acids, cholesterol and phospholipids that are delivered to the small intestine (Fevery 2008). There, bacterial enzymes deconjugate and reduce bilirubin to urobilinogen and stercobilinogen. These compounds are oxidized to urobilin and stercobilin, which are excreted in feces and contribute to its characteristic brown color (Kalakonda et al. 2022). Around 10-20% of urobilinogen is reabsorbed into the portal circulation and may reenter the liver as part of the enterohepatic circulation. While the majority of reabsorbed urobilinogen is taken up again by hepatocytes and re-excreted into bile, a small proportion escapes hepatic reuptake and is ultimately excreted in urine (Gilles J. Hoilat et al. 2023). In the urinary tract, urobilinogen can spontaneously oxidize to urobilin, which gives urine its yellow color (Kalakonda et al. 2022).

Bilirubin and the microbiome

Transformation of conjugated bilirubin in the small intestine is largely dependent on the gut microbiota, particularly bacterial enzymes like β-glucuronidases (Leung et al. 2001). Recently, bilirubin reductase (BilR) was identified as the first microbial enzyme that could reduce bilirubin to urobilinogen-like compounds. BilR is expressed by several members of the Firmicutes phylum and supports microbial participation in host heme metabolism (Hall et al. 2024). However, the precise enzymatic steps responsible for converting urobilinogen to stercobilinogen remain undefined.

Microbiome immaturity or disruption can alter this process. In neonates, low BilR activity hinders bilirubin degradation, contributing to neonatal jaundice (Hall et al. 2024; You et al. 2023). In adults, inflammatory bowel disease (IBD) and other forms of dysbiosis may impair bilirubin metabolism, leading to elevated circulating levels and disrupted enterohepatic cycling (Hall et al. 2024).

Importantly, the relationship between bilirubin and the microbiome is bidirectional. By exerting oxidative stress on gram-positive bacteria, bilirubin suppresses microbial growth, while gram-negative taxa such as Bacteroidetes are often positively associated with serum bilirubin levels in human microbiome studies (Nobles et al. 2013; You et al. 2023).

Bilirubin and cardiometabolic disease

As a central product of heme catabolism, bilirubin serves not only as a biomarker of hepatic function but also as a biologically active molecule with far-reaching effects on metabolic health.

Under normal conditions, glucuronidation is the rate-limiting step in bilirubin metabolism. However, it is the canalicular secretion into bile that is most vulnerable to disruption. In conditions such as intrahepatic cholestasis or biliary obstruction, this excretory pathway is impaired, causing conjugated bilirubin to accumulate in the bloodstream (Fevery 2008). Clinically, elevated conjugated and delta bilirubin (bound to albumin) are key indicators of cholestatic liver injury (Kalakonda et al. 2022).

In contrast, unconjugated hyperbilirubinemia arises from overproduction or impaired conjugation of bilirubin, as seen in hemolytic anemia, ineffective erythropoiesis, or genetic disorders such as Crigler–Najjar and Gilbert’s syndrome (Ramírez-Mejía et al. 2024; Fevery 2008).

Mechanistic studies suggest that bilirubin acts as a metabolic buffer, through multiple pathways. It scavenges reactive oxygen species, protects vascular endothelium, and downregulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cytokine production. It also reduces lipogenesis, enhances fatty acid oxidation, inhibits gluconeogenesis and improves insulin sensitivity. These actions contribute to a lower risk of cardiovascular disease, obesity and type 2 diabetes, making bilirubin a molecule of increasing interest in preventive metabolic health (Ramírez-Mejía et al. 2024).

Bilirubin and neurology

While bilirubin plays protective roles in peripheral tissues, it poses a distinct risk within the central nervous system. Unconjugated bilirubin is lipophilic and capable of crossing the blood–brain barrier, where it can accumulate in neural tissue. This is especially critical in neonates, whose immature liver conjugation systems, biliary secretory apparatus and microbiota make them highly susceptible to bilirubin neurotoxicity (Fevery 2008).

At the cellular level, unconjugated bilirubin interferes with several neural processes. It impairs mitochondrial function, disrupts energy metabolism and alters neurotransmitter synthesis, release and uptake. It also inhibits glutamate uptake by astrocytes, leading to excitotoxicity – a mechanism associated with neurodegeneration (Ramírez-Mejía et al. 2024). Moreover, bilirubin can trigger neuroinflammation, activating microglia and inducing proinflammatory signaling cascades (Zhang et al. 2023).

Despite these risks, emerging evidence suggests that moderate systemic bilirubin levels may exert neuroprotective effects via antioxidant and anti-inflammatory pathways, potentially influencing cognitive aging and neurodegenerative disease risk (Kaur et al. 2025). However, these dual properties remain context- and concentration-dependent, underlining the need for precise regulation of bilirubin metabolism to protect brain health.

Bilirubin and oncology

Recent research is repositioning bilirubin as a regulatory metabolite in cancer biology. While bilirubin’s systemic antioxidant capacity is well-known, its local effects within the tumor microenvironment and its metabolic reprogramming in cancer cells are gaining attention.

Tumors may actively reshape bilirubin metabolism to modulate intracellular redox states. In some cancers, UGT1A1 is downregulated, allowing unconjugated bilirubin to accumulate and buffer against oxidative stress from rapid proliferation or immune surveillance (Yi et al. 2025). Other tumors upregulate heme oxygenase-1 (Ren et al. 2024), shifting heme metabolism toward biliverdin and carbon monoxide, which contribute to immune modulation and angiogenesis (Loboda et al. 2015).

Bilirubin also affects immune cell function in ways that might either suppress tumor-promoting inflammation or impair antitumor immunity (Yi et al. 2025; Ren et al. 2024). These immunomodulatory effects are being explored in the context of tumor immune evasion and response to immunotherapies (Yi et al. 2025; Lee et al. 2023; Ren et al. 2024).

At the cellular level, bilirubin alters checkpoint regulators, kinase signaling, mitochondrial membrane potential and intracellular calcium homeostasis. These changes drive apoptosis, autophagy and growth arrest in cancer cells, while also disrupting invasion and vascular remodeling. Through transcriptional regulators like NF-κB, p53 and extracellular signaling-regulated kinase (ERK), bilirubin shapes the balance between tumor-promoting and tumor-suppressive signaling networks (Yi et al. 2025).

Future research will need to clarify when bilirubin acts as a protective agent and when it might be co-opted as a tumor-supportive factor.

Bilirubin and 5P medicine

Like many metabolites, bilirubin is now seen not just as a simple waste product but also as a multifunctional regulatory molecule. As we learn more about its relevance to cellular and systemic mechanisms, bilirubin will surely make its mark in 5P medicine.

Bilirubin levels are already established biomarkers in clinical diagnostics, predicting liver dysfunction, hemolytic disorders and neonatal risk for kernicterus. Moderate bilirubin elevations have also been associated with reduced cardiovascular and metabolic risk (Ramírez-Mejía et al. 2024), extending its predictive value for chronic disease susceptibility.

The molecule’s antioxidant, anti-inflammatory and immunomodulatory properties suggest new avenues for preventive strategies in oxidative stress-driven diseases such as atherosclerosis, diabetes or neurodegeneration (Ramírez-Mejía et al. 2024).

In oncology, the dual role of bilirubin as both a potential tumor-protective and tumor-supportive factor underscores the need for personalized approaches (Ren et al. 2024; Yi et al. 2025). Patient-specific bilirubin metabolism profiles could inform treatment decisions, particularly in immunotherapy and redox-targeted therapies.

References

Berk, P.D. et al.: International Symposium on Chemistry and Physiology of Bile Pigments (1977).

Blanckaert, N. et al.: Synthesis and separation by thin-layer chromatography of bilirubin-IX isomers. Their identification as tetrapyrroles and dipyrrolic ethyl anthranilate azo derivatives (1976) The Biochemical journal | https://doi.org/10.1042/bj1550405

Fevery, J.: Bilirubin in clinical practice: a review (2008) Liver International | https://doi.org/10.1111/j.1478-3231.2008.01716.x

Gilles J. Hoilat et al.: Bilirubinuria (2023). | https://www.ncbi.nlm.nih.gov/books/NBK557439/

Hall, B. et al.: BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen (2024) Nature Microbiology | https://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2008.01716.x

Heirwegh, K.P. et al.: Chromatographic analysis and structure determination of biliverdins and bilirubins (1989) Journal of chromatography | https://doi.org/10.1016/s0378-4347(00)82549-9

Hopper, C.P. et al.: A brief history of carbon monoxide and its therapeutic origins (2021) Nitric oxide : biology and chemistry | https://doi.org/10.1016/j.niox.2021.04.001

Kalakonda, A. et al.: Physiology, Bilirubin (2022). | https://www.ncbi.nlm.nih.gov/books/NBK470290/

Kaur, A. et al.: Unraveling the dual role of bilirubin in neurological Diseases: A Comprehensive exploration of its neuroprotective and neurotoxic effects (2025) Brain Research | https://doi.org/10.1016/j.brainres.2025.149472

Lee, Y. et al.: Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy (2023) Nature Communications | https://doi.org/10.1038/s41467-023-40270-5

Leung, J.W. et al.: Expression of bacterial beta-glucuronidase in human bile: an in vitro study (2001) Gastrointestinal Endoscopy | https://doi.org/10.1067/mge.2001.117546

Lightner, D.A.: Bilirubin (2013) | ISBN: 9783709116371.

Loboda, A. et al.: HO-1/CO system in tumor growth, angiogenesis and metabolism – Targeting HO-1 as an anti-tumor therapy (2015) Vascular Pharmacology | https://doi.org/10.1016/j.vph.2015.09.004

Nobles, C.L. et al.: A product of heme catabolism modulates bacterial function and survival (2013) PLoS Pathogens | https://doi.org/10.1371/journal.ppat.1003507

Ramírez-Mejía, M.M. et al.: The Multifaceted Role of Bilirubin in Liver Disease: A Literature Review (2024) Journal of Clinical and Translational Hepatology | https://doi.org/10.14218/JCTH.2024.00156

Ren, K. et al.: Prognostic and immunotherapeutic implications of bilirubin metabolism-associated genes in lung adenocarcinoma (2024) Journal of Cellular and Molecular Medicine | https://doi.org/10.1111/jcmm.18346

Ryter, S.W. et al.: Carbon monoxide and bilirubin: potential therapies for pulmonary/vascular injury and disease (2007) American Journal of Respiratory Cell and Molecular Biology | https://doi.org/10.1165/rcmb.2006-0333TR

Yi, F. et al.: Bilirubin metabolism in relation to cancer (2025) Frontiers in Oncology | https://doi.org/10.3389/fonc.2025.1570288

You, J.J. et al.: The relationship between gut microbiota and neonatal pathologic jaundice: A pilot case-control study (2023) Frontiers in Microbiology | https://doi.org/10.3389/fmicb.2023.1122172

Zhang, F. et al.: Neuroinflammation in Bilirubin Neurotoxicity (2023) Journal of integrative neuroscience | https://doi.org/10.31083/j.jin2201009

• History & Evolution
• Biosynthesis & dietary uptake
• Itaconic acid and the microbiome
• Itaconic acid, immunity and inflammation
• Itaconic acid and cardiovascular disease
• Itaconic acid and neurology
• Itaconic acid and oncology
• Itaconic acid and 5P medicine
• References

History & Evolution

1836: discovery (Baup, 1836) | 1840: first synthesis (Crasso, G., 1840) | 1960s: first industrial applications | 2012: first synthesized in mammalian cells (Sugimoto, et al., 2011)

In 1836, Swiss chemist Samuel Baup discovered an unknown compound when experimenting with the distillation of citric acid (Baup, 1836). In 1840, Gustav Crasso synthesized the same compound through the decarboxylation of aconitate, and called it itaconate – an anagram of its precursor (Crasso, 1840). This unsaturated dicarboxylic acid received little attention for almost a hundred years, until 1931, when Japanese mycologist Kinoshita discovered a strain of Aspergillus fungi in salted prune juice that produced the metabolite (Kinoshita, 1932). He named the fungus Aspergillus itaconicus.

By the 1960s, itaconic acid had caught the attention of the polymer industry, thanks to the useful double bond of its methylene group. Now, around 40,000 tons are produced each year, primarily synthesized from Aspergillus terreus (Cordes, 2015).

Scientific interest in itaconate’s biological role was renewed in the early 2010s, when Sugimoto et al. discovered that it could be synthesized in mammalian immune cells (Sugimoto et al., 2011). Since then, itaconic acid’s role as a key player in immunometabolism and inflammatory regulation has become an active area of research (Diotallevi et al., 2021).

Biosynthesis vs. dietary uptake

In humans, itaconic acid is an endogenous metabolite synthesized primarily in the mitochondria of activated macrophages (Peace et al., 2022). It is synthesized by decarboxylating cis-aconitate, an intermediate of the tricarboxylic acid (TCA) cycle. Metabolomics has shown that this occurs through the action of the enzyme cis-aconitase decarboxylase, also known as immune-responsive gene 1 (IRG1 or ACOD1) (Michelucci et al., 2013). Expression of IRG1 is upregulated during infection and inflammation, leading to increased itaconate production. Plasma concentrations are therefore highly variable, depending on immune status.

Humans do not obtain itaconic acid directly from the diet, but dietary factors may affect its production. For example, carbohydrate intake affects the TCA cycle and energy metabolism, which in turn influences the availability of itaconate precursors like cis-aconitate. Under inflammatory conditions, nutrient availability may affect itaconate synthesis.

Itaconate is the biologically active, deprotonated form of itaconic acid, which contains two carboxylic acid groups that lose protons at pH levels above 7. This gives itaconate a double negative charge and makes it the dominant form found in the bloodstream. Structurally, it resembles other dicarboxylates such as succinate, malonate, phosphoenolpyruvate and fumarate (Peace et al., 2022).

Itaconic acid and the microbiome

While itaconic acid is synthesized by environmental microbes, like some Aspergillus species, it does not appear to be produced by gut microbiota in significant amounts. That said, it has been described as a “microbiota-associated metabolite” because its production in the mitochondria of host immune cells is triggered by microbial components such as lipopolysaccharide (LPS) from Gram-negative bacteria (Fedotcheva et al., 2022).

A study using integrated multiomics approaches showed that altered itaconate metabolism leads to significant changes in gut microbiota composition. Using a mouse model, Eberhart et al. (2024) found that in response to a high-fat diet, the itaconate-synthesizing enzyme ACOD1 promotes gut dysbiosis associated with obesity and inflammation, while genetic deletion of ACOD1 protects against metabolic disease (Eberhart et al., 2024). In addition, fecal metagenomics and microbiota transplantation showed that itaconate inhibits growth of Bacteroidaceae. These findings suggest that itaconate plays a role in diet-induced obesity and positions the ACOD1–itaconate pathway as a potential therapeutic target for the inflammatory effects of obesity.

Itaconic acid also inhibits bacterial isocitrate lyase, a key enzyme in the glyoxylate shunt during bacterial infection (Peace, 2022). This limits the growth of pathogens like Mycobacterium tuberculosis, Pseudomonas indigofera and Salmonella. However, some bacteria have developed strategies to protect themselves against itaconate’s antimicrobial properties (Peace, 2022). For example, Pseudomonas aeruginosa, Yersinia pestis and M. tuberculosis can break down itaconate into pyruvate and acetyl-CoA, while P. aeruginosa and Staphylococcus aureus respond to itaconate-induced stress by shifting from LPS to extracellular polysaccharide production, leading to biofilm formation that provides intracellular protection for the bacteria.

See how the MxP® Quant 1000 assay helps scientists investigate the impact of energy metabolism on health by accurately profiling TCA metabolites with targeted metabolomics

Itaconic acid, immunity and inflammation

Itaconic acid plays an important role in immune regulation and inflammation through the antibacterial mechanisms mentioned above. It also modulates the production of reactive oxygen species (ROS), which helps defend against bacterial and viral infections. Itaconate’s antiviral properties have been found to inhibit Zika virus replication (Daniels et al., 2019).

Beyond its antimicrobial activity, itaconic acid also acts as an anti-inflammatory metabolite by targeting key metabolic pathways in activated macrophages. It inhibits succinate dehydrogenase, a key enzyme in the TCA cycle, which alters mitochondrial metabolism and promotes anti-inflammatory cytokine production (Cordes et al., 2016). It also disrupts mitochondrial energy metabolism by disrupting oxidative phosphorylation and fatty acid oxidation. Recent studies have shown that itaconic acid can promote the pentose phosphate pathway, increasing nicotinamide adenine dinucleotide phosphate (NADPH) levels and enhancing NADPH oxidase-mediated ROS production. These ROS contribute to the expression of anti-inflammatory genes, restrict pathogens like Salmonella typhimurium and reduce pro-inflammatory cytokine production (Zhu et al., 2021).

These findings have led to broader recognition of the itaconate pathway in immune regulation. A review by Li et al. (2020) describes the IRG1/itaconate axis as a central feature in immunometabolic regulation, supported by metabolomics data that link itaconate to changes in mitochondrial respiration, oxidative stress and inflammatory signaling in macrophages (Li et al., 2020).

Given these properties, itaconic acid has emerged as a metabolite of interest in immune-mediated diseases. A recent review by Luo et al. (2024) suggests itaconate and its derivatives may play a role in conditions such as rheumatoid arthritis, multiple sclerosis , type 1 diabetes mellitus and autoimmune hepatitis (Luo et al., 2025).

Itaconic acid and cardiovascular disease

Research shows that itaconate may have a protective effect in cardiovascular disease. In models of atherosclerosis, IRG1 deficiency has been shown to increase plaque burden (Harber et al., 2024), while treatment with 4-octyl itaconate (4-OI) reversed plaque inflammation in mice and reduce cardiovascular inflammation in human immune cells (Cyr et al., 2024).

Itaconate also supports cardiac repair after myocardial infarction. A study using targeted metabolomics found that after efferocytosis (the clearing of dead cells which is essential for cardiac repair), altered signaling in macrophages expressing the TREM2 receptor disrupted the TCA cycle (Gong et al., 2024). This resulting increase in itaconate production reduced cardiomyocyte apoptosis and promoted fibroblast proliferation. Increased TREM2 levels led to improved cardiac function.

Itaconic acid and neurology

Neuroinflammation is a well-established driver in the progression of numerous neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS) and stroke. Itaconate and its derivatives may help counteract this neuroinflammatory activity in the central nervous system through the regulation of immune pathways including Nrf2/KEAP1, ROS production and the NLRP3 inflammasome (Kong et al., 2024).

In LPS-induced neuroinflammation, both itaconate and the related isomer mesaconate have been found to reduce inflammation in the brain and improve synaptic plasticity, linked to memory and cognitive processes (Ohm et al., 2024). A study using untargeted serum metabolomics in PD patients also identified reduced levels of circulating itaconate, suggesting a role in disease-associated immune dysregulation (Paul et al., 2023).

These findings suggest that itaconate may be a promising candidate as a biomarker and therapeutic target in neurological conditions.

Itaconic acid and oncology

Itaconic acid has also been implicated in cancer biology. In peritoneal tumors such as melanoma and ovarian carcinoma, metabolomics techniques have shown an upregulation of itaconic acid (Weiss et al., 2018). Tumor-associated macrophages were found to accumulate itaconate, resulting in increased oxidative phosphorylation and mitochondrial ROS production, and in turn promoting tumor growth. Silencing IRG1 was found to reduce the tumor burden.

However, there is also evidence that itaconic acid has anti-tumor effects (Perkovic et al., 2020) (Wang, Z. et al., 2024). A mouse model showed that dimethyl itaconate suppresses colitis-associated colorectal cancer (Wang et al., 2020). In another animal study, 4-OI was found to induce ferroptosis in the treatment of retinoblastoma (Liu et al., 2022).

Thes findings suggest that more research is needed to fully understand the role of itaconic acid in different types of cancer.

Itaconic acid and 5P medicine

In the context of 5P medicine – predictive, preventive, precision, population-based, participatory medicine – itaconic acid is again relevant due to its role in mediating immune responses and inflammation, both of which contribute to many prevalent chronic diseases. A white paper by biocrates, “Chronic diseases have a common origin”, highlights the underlying role of inflammation in complex chronic disease.

Obesity is a major public health concern and key target for preventive strategies. Dietary itaconate has been shown to reduce visceral fat accumulation in rats, highlighting a potential role in early intervention and metabolic regulation (Sakai et al., 2004).

As a biomarker of disease, itaconate levels in blood or immune cells may signal early inflammatory activity or therapeutic response, as seen in conditions like rheumatoid arthritis (Daly et al., 2020), non-alcoholic fatty liver disease (Weiss et al., 2018) and bacterial infections (Singh et al., 2021). In each of these examples, metabolomics has played a role in providing insights about the presence and behavior of this important metabolite.

Itaconic acid is a promising focus for future research, with omics technologies offering a powerful tool to support 5P medicine.

References

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Cordes, T. et al.: Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite. (2015) Annual Review of Nutrition | https://doi.org/10.1146/annurev-nutr-071714-034243.

Cordes, T. et al.: Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels. (2016) J Biol Chem.| https://doi.org/10.1074/jbc.M115.685792.

Crasso, G.: Untersuchungen über das Verhalten der Citronsäure in höherer Temperatur und die daraus hervorgehenden Produkte (1840) Ann. Chem. Pharm. | https://doi.org/10.1002/jlac.18400340104.

Cyr, Y. et al.: The IRG1–itaconate axis protects from cholesterol-induced inflammation and atherosclerosis. (2024) Natl Acad Sci USA | https://doi.org/10.1073/pnas.2400675121.

Daly, R. et al.: Changes in Plasma Itaconate Elevation in Early Rheumatoid Arthritis Patients Elucidates Disease Activity Associated Macrophage Activation. (2020) Metabolites | https://doi.org/10.3390/metabo10060241.

Daniels, B. et al.: The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to promote an antiviral metabolic state in neurons.(2019) Immunity | https://doi.org/10.1016/j.immuni.2018.11.017.

Diotallevi, M. et al.: Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine. (2021) Biochem Soc Trans, | https://doi.org/10.1042/BST20210269.

Eberhart, T. et al.: ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota. (2024) Cell Death Dis. | https://doi.org/10.1038/s41419-024-06483-2.

Fedotcheva, N. et al.: Influence of Microbial Metabolites and Itaconic Acid Involved in Bacterial Inflammation on the Activity of Mitochondrial Enzymes and the Protective Role of Alkalization.(2022) Int J Mol Sci. | https://doi.org/10.3390/ijms23169069.

Gong, S. et al.: TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53. (2024) Death Differ. | https://doi.org/10.1038/s41418-023-01252-8.

Harber, K. et al.: Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques. (2024) Biol. | https://doi.org/10.1016/j.redox.2024.103054.

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Kong, X. et al.: The anti-inflammatory effects of itaconate and its derivatives in neurological disorders. (2024) Cytokine & Growth Factor Reviews, | https://doi.org/10.1016/j.cytogfr.2024.07.001.

Li, R. et al.: Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress. (2020) Oxid Med Cell Longev.| https://doi.org/10.1155/2020/5404780.

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• History & Evolution
• Biosynthesis & dietary uptake
• Methylmalonic acid and the microbiome
• Methylmalonic acid and vitamin B12 deficiency
• Methylmalonic acid and neurology
• Methylmalonic acid and 5P medicine
• References

History & Evolution

1963: First clinical description in pernicious anemia | 1967: Discovery of methylmalonic aciduria | 1968: Vitamin B12 responders in methylmalonyl-CoA deficiency | 1993: Methylmalonic acid (MMA) as biomarker for vitamin B12 deficiency

Methylmalonic acid (MMA) was first linked to human disease in 1963, when researchers observed elevated urinary levels in patients with pernicious anemia (Barness et al. 1963), a rare and fatal disease marked by progressive anemia and neurological decline (American Chemical Society 2025). In 1967, MMA was identified as the hallmark of a newly described inborn error of metabolism, methylmalonic aciduria (Oberholzer et al. 1967). The underlying cause—methylmalonyl-CoA mutase deficiency—was discovered soon after in 1968 (Rosenberg et al. 1968a). However, not all cases were due to a defect in the enzyme itself. Some patients showed a biochemical response to vitamin B12 supplementation, leading to the identification of B12-responsive subtypes (Rosenberg et al. 1968b).

Accordingly, in 1993, MMA was established as a sensitive biomarker for detecting early or subclinical vitamin B12 deficiency, often before B12 levels dropped (Allen et al. 1993). Recognizing its diagnostic value, MMA measurement was added to the U.S. newborn screening panel in 2006 to detect methylmalonic acidemia. More recently, large population studies linked elevated MMA to cognitive decline (Clarke et al. 2007), depressive symptoms and increased mortality (Cao et al. 2024), underscoring its broader relevance in aging and public health (Tejero et al. 2024).

Biosynthesis vs. dietary uptake

MMA is a short-chain dicarboxylic acid and an intermediate in the catabolism of certain amino acids, fatty acids and cholesterol. It is not obtained from the diet but is synthesized endogenously as part of normal human metabolism. The primary biosynthetic route to MMA occurs in the mitochondria through the conversion of propionyl-coenzyme A (CoA).

In this pathway, propionyl-CoA is first carboxylated to D-methylmalonyl-CoA by propionyl-CoA carboxylase, a biotin-dependent enzyme. D-methylmalonyl-CoA is then converted to its L-isomer by methylmalonyl-CoA epimerase (Tejero et al. 2024). Subsequently, the L-isomer is converted to succinyl-CoA by methylmalonyl-CoA mutase (MUT), a mitochondrial enzyme that requires the active coenzyme form of vitamin B12, adenosylcobalamin (Takahashi-Iñiguez et al. 2012). Finally, the resulting succinyl-CoA enters the tricarboxylic acid cycle (Tejero et al. 2024).

When MUT activity is impaired due to genetic mutations or functional vitamin B12 deficiency, methylmalonyl-CoA cannot be efficiently converted into succinyl-CoA. As a result, it accumulates and is hydrolyzed to free MMA, which then appears in plasma (Allen et al. 1993).

Under normal physiological conditions, plasma MMA concentrations are low (typically <0.3 µmol/L in adults), reflecting efficient MUT activity and adequate cobalamin status. Elevated MMA is one of the earliest and most specific indicators of intracellular B12 deficiency, and unlike homocysteine, its levels are not influenced by folate or vitamin B6 status (O’Leary et al. 2010).

Once produced, MMA is not reused; instead, it is filtered by the kidneys and eliminated in urine. Renal function therefore plays a critical role in regulating plasma MMA levels, and mild elevations can also be observed in renal impairment (Supakul et al. 2020).

Methylmalonic acid and the microbiome

Emerging evidence suggests that circulating levels of MMA can be shaped by the gut microbiome, complicating their use as a straightforward biomarker of B12 deficiency in clinical settings.

Recent studies have shown that certain gut microbial communities are significantly associated with serum MMA concentrations, independently of host B12 status. For example, in healthy adults, oral antibiotic treatment led to a reduction in serum MMA, implying that gut bacteria contribute to its circulating pool (Miller et al. 2025).

Microbial co-abundance guilds (groups of taxa with correlated abundance patterns) have been found to associate with either serum MMA or B12, but not both. This suggests that different microbial profiles influence MMA through mechanisms beyond B12 availability, such as enhanced propionate production or altered short-chain fatty acid (SCFA) metabolism (Miller et al. 2025). Among SCFAs, propionate uniquely accounted for a significant portion of the variance in MMA levels, further highlighting the specificity of this microbial-metabolite link.

The clinical relevance of this microbiota–MMA axis has become particularly evident in metabolic disease. In gestational diabetes mellitus (GDM), integrated multiomics approaches have revealed close correlations between the fecal microbiota and plasma metabolome. Specifically, plasma levels of MMA were strongly associated with alterations in gut microbiota composition (Dong et al. 2020).

Moreover, case reports in patients with small intestinal bacterial overgrowth further support a microbial contribution to elevated MMA: in such individuals, broad-spectrum antibiotics normalized MMA levels, suggesting that gut bacteria capable of producing propionate—and potentially MMA itself—can significantly elevate systemic concentrations (Tejero et al. 2024).

Together, these findings challenge the long-held assumption that elevated MMA is a direct marker of B12 deficiency. Instead, gut microbial activity, particularly through propionate-producing pathways, may represent an additional, independent source of MMA in the circulation of the host.

Methylmalonic acid and vitamin B12 deficiency

Despite growing interest in its microbial origins, MMA’s primary clinical role remains as the most specific functional marker of vitamin B12 (cobalamin) status. When B12 is insufficient at the cellular level, related metabolic processes begin to fail, such as the conversion of methylmalonyl-CoA to succinyl-CoA. As a result, MMA levels in the blood often increase before B12 falls below the classical deficiency cut-off of 200 pg/mL, making it a useful marker of “functional” deficiency in patients whose total B12 level remains within the low-normal range (201–350 pg/mL) (Ankar et al. 2025; Office of Dietary Supplements 2024).

In a 2015 article, Fedosov et al. recommend the inclusion of MMA as part of a comprehensive diagnostic panel alongside total serum B12, holotranscobalamin (active B12) and homocysteine to monitor B12 status (Fedosov et al. 2015).

Functionally, MMA is more than a diagnostic tool: it is implicated in the pathology of B12 deficiency. Elevated MMA disrupts normal lipid metabolism and mitochondrial energy production, contributing to myelin sheath instability and neurotoxicity (Ankar et al. 2025). These mechanisms are thought to underlie many of the neurological symptoms associated with B12 deficiency, including peripheral neuropathy, ataxia, cognitive dysfunction and dementia-like presentations (Langan et al. 2017; Brito et al. 2017; Ankar et al. 2025)

Methylmalonic acid and neurology

MMA accumulation following decreased conversion of methylmalonyl-CoA to succinyl-CoA also impairs TCA cycle flux. This contributes to mitochondrial dysfunction and promotes oxidative stress through inhibition of respiratory chain complexes and lipid peroxidation. These effects are particularly damaging to the central nervous system, which relies heavily on mitochondrial ATP production and intact myelin structure for normal function (Denley et al. 2025).

High MMA levels associate with a range of neurological conditions, including depression and cognitive impairment, as well as increased risk of neurodegenerative disease. In a large cross-sectional analysis of the U.S. National Health and Nutrition Examination Survey (NHANES) data, higher circulating MMA was independently associated with increased depressive symptoms and a ~25% increase in all-cause mortality, even after adjusting for serum B12 and folate levels (Cao et al. 2024). Additional analyses have confirmed that elevated MMA is more prevalent among individuals with dementia and Alzheimer’s disease than in cognitively healthy controls (Refsum et al. 2003; O’Leary et al. 2012). Clinical observations also suggest a high co-occurrence of elevated MMA and subclinical B12 deficiency in patients presenting with neuropsychiatric complaints, including memory loss, fatigue and mood disorders (Nalder et al. 2021; Moore et al. 2012)

Longitudinal data support these findings. In the Oxford Age and Nutrition Project, doubling of baseline MMA concentrations (from 0.25 to 0.50 µM) was associated with a 50% faster rate of cognitive decline (Clarke et al. 2007). Similarly, the Chicago Memory and Aging Project found that higher MMA levels predicted steeper six-year decline in memory and executive function (Tangney et al. 2009). In children, elevated MMA was also linked to reduced cognitive performance in later years (Kvestad et al. 2017).

In a clinical trial involving elderly Chilean participants with vitamin B12 deficiency and elevated levels of MMA, B12 repletion led to increased serum concentrations of acylcarnitines, plasmalogens, phospholipids, and decreased methionine and cysteine. This metabolite shifts are indicative of enhanced mitochondrial function and one-carbon metabolism and coincided with improved peripheral nerve conduction, suggesting a direct link between B12 status, metabolic repair and neural function (Brito et al. 2017).

Methylmalonic acid and aging

MMA accumulates progressively with age, even in individuals without overt B12 deficiency or renal dysfunction (O’Leary et al., 2012; Clarke et al., 2007). This age-related rise in MMA has been linked to cognitive decline, physical frailty and increased mortality (Cao et al., 2024; Tangney et al., 2009).

Mechanistically, elevated MMA interferes with mitochondrial function, impairs cellular energy metabolism, promotes oxidative stress and triggers pro-inflammatory signaling (Tejero et al. 2024). These effects mirror several hallmarks of aging, including mitochondrial dysfunction, chronic inflammation and disrupted intercellular communication (López-Otín et al. 2023).

Further findings also connect MMA to cancer progression. In elderly individuals, elevated circulating MMA creates a systemic environment that promotes tumor aggressiveness by inducing transcriptional programs such as SRY-Box Transcription Factor 4 (SOX4) and driving processes like epithelial-to-mesenchymal transition (Gomes et al. 2020). This positions MMA as a molecular bridge between aging and cancer biology, suggesting that targeting MMA accumulation may offer a novel strategy to counteract both age-related decline and tumor progression.

Methylmalonic acid and 5P medicine

MMA is a valuable tool in predictive and preventive medicine. As one of the earliest markers of functional vitamin B12 deficiency, rising MMA levels can signal risk for neurological decline, frailty and even cancer progression, often before symptoms appear. When combined with genetic or metabolic information, MMA helps deliver precision medicine, distinguishing between inherited disorders, functional B12 deficiency or microbiome-related causes. This allows for early, targeted interventions such as B12 supplementation or microbiome-based strategies to prevent further damage. Finally, MMA empowers both clinicians and patients to take informed action, shifting care from reaction to prevention.

References

Allen, R.H. et al.: Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency (1993) FASEB journal : official publication of the Federation of American Societies for Experimental Biology | DOI: 10.1096/fasebj.7.14.7901104.

Ankar, A. et al.: Vitamin B12 Deficiency (2025) | https://www.ncbi.nlm.nih.gov/books/NBK441923/.

Barness, L.A. et al.: Methylmalonate excretion in a patient with pernicious anemia (1963) The New England journal of medicine | DOI: 10.1056/NEJM196301172680309.

Brito, A. et al.: The Human Serum Metabolome of Vitamin B-12 Deficiency and Repletion, and Associations with Neurological Function in Elderly Adults (2017) The Journal of nutrition | DOI: 10.3945/jn.117.248278.

Cao, B. et al.: Associations of methylmalonic acid and depressive symptoms with mortality: a population-based study (2024) Translational Psychiatry | DOI: 10.1038/s41398-024-03015-6.

Clarke, R. et al.: Low vitamin B-12 status and risk of cognitive decline in older adults (2007) The American Journal of Clinical Nutrition | DOI: 10.1093/ajcn/86.5.1384.

Denley, M.C.S. et al.: Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria (2025) Communications Biology | DOI: 10.1038/s42003-025-07828-z.

Dong, L. et al.: Integrated microbiome-metabolome analysis reveals novel associations between fecal microbiota and hyperglycemia-related changes of plasma metabolome in gestational diabetes mellitus (2020) RSC advances | DOI: 10.1039/C9RA07799E.

Fedosov, S.N. et al.: Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points (2015) Clinical chemistry and laboratory medicine | DOI: 10.1515/cclm-2014-0818.

Gomes, A.P. et al.: Age-induced accumulation of methylmalonic acid promotes tumour progression (2020) Nature | DOI: 10.1038/s41586-020-2630-0.

Kvestad, I. et al.: Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children (2017) The American Journal of Clinical Nutrition | DOI: 10.3945/ajcn.116.144931.

Langan, R.C. et al.: Vitamin B12 Deficiency: Recognition and Management (2017) American family physician | PMID: 28925645.

López-Otín, C. et al.: Hallmarks of aging: An expanding universe (2023) Cell | DOI: 10.1016/j.cell.2022.11.001.

Miller, J.W. et al.: Serum Methylmalonic Acid Is Associated With Gut Microbial Co-Abundance Guilds and Circulating Propionate in Healthy Adults (2025) Current Developments in Nutrition | DOI: 10.1016/j.cdnut.2025.107421.

Moore, E. et al.: Cognitive impairment and vitamin B12: a review (2012) International psychogeriatrics | DOI: 10.1017/S1041610211002511.

Nalder, L. et al.: Vitamin B12 and Folate Status in Cognitively Healthy Older Adults and Associations with Cognitive Performance (2021) The journal of nutrition, health & aging | DOI: 10.1007/s12603-020-1489-y.

Oberholzer, V.G. et al.: Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis (1967) Archives of disease in childhood | DOI: 10.1136/adc.42.225.492.

Office of Dietary Supplements: Office of Dietary Supplements – Vitamin B12 (2024) | https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/.

O’Leary, F. et al.: Vitamin B12 in health and disease (2010) Nutrients | DOI: 10.3390/nu2030299.

O’Leary, F. et al.: Vitamin B₁₂ status, cognitive decline and dementia: a systematic review of prospective cohort studies (2012) British Journal of Nutrition | DOI: 10.1017/S0007114512004175.

Refsum, H. et al.: Low vitamin B-12 status in confirmed Alzheimer’s disease as revealed by serum holotranscobalamin (2003) Journal of neurology, neurosurgery, and psychiatry | DOI: 10.1136/jnnp.74.7.959.

Rosenberg, L.E. et al.: Methylmalonic aciduria. An inborn error leading to metabolic acidosis, long-chain ketonuria and intermittent hyperglycinemia (1968a) The New England journal of medicine | DOI: 10.1056/NEJM196806132782404.

Rosenberg, L.E. et al.: Methylmalonic aciduria: metabolic block localization and vitamin B 12 dependency (1968b) Science (New York, N.Y.) | DOI: 10.1126/science.162.3855.805.

Supakul, S. et al.: Diagnostic Performances of Urinary Methylmalonic Acid/Creatinine Ratio in Vitamin B12 Deficiency (2020) Journal of Clinical Medicine | DOI: 10.3390/jcm9082335.

Takahashi-Iñiguez, T. et al.: Role of vitamin B12 on methylmalonyl-CoA mutase activity (2012) Journal of Zhejiang University. Science. B | DOI: 10.1631/jzus.B1100329.

Tangney, C.C. et al.: Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline (2009) Neurology | DOI: 10.1212/01.wnl.0000341272.48617.b0.

Tejero, J. et al.: Methylmalonic acid in aging and disease (2024) Trends in endocrinology and metabolism: TEM | DOI: 10.1016/j.tem.2023.11.001.

• History & Evolution
• Biosynthesis & dietary uptake
• UDCA and the microbiome
• UDCA and signaling
• UDCA as therapeutic drug
• UDCA and 5P medicine
• References

History & Evolution

1902: discovery in bear bile (Hammarsten) | 1927: isolation and naming (Shoda) | 1980s: approval for liver diseases

Ursodeoxycholic acid (UDCA) is a secondary bile acid with a long history in traditional medicine and modern hepatology. First identified in bear bile by Hammarsten in 1902 and isolated by Shoda in 1927, UDCA takes its name from Ursus, Latin for bear (Lazaridis et al. 2001). It became clinically relevant in the 1980s, when synthetic UDCA was approved for treating cholestatic liver diseases such as primary biliary cholangitis (PBC) (Ishizaki et al. 2005). Today, UDCA is recognized as a key therapeutic bile acid with a range of anti-apoptotic, cytoprotective and immunomodulatory functions (Lazaridis et al. 2001; Amaral et al. 2009).

Biosynthesis vs. dietary uptake

Bile acids are formed from cholesterol in the liver and secreted into the intestine. Gut microbiota metabolize these bile acids through deconjugation, dehydroxylation and epimerization (Keely et al. 2019). In this way, the secondary bile acid UDCA is produced in the colon through microbial transformation of the primary bile acid chenodeoxycholic acid (CDCA), first through deconjugation via bile salt hydrolases, then via epimerization at the 7-position (Daruich et al. 2019; Ridlon et al. 2015). Once formed, UDCA is passively absorbed in the colon and returns to the liver through the portal circulation. There, it is reconjugated with taurine or glycine into glyco- or tauro-ursodeoxycholic acid (GUDCA and TUDCA, respectively) as part of the enterohepatic circulation (Lazaridis et al. 2001). This recycling loop helps maintain bile acid pool stability and amplifies the systemic availability of UDCA. TUDCA and other conjugated forms of UDCA are increasingly recognized for their cytoprotective and anti-inflammatory properties (Daruich et al. 2019).

UDCA is not only a product of gut microbiota, but also a substrate for further transformation. The major metabolite of UDCA is lithocholic acid (LCA), which has been regarded as the most cytotoxic of the secondary bile acids, especially in the liver (Hofmann 2004). However, this view is increasingly being challenged. Emerging evidence suggests that the beneficial effects of UDCA on epithelial integrity and inflammation may, at least in part, depend on its microbial conversion to LCA (Lajczak-McGinley et al. 2020; Keely et al. 2019).

Additionally, UDCA can be reconverted into isoUDCA by microbial and hepatic enzymes. The ratio of isoUDCA to UDCA has been proposed as a potential biomarker of bile acid pool dynamics and therapeutic efficacy, particularly in cholestatic liver diseases (Beuers et al. 1991). This ratio reflects the delicate interplay between microbial metabolism and host bile acid handling; factors critical for maintaining bile acid homeostasis and preventing liver injury (Marschall et al. 2001).

UDCA and the microbiome

UDCA is both a product of microbial activity and a potent modulator of the gut microbiome itself. While its formation depends on bacterial enzymes, UDCA also feeds back into the intestinal environment, influencing microbial composition and function. This bidirectional relationship underlies many of UDCA’s therapeutic effects.

One of the key microbiome-level impacts of UDCA is its ability to shift microbial communities toward more balanced and less pro-inflammatory configurations (Wahlström et al. 2016). For instance, in experimental models of colitis, UDCA and its taurine-conjugated form TUDCA have been shown to normalize the Firmicutes-to-Bacteroidetes ratio, which can be indicative of microbial balance often disrupted in inflammatory and metabolic conditions. Such rebalancing may reflect reduced bile acid toxicity, improved mucosal barrier function, and downstream effects on immune regulation (Keely et al. 2019).

These microbiome changes are not only compositional but also functional. UDCA treatment is associated with a reduction in microbial pathways linked to harmful metabolites like enterobactin and lactate, while supporting bile acid transformations that favor anti-inflammatory and cytoprotective signaling (Lee et al. 2024).

Altogether, UDCA’s ability to modulate the microbiome reflects a broader mechanism of action that goes beyond its direct effects on bile flow or hepatocyte protection. Its role in shaping a gut ecosystem that supports intestinal and systemic homeostasis – an aspect of its therapeutic profile that is gaining increasing attention.

UDCA and signaling

In addition to its choleretic (promoting bile synthesis and bile flow) and cytoprotective effects, UDCA is increasingly recognized as a signaling molecule that modulates a range of nuclear- and membrane-bound receptors in human tissues (Marchianò et al. 2023). Although a relatively weak agonist compared to more hydrophobic bile acids like LCA or deoxycholic acid (DCA), which passively diffuse into epithelial colonic cells and activate nuclear receptors, UDCA exerts regulatory effects through both direct receptor engagement and indirect metabolic reshaping of the bile acid pool (Hanafi et al. 2018). These interactions contribute to UDCA’s therapeutic profile in liver and intestinal diseases (Lin et al. 2025).

Key receptor and signaling interactions

• Takeda G protein-coupled receptor 5 (TGR5, also known as GPBAR1): UDCA modestly activates this G-protein-coupled receptor, especially in enteroendocrine and immune cells. TGR5 activation enhances secretion of glucagon-like peptide-1 (GLP-1), supports glucose homeostasis, and suppresses pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) (Hanafi et al. 2018), reinforcing UDCA’s metabolic and anti-inflammatory effects (Lin et al. 2025; Guzior et al. 2021).

• Farnesoid X Receptor (FXR): While UDCA is not a strong FXR agonist, it modulates FXR signaling indirectly by altering bile acid pool composition, notably by reducing antagonists like LCA (Hanafi et al. 2018). In inflammatory settings, UDCA can selectively downregulate FXR expression while upregulating FXR target genes like SHP, in turn influencing genes such as CYP7A1 and BSEP involved in bile acid synthesis and transport (Lin et al. 2025; Guzior et al. 2021).

• Pregnane X and Vitamin D Receptors (PXR and VDR): UDCA does not directly activate these receptors, but by reducing LCA – a potent ligand for both – it may help regulate detoxification pathways, epithelial integrity and immune homeostasis. These are especially relevant in gut-liver disorders and cholestasis (Hanafi et al. 2018; Keely et al. 2019).

There is also an epigenetic layer to UDCA’s anti-inflammatory and anti-tumorigenic mechanisms: UDCA downregulates miRNA-21, a pro-inflammatory and pro-carcinogenic microRNA that is upregulated by lipopolysaccharide (LPS) and in chronic liver inflammation (Peng et al. 2024).

UDCA as therapeutic drug

UDCA is a cornerstone therapy for chronic cholestatic liver diseases such as PBC, with growing relevance in metabolic and immunological conditions (Keely et al. 2019). While its core mechanisms are hepatoprotective and choleretic, UDCA also engages complex signaling and microbiome-modulating pathways that may benefit extrahepatic disorders like inflammatory bowel disease (Lin et al. 2025). As research evolves, combination therapies and system-level understanding will likely expand UDCA’s clinical applications across liver and gut health.

UDCA’s therapeutic effects stem from its ability to balance the bile acid pool, stabilize hepatocyte membranes, reduce oxidative stress and modulate immune responses (Kumar et al. 2001). These actions translate into anti-apoptotic, cytoprotective, choleretic and immunomodulatory benefits (Keely et al. 2019). In PBC, long-term UDCA therapy (13–15 mg/kg/day) improves liver biochemistry, slows histological progression and reduces the need for liver transplantation. It is most effective when started early and has become the standard of care (Kumar et al. 2001).

UDCA is also used in primary sclerosing cholangitis (PSC), though its benefits are modest and may be enhanced when combined with endoscopic therapy. It is the treatment of choice in intrahepatic cholestasis of pregnancy (ICP) and shows benefit in cystic fibrosis–associated liver disease, graft-versus-host disease, and pediatric cholestasis by reducing bile acid toxicity and supporting bile flow (Ted George O. Achufusi et al. 2023).

In metabolic dysfunction-associated steatohepatitis (MASH), UDCA alone has limited therapeutic efficacy but can enhance the effects of FXR/TGR5 agonists. Recent research showed that combining UDCA with such agents led to reversal of liver inflammation and fibrosis, improved bile acid signaling and greater metabolic gene regulation than either treatment alone (Marchianò et al. 2023). This positions UDCA as a synergistic component in multi-targeted approaches for metabolic liver diseases.

UDCA and 5P medicine

UDCA and its derivatives align well with all principles of 5P medicine:

• Predictive and personalized medicine: The isoUDCA/UDCA ratio has emerged as a potential biomarker for therapeutic response and bile acid pool dynamics in cholestatic liver diseases (Beuers et al. 1991). These profiles reflect microbial-host interactions and support individualized monitoring strategies (Marschall et al. 2001)

• Precision medicine: UDCA is an approved treatment for PBC, PSC and ICP (Kumar et al. 2001; Ted George O. Achufusi et al. 2023). It modulates bile acid receptors (FXR, TGR5), transporters and inflammatory responses (Hanafi et al. 2018; Keely et al. 2019). In MASH, UDCA is being tested in combination with receptor agonists like BAR502 (Marchianò et al. 2023). It also reshapes bile acid pools, reducing hepatotoxic intermediates such as LCA (Hanafi et al. 2018), thus acting as both a treatment and response-modifying agent.

• Participatory medicine: UDCA’s oral administration and safety profile allow patients to engage in long-term, proactive care. It is widely used to prevent gallstones in post-bariatric patients (Gideon M. Hirschfield et al. 2017) and treat pregnancy-related cholestasis (Kumar et al. 2001).

• Population-based medicine: UDCA is included in international clinical guidelines for PBC and other liver diseases (Lindor et al. 2019; Gideon M. Hirschfield et al. 2017). Its safety and efficacy support preventive use, although global access and cost remain variable.

References

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