History and evolution

1886: first isolated from ox bile (Hofmann and Hagey 2014) | 1911: first isolated from human samples (Carey and Watson 1955) | 1950s: confirmed as secondary bile acid (Hofmann and Hagey 2014)

Deoxycholic acid (DCA) is a secondary bile acid produced when intestinal bacteria metabolize the primary bile acid cholic acid (Šarenac and Mikov 2018). DCA was first isolated from human fecal samples in 1911 by Fischer, though subsequent investigations focused on cholic acid and rather ignored DCA (Carey and Watson 1955). Interest in DCA was revived in the 1940s, when it was identified as a precursor for the synthesis of corticosteroids (Hofmann and Hagey 2014). Of those, cortisone was a particularly promising new treatment against rheumatoid arthritis, and commercial production boomed after Sarett determined a process for synthesizing cortisone from DCA (Sarett 1946). Since then, other precursors have been used for this application, but DCA still serves in several medical applications, most notably the dissolution of gallstones.

DCA plays an important role in many physiological processes including gut homeostasis, immune cell function and inflammation and is a prominent player in the modulation of bile flow and the absorption of dietary fats. (Su et al. 2023). In research, DCA is used as a detergent to isolate membrane proteins, and is being investigated as a potential component in nanomedicine (Deng and Bae 2023). Because of its ability to disrupt cell membranes in adipocytes and destroy fat cells, DCA is commonly used in lipolysis, either alone or together with phosphatidylcholines, as an injectable to treat “submental fullness” (double chin), though results are mixed (Muskat et al. 2022).

However, bile acids can also have detrimental effects on human health: high exposure to bile acids including DCA seems to be a risk factor for cancer (Ajouz et al. 2014). Current interest in DCA is related to the discovery that bile acids have signaling properties as ligands of receptors in the enterohepatic pathway, meaning that they may be categorized as hormones (Modica et al. 2010). These signaling cascades may help to explain the relationship between diet, gut dysbiosis and complex chronic diseases as discussed below.

Biosynthesis vs. dietary uptake

Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the main primary bile acids formed in humans, derived from cholesterol through a series of hepatic enzymatic reactions (Funabashi et al. 2020). Primary bile acids are conjugated to glycine or taurine to form bile salts that are transported to and stored in the gallbladder. Food consumption prompts the release of bile rich in bile salts from the gallbladder into the small intestine, where they aid the digestion and absorption of lipids, particularly of triglycerides.

Most primary bile acids are re-absorbed in the distal ileum before entering the colon, but about 5% escape this route and are deconjugated by gut bacteria to serve as substrate fro secondary bile acid synthesis (Ajouz et al. 2014): CA is typically converted to DCA, and CDCA to ursodeoxycholic acid (UDCA) and lithocholic acid (LCA). DCA can also be conjugated with glycine or taurine to form the conjugates GDCA and TDCA, respectively. In humans, DCA is the main secondary bile acid found in the bile acid pool. DCA is mainly re-absorbed in the colon and enters enterohepatic circulation, reaching the liver where it is re-conjugated and secreted in bile.

While this is an endogenous process, it is highly dependent on dietary intake. Fat and fiber consumption influence gut microbiota composition and studies have shown that diet influences DCA levels in the colon (Ghaffarzadegan et al. 2019). Switching to an animal-based diet rich in meat, dairy and eggs led to a 2- to 10-fold increase in fecal DCA levels in human subjects (David et al. 2014). Increasing protein intake on a high fat diet increased plasma DCA by almost 50% (Bortolotti et al. 2009).

DCA and the microbiome

Bile acid concentrations have long been known to influence health and disease. DCA is among the most abundant secondary bile acids, comprising around 20% of the bile acid pool in the bile of adult humans (Hofmann 1999). This amounts to around 500mg, with the excess excreted through feces (Marcus and Heaton 1988). DCA and its derivatives play a vital role in limiting Clostridium difficile production and regulating host metabolism and immune response. High levels of DCA are particularly associated with gut dysbiosis and disease, including hepatocellular carcinogenesis (Funabashi et al. 2020). DCA pool size is also associated with the precipitation of gallstones (Dowling 2000).

A recent study using metabolomic profiling in mice has shown that in addition to the traditional pathways described above, bile acids can be conjugated to amino acids such as phenylalanine, tyrosine, and leucine, by gut microbiota (Quinn et al. 2020). When conjugates and different hydroxyl group states were included, these new “microbially conjugated bile acids” could amount to more than 2800 metabolites, opening up a fascinating new area of research into the impact of bile acid diversity on the wider microbiome (Guzior and Quinn 2021).

The size and diversity of the bile acid pool is regulated by several nuclear and membrane receptors. Bile acids including DCA are ligands of the farnesoid X receptor (FXR), which acts as a “bile acid sensor” to regulate bile acid synthesis (Zhang 2010). Functional FXR is expressed in a wide range of tissues including in brain neurons, the adrenal cortex and pancreatic beta cells. FXR governs the expression of genes related to energy metabolism, bile acid metabolism, insulin signaling, immune cells regulation, mitochondrial physiology, and stability of the tumor suppressor protein p53 (Qiao et al. 2001).

Primary and secondary bile acids have very different actions on FXR. Several primary bile acids are potent agonists, while several secondary bile acids, including DCA, have antagonistic effects (Lefebvre et al. 2009). If the ratios change due to dysbiosis, this can affect the host’s physiology. For example, in non-alcoholic fatty liver disease (NAFLD), bile acid levels are increased but hepatic FXR signaling is downregulated. This is thought to arise from an increase in DCA levels (FXR antagonist) and reduced levels of the primary bile acid CDCA (FXR agonist) (Jiao et al. 2018).

DCA, mitochondria, and neurology

DCA’s emulsifying properties make it very efficient at intercalating within membranes (Sousa et al. 2015). An imbalance in the secondary to primary bile acids ratio can affect cell membranes, especially those already disturbed by high levels of saturated and oxidized fatty acids due, for example to an unhealthy diet. These membranes may become more susceptible to disruption by secondary bile acids, contributing to inflammation, mitochondrial damage, and the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative damage to DNA via ROS and RNS can also promote genomic instability. In addition, DCA can disrupt several DNA mismatch repair enzymes, such as anaphase promoting complex (APC) and p53, by inducing mutations (Liu et al. 2022).

DCA’s effect on mitochondrial metabolism and FXR signaling has implications for the brain. In Alzheimer’s disease (AD), bile acid synthesis has been shown to be affected by FXR. MahmoudianDehkordi et al. (2019) have shown that an increased secondary/primary bile acids ratio in brain tissue and blood correlates with cognitive decline. If high levels of DCA inhibit neuronal FXR, this may lead to other changes in energy homeostasis, such as the down-regulation of glucose transporter-3 (GLUT3) expression, leading to incremental intracellular malnutrition.

When glycolysis cannot be performed due to a lack of intercellular glucose, compensatory processes shift energy supply toward fatty acid oxidation, which increases the demand on the mitochondria. When combined with the membrane disruptions caused by secondary bile acids, this environment can easily lead to mitochondrial dysfunction and incomplete fatty acid oxidation. Such metabolic impairments can be detected in the blood as a complex mixture of acylcarnitines, another marker of late-stage AD (Toledo et al. 2017). This suggests that part of AD pathology may be of metabolic origin and caused by malnutrition in the brain, supporting the reclassification for AD as type 3 diabetes.

DCA and cancer

DCA’s role in tumor growth has been documented since the 1940s (Ajouz et al. 2014). Chronically elevated levels of DCA are associated with colorectal cancer, pancreatic cancer, esophageal cancer and other gastrointestinal cancers. Research suggests that dietary factors play a major role in DCA’s involvement in carcinogenesis, as high levels of bile acids are associated with high fat diets (Ajouz et al. 2014). Population-based studies show similar patterns of elevated secondary bile acid levels in people who consume high-fat and high-beef diets, and in people with colonic carcinomas (Ajouz et al. 2014). A case-control study found a positive association between serum DCA levels and colorectal adenomas (Bayerdörffer et al. 1993).The levels of DCA and other secondary bile acids have often been found increased in the feces of humans and mice fed a high-fat diet, as well as the feces of humans with colorectal cancer ( Liu et al. 2022). Since DCA can promote apoptosis in normal intestinal cells, this could potentially contribute to a carcinogenic environment (Schlottman et al. 2020).

Diet has also been shown to play a role in obesity-related hepatocellular cancers: a mouse model demonstrated that the gut microbiome was altered in obese phenotypes, leading to higher levels of DCA (Yoshimoto et al. 2013). Blocking DCA production and reducing gut bacteria inhibited cancer development in obese mice. Animal studies have also shown DCA to be hepatotoxic (Delzenne et al. 1992). These effects are thought to result from DCA’s involvement in signaling cascades through membrane disruption and receptor activation, as described above.

DCA and immunology

DCA’s role as a signaling molecule is also crucial in the immune response. As well as acting on FXR, DCA acts on G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), which modulates the inflammatory response (Fiorucci et al. 2018). Both FXR and TGR5 are highly expressed in immune cells. Patients with the autoimmune disease rheumatoid arthritis (RA) have been found to have elevated bile acid levels, linked to proinflammatory cytokine levels, and primary bile acids may be used to predict RA severity (Su et al. 2023). In mice, DCA has been found to enhance macrophage cytokine production via FXR (Yan et al. 2021).

Multiple studies have shown that patients with active inflammatory bowel disease (IBD) have reduced secondary bile acid levels in plasma and stool (Thomas et al. 2022). However, bile acid profiles in early- and late-stage IBD patients vary greatly in response to inflammation-induced microbiome changes, suggesting a correlation between bile acid pools and disease progression. Reports have shown that FXR expression is repressed in early stages of IBD, which again may contribute to changes in microbiome composition and a hyperinflammatory environment.

Learn more about the roles DCA and other secondary bile acids in complex chronic diseases such as cancer, Alzheimer’s disease, depression, inflammatory bowel disease, multiple sclerosis and diabetes in our whitepaper “Complex chronic diseases have a common origin”.

References

Ajouz et al.: Secondary bile acids: an underrecognized cause of colon cancer. (2014) World Journal of Surgical Oncology | https://doi.org/10.1186/1477-7819-12-164

Bayerdörffer et al.: Increased serum deoxycholic acid levels in men with colorectal adenomas. (1993) Gastroenterology | https://doi.org/10.1016/0016-5085(93)90846-5

Bortolotti et al.: High protein intake reduces intrahepatocellular lipid deposition in humans. (2009) The American Journal of Clinical Nutrition | https://doi.org/10.3945/ajcn.2008.27296

Carey and Watson: Isolation of deoxycholic acid from normal human feces. (1955) Journal of Biological Chemistry | https://doi.org/10.1016/S0021-9258(19)81438-2

David et al.: Diet rapidly and reproducibly alters the human gut microbiome. (2014) Nature | https://doi.org/10.1038/nature12820

Delzenne et al.: Comparative hepatotoxicity of cholic acid, deoxycholic acid and lithocholic acid in the rat: in vivo and in vitro studies. (1992) Toxicol Lett | https://doi.org/10.1016/0378-4274(92)90156-e

Deng and Bae: Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport. (2023) Nanomedicine: Nanotechnology, Biology and Medicine | https://doi.org/10.1016/j.nano.2022.102629

Dowling et al.: Review: pathogenesis of gallstones. (2000) Alimentary Pharmacology and Therapeutics | https://doi.org/10.1046/j.1365-2036.2000.014s2039.x

Fiorucci et al.: Bile Acids Activated Receptors Regulate Innate Immunity. (2018) Front Immunol | https://doi.org/10.3389/fimmu.2018.01853

Funabashi et al.: A metabolic pathway for bile acid dehydroxylation by the gut microbiome. (2020) Nature | https://doi.org/10.1038/s41586-020-2396-4

Ghaffarzadegan et al.: Determination of free and conjugated bile acids in serum of Apoe(−/−) mice fed different lingonberry fractions by UHPLC-MS. (2019) Sci Rep | https://doi.org/10.1038/s41598-019-40272-8

Guzior and Quinn: Review: microbial transformations of human bile acids. (2021) Microbiome | https://doi.org/10.1186/s40168-021-01101-1

Hofmann et al.: The Continuing Importance of Bile Acids in Liver and Intestinal Disease. (1999) Arch Intern Med | https://doi.org/10.1001/archinte.159.22.2647

Hofmann and Hagey: Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. (2014) J Lipid Res | https://doi.org/10.1194/jlr.R049437

Jiao et al.: Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. (2018) Gut | https://doi.org/10.1136/gutjnl-2017-314307

Lefebvre et al.: Role of bile acids and bile acid receptors in metabolic regulation. (2009) Physiol Rev | https://doi.org/10.1152/physrev.00010.2008

Liu et al.: Secondary Bile Acids and Tumorigenesis in Colorectal Cancer. (2022) Front Oncol | https://doi.org/10.3389/fonc.2022.813745

MahmoudianDehkordi et al.: Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease – An emerging role for gut microbiome. (2019) Alzheimers Dement | https://doi.org/10.1016/j.jalz.2018.07.217

Marcus and Heaton: Deoxycholic acid and the pathogenesis of gall stones. (1988) Gut | https://doi.org/10.1136/gut.29.4.522

Modica et al.: Deciphering the nuclear bile acid receptor FXR paradigm. (2010) Nucl Recept Signal | https://doi.org/10.1621/nrs.08005

Muskat et al.: The role of fat reducing agents on adipocyte death and adipose tissue inflammation. (2022) Front. Endocrinol | https://doi.org/10.3389/fendo.2022.841889

Qiao et al.: Deoxycholic acid suppresses p53 by stimulating proteasome-mediated p53 protein degradation. (2001) Carcinogenesis | https://doi.org/10.1093/carcin/22.6.957

Quinn et al.: Global Chemical Impact of the Microbiome Includes Novel Bile Acid Conjugations. (2020) Nature | https://doi.org/10.1038/s41586-020-2047-9

Šarenac and Mikov: Bile acid synthesis: From nature to the chemical modification and synthesis and their applications as drugs and nutrients. (2018) Front. Pharmacol | https://doi.org/10.3389/fphar.2018.00939

Sarett et al.: Partial synthesis of pregnene-4-triol-17(beta), 20(beta), 21-dione-3,11 and pregnene-4-diol-17(beta), 21-trione-3,11,20 monoace. (1946) J Biol Chem

Schlottman et al.: Characterization of Bile Salt-Induced Apoptosis in Colon Cancer Cell Lines. (2000) Cancer Res | https://encr.pw/5kwuw

Sousa et al.: Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties. (2015) J Lipid Res | https://doi.org/10.1194/jlr.M062653

Su et al.: Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity. (2023) Front. Immunol | https://doi.org/10.3389/fimmu.2023.1127743

Thomas et al.: The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease. (2022) Front Immunol | https://doi.org/10.3389/fimmu.2022.829525

Toledo et al.: Metabolic network failures in Alzheimer’s disease: A biochemical road map. (2017) Alzheimer’s & Dementia | https://doi.org/10.1016/j.jalz.2017.01.020

Yan et al.: FXR-Deoxycholic Acid-TNF-α Axis Modulates Acetaminophen-Induced Hepatotoxicity. (2021) Toxicol Sci | https://doi.org/10.1093/toxsci/kfab027

Yoshimoto et al.: Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. (2013) Nature | https://doi.org/10.1038/nature12347

Yujing et al.: Secondary Bile Acids and Tumorigenesis in Colorectal Cancer (2020) Frontiers in Oncology | https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.813745

Zhang et al.: Farnesoid X receptor–Acting through bile acids to treat metabolic disorders. (2010) Drugs Future | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899934/

History and evolution

1883: GABA first synthesized (Vlainic and Jembrek 2018) | 1950: GABA found in mammalian brains | 1967: discovery of GABA’s role as inhibitory neurotransmitter

Alpha-, beta- and gamma-aminobutyric acids (AABA, BABA and GABA) are a group of structurally similar nonproteinogenic amino acids.

GABA is the most well-known and widely studied. Initially thought to exist only in plants and microbes, GABA was first discovered in rotten pancreas in 1912 (Obata et al. 2013). Its presence in human and animal brains was confirmed by Roberts and Awapara in 1950, using paper chromatography (Awapara et al. 1950, Roberts and Frankel 1950). Since then, GABA has been the subject of extensive research as the main inhibitory neurotransmitter in the central nervous system.

GABA is also involved in the regulation of many other physiological processes in tissues such as blood vessels, skeletal muscles, gastrointestinal tract, pituitary, thyroid, adrenal gland and thymus (Watanabe et al. 2002). Drugs that target the GABA system are used to treat a variety of conditions, including anxiety disorders, epilepsy, hypertension and insomnia (Evenseth et al. 2020).

AABA and BABA are isomers of GABA. AABA is found in smaller amounts in the human body, though remains a metabolite of interest for its potential effects on neurotransmission. BABA is a rare amino acid found in certain bacteria and plants, but not commonly found in humans. Interestingly, particles returned by the JAXA Hayabusa mission to asteroid Itokawa found traces of BABA, with sufficiently high levels to suggest that they were of non-terrestrial origin (Parker et al. 2021).

The term “aminobutyric acid” refers to the molecules’ structure. Each contains a butyric acid molecule with an amino group attached to one end. They are named according to the position of the amino group. Thus, in an AABA molecule, the amino group is attached to the first carbon in the butyric acid molecule (the alpha position), BABA has an amino group attached to the second carbon, and in a GABA molecule, the amino group is attached to the third carbon.

Biosynthesis vs. dietary uptake

Aminobutyric acids can be obtained from the diet or synthesized in the body. GABA is found in a variety of foods, particularly in tea, tomato, pulses and fermented foods, like kimchi and miso (Sahab et al. 2020). It’s not clear how much GABA is absorbed through the diet, though some studies suggest that consuming GABA-rich foods may increases GABA levels in the body (Hepsomali et al. 2020).

Around 30% of cerebral neurons contain GABA (Gladkevich et al. 2006). GABA is synthesized in vivo in the central nervous system by a metabolic pathway that bypasses the TCA cycle, known as the GABA shunt (Olsen et al. 1999). First, alpha-ketoglutarate generated by the TCA cycle produces glutamate. The enzyme glutamic acid decarboxylase (GAD) converts glutamate to GABA, using pyridoxal phosphate (vitamin B6) as a cofactor. GABA can be broken down by the enzyme GABA transaminase (GABA-T) to form succinic semialdehyde. Enzymes convert this to succinate, which then enters the TCA cycle, completing the “shunt”.

In the gut, it’s thought that bacteria such as Lactobacillus and Bifidobacterium use glutamate as a substrate, producing GABA through an enzymatic reaction with GAD (Pokusaeva et al. 2017). GABA may also be synthesized to a lesser extent in the pancreas, kidneys and liver.

AABA can be synthesized through various metabolic pathways, through the conversion of precursor molecules by specific enzymes. These include transamination, decarboxylation, and deamination of other amino acids, such as threonine, methionine, serine or isoleucine (HMDB 2023).

AABA in health and disease

AABA is thought to have antioxidant effects and is a biomarker for alcohol liver injury, sepsis, malnutrition, depression, and osteoporosis (Effros et al. 2011). AABA is elevated in the plasma of children with diseases such as Reye’s syndrome. (Wang et al. 2020)

Recent research using metabolomics shows the ratio of GABA and AABA is closely associated with aging-related physical performance (Wang et al. 2023). Therefore, these metabolites could be used as biomarkers to predict correlations among aging, physical performance and effects of physical activity, and potentially lead to therapeutic targets for muscle disorders such as stiff man syndrome and sarcopenia.

A study of 918 older men confirmed a relationship between branched chain amino acids and other amino acids, including AABA, with cardiovascular risk factors and mortality (LeCouteur et al. 2020). Frail participants were found to have lower levels of AABA.

GABA and neurology

Since Roberts’ discovery in 1957, GABA’s role as an inhibitory neurotransmitter has been heavily researched. GABA is the most abundant inhibitor of neurotransmission, making it an appealing target for the management of neurological disorders.

For example, epilepsy is characterized by an overexcitation of neurons, and in animal models, GABA has been shown to regulate cortical activity and predisposition to epileptic seizures (Benarroch et al. 2021). Decreased GABA levels have also been found in severe cases of Alzheimer’s disease, and dementia-associated agitation can be treated with the GABA analog, Gabapentin (Solas et al. 2015, Roane et al. 2000).

GABA may also inhibit dopamine release. Dopamine’s association with impulsive behavior therefore makes GABA a metabolite of interest in treatments for addiction and mood disorders (Trujillo et al. 2022). Similarly, GABA has also been investigated as a potential therapeutic target for Parkinson’s disease, in which dopamine is suppressed, though results are mixed. Notably, in patients with Parkinson’s disease, motor cortex GABA levels have been found to be inversely correlated with disease severity, in a study using magnetic resonance spectroscopy (Nuland et al. 2020). This suggests that GABA depletion may contribute to increased motor symptom expression.

GABA is known to reduce stress and promote sleep, but clinical trials investigating the effect of oral GABA intake for stress and sleep have had mixed results (Hepsomali et al. 2020).

Another outstanding question concerns GABA’s ability to penetrate the blood-brain barrier (BBB) (Hepsomali et al. 2020). Historically, researchers believed that GABA could not cross the BBB. However, recent research offers mixed accounts, with some researchers suggesting that small amounts of GABA can cross the BBB, and others finding larger amounts can cross. GABA’s presence in the enteric nervous system may suggest a mechanism of action on the peripheral nervous system via the gut-brain axis (Cryan et al. 2012).

GABA and the gastrointestinal tract

GABA is an established mediator of gastrointestinal function. GABAergic signaling is mediated by different types of GABA receptors, regulating both motor and secretory GI activity. Recent studies suggest that GABA may play a role in neuroimmune reactions associated with enteric inflammatory conditions, such as inflammatory bowel disease (IBD) (Auteri et al. 2015).

Treatment of IBD and irritable bowel syndrome (IBS) focus mostly on symptom relief. However, given the presence of GABA receptors in the GI system, GABAergic drugs such as benzodiazepines may offer a more comprehensive treatment (Jembrek et al. 2017). The effects of benzodiazepines include neuroimmunomodulation, pain relief and anxiolytic action.

In a study of patients with diarrhea-predominant IBS (IBS-D), patients were found to have lower levels of GABA compared to controls (Aggarwal et al. 2018). In vitro studies showed that a GABA antagonist could block the inhibitory effect of GABA, again suggesting they may be used to treat IBS-D and other inflammatory diseases.

GABA and diabetes

GABA may also be an effective treatment for type 1 diabetes. In experimental studies with rodent and human beta-cells, GABA has been shown to reverse diabetes by stimulating beta-cell regeneration (Wan et al. 2015). In addition to cell proliferation and antiapoptotic effects, it has also been found to prevent insulitis in preclinical models, suggesting that GABA may be a potential preventative treatment, too.

References

Aggarwal et al.: Dysregulation of GABAergic Signalling Contributes in the Pathogenesis of Diarrhea-predominant Irritable Bowel Syndrome. (2018) J Neurogastroenterol Motil | https://doi.org/10.5056/jnm17100

Auteri et al.: GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. (2015) Pharmacol Res | https://doi.org/10.1016/j.phrs.2014.12.001

Awapara et al.: Free γ-aminobutyric acid in brain. (1950) J. Biol. Chem | https://www.jbc.org/article/S0021-9258(19)50926-7/pdf

Benarroch et al.: What Is the Role of GABA Transporters in Seizures? (2021) Neurology | https://doi.org/10.1212/WNL.0000000000012574

Cryan et al.: Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. (2012) Neurology | https://doi.org/10.1212/10.1038/nrn3346

Effros et al.: Alpha aminobutyric acid, an alternative measure of hepatic injury in sepsis? (2011) Translational Research | https://doi.org/10.1016/j.trsl.2011.07.003

Evenseth et al.: The GABAB Receptor-Structure, Ligand Binding and Drug Development. (2020) Molecules | https://doi.org/10.3390/molecules25133093

Gladkevich et al.: The peripheral GABAergic system as a target in endocrine disorders. (2006) Auton Neurosci | https://doi.org/10.3390/molecules25133093

Hepsomali et al.: Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. (2020) Front Neurosci | https://doi.org/10.3389/fnins.2020.00923

Jembrek et al.: GABAergic System in Action: Connection to Gastrointestinal Stress-related Disorders. (2017) Curr Pharm Des | https://doi.org/10.2174/1381612823666170209155753

LeCouteur et al.: Branched Chain Amino Acids, Cardiometabolic Risk Factors and Outcomes in Older Men: The Concord Health and Ageing in Men Project. (2020) The Journals of Gerontology | https://doi.org/10.1093/gerona/glz192

Obata et al.: Synaptic inhibition and γ-aminobutyric acid in the mammalian central nervous system. (2013) Proc Jpn Acad Ser B Phys Biol Sci | https://doi.org/10.2183/pjab.89.139/

Olsen et al.: GABA Synthesis, Uptake and Release. (1999) In Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. | https://www.ncbi.nlm.nih.gov/books/NBK27979/

Parker et al.: Extraterrestrial Non-Protein Amino Acids Identified In Carbon-Rich Particles Returned From Asteroid Itokawa. (2021) 84th Annual Meeting of The Meteoritical Society 2021 | https://doi.org/10.1111/maps.13794

Pokusaeva et al.: GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. (2017) Neurogastroenterology & Motility | https://doi.org/10.1111/nmo.12904

Roane et al.: Treatment of Dementia-Associated Agitation With Gabapentin. (2000) Neuropsychiatry Clin Neurosci | https://doi.org/10.1176/jnp.12.1.40

Roberts and Frankel: γ-Aminobutyric acid in brain: its formation from glutamic acid. (1950) J. Biol. Chem | https://www.jbc.org/article/S0021-9258(19)50929-2/pdf

Sahab et al.: γ-Aminobutyric acid found in fermented foods and beverages: current trends. (2020) Neuropsychiatry Clin Neurosci | https://doi.org/10.1016/j.heliyon.2020.e05526

Solas et al.: Treatment Options in Alzheimer`s Disease: The GABA Story. (2015) Curr Pharm Des | https://doi.org/10.1016/j.heliyon.2020.e05526

Trujillo et al.: Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients. (2022) npj Parkinson’s Disease | https://doi.org/10.1038/s41531-022-00298-8

van Nuland et al.: GABAergic changes in the thalamocortical circuit in Parkinson’s disease. (2020) npj Parkinson’s Disease | https://doi.org/10.1002/hbm.24857

Vlainic et al.: GABA (γ-Aminobutyric Acid). (2018) In Encyclopedia of Signaling Molecules by S. (eds) Choi. Springer, Cham.

Wan et al.: GABAergic system in the endocrine pancreas: a new target for diabetes treatment. (2015) Diabetes Metab Syndr Obes | https://doi.org/10.2147/DMSO.S50642

Wang et al.: γ-Aminobutyric acids (GABA) and serum GABA/AABA (G/A) ratio as potential biomarkers of physical performance and aging (preprint). (2023) Research Square | https://doi.org/10.21203/rs.3.rs-2492780/v1

Wang et al.: Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis. (2020) Commun Biol | https://doi.org/10.1038/s42003-020-0766-y

Watanabe et al.: GABA and GABA receptors in the central nervous system and other organs. (2002) Int Rev Cytol | https://doi.org/10.1016/s0074-7696(02)13011-7

History and evolution

1907: first synthesis from histidine (Tiligada et al. 2020) | 1910: first isolated from mold | 1937: synthesis of first antihistamine

Histamine is an amine with multiple physiological effects, best known for its role in allergies and anaphylaxis. Histamine was first synthesized by Windhaus and Vogt in 1907, then isolated from mold by Dale and Laidlaw in 1910 (Dale et al. 1910). They referred to the substance as β-imidazolylethylamine, but it later became known as “histamine”, taking its name from the Greek word for tissue, histos (Tiligada et al. 2020). Histamine has since become one of the most well-researched substances in biomedical science, linked to multiple Nobel Prize awards. It’s also the only metabolite to have its very own anthem, courtesy of the European Histamine Research Society (EHRS, 2018).

Histamine is found in stinging nettles and insect venom, causing an itchy, painful reaction in anyone who is stung or bitten. In humans, early research focused on histamine’s role in the inflammatory response, particularly in local reactions to allergies. The discovery of antihistamines led to ground-breaking treatment for allergic disorders, and more recently in other immune-related disorders (Cataldi et al. 2014).

Histamine is found in nearly all tissues in the human body. It stimulates smooth muscle contraction, vasodilation, and gastric acid secretion, and plays a role in cell differentiation, proliferation and regeneration (Branco et al. 2018). In the brain, it acts as a neurotransmitter, carrying messages through the central nervous system (CNS). It has even been linked to sleep regulation, diabetes and obesity (Yoshimoto et al. 2006). Thus, histamine is a metabolite of interest in multiple disorders and potential treatments.

Biosynthesis vs. dietary uptake

Histamine is synthesized via the decarboxylation of the essential amino acid histidine. This occurs primarily in mast cells, but also in basophils throughout the body, histaminergic neurons in the brain, and enterochromaffin-like cells in the stomach (Huang et al. 2018). Basophils and mast cells can synthesize and store large amounts of histamine, whereas myeloid and lymphoid cells synthesize it without storing (Patel et al. 2022).

Histamine is stored in intracellular granules and released in response to different stimuli, such as immunoglobulin E (IgE) antibodies produced by the immune system. Degranulation is catalyzed by enzymes including diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT). The DAO pathway converts histamine to imidazole-4-acetate and is associated with gastrointestinal activity. HNMT converts histamine to N-methylhistamine and acts in the CNS and airways. Around 50-80% of synthesized histamine is metabolized in the HNMT pathway, 15-30% in the DAO pathway, and 2-3% is excreted unchanged (Patel et al. 2022).

Once released, histamine binds to four different G protein-coupled receptors (GPCR), referred to as H1 to H4. Each one is activated in response to a different concentration of histamine, depending on where in the body the histamine is released (Panula et al. 2015). GPCRs form part of the largest family of membrane proteins in the human genome. Their structure includes an extracellular N terminus, intracellular C terminus and seven transmembrane helices joined by three intracellular and three extracellular loops (Panula et al. 2015).

The expression of these receptors and their response to histamine is as follows :

• H1-Receptors (H1R) are expressed in multiple cells and tissues in response to endogenous histamine. They play a key role in allergy and inflammation. Stimulation causes vasodilation, bronchoconstriction, mucus secretion and platelet activation (Thangam et al. 2018).
• H2-Receptors (H2R) are also widely expressed, and when activated can cause excess mucus in the airways, vascular permeability, increased heart rate and gastric acid secretion (Thangam et al. 2018).
• H3-Receptors (H3R) are found in the nervous system, regulating histamine by inhibiting histamine synthesis. H3R are involved in blood-brain barrier function, sleep cycles, cognitive function, homeostatic energy regulation and neurotransmission (Yoshimoto et al. 2006).
• H4-Receptors (H4R) are expressed in mast cells, particularly in bone marrow, white blood cells and the oral epithelium. While H3R inhibits histamine production, H4R stimulates histamine and cytokine production. H4R was discovered via the human genomic DNA database in 2000 (Oda et al. 2000).

Histamine can also be synthesized from bacteria in food, such as histidine decarboxylases found in lactic acid bacteria in fermented food (Landete et al. 2008). Histamine-rich foods include alcohol, dairy products, fermented foods and certain vegetables (Reese et al. 2018).

Histamine, the immune system, and allergies

Histamine’s role in allergic reactions was first discovered in 1932, and we now know it plays a central role in autoimmune conditions, inflammation and inflammatory disease (Patel et al. 2022). It has both pro- and anti-inflammatory effects, depending on which receptor is activated and in which cells. In the event of local tissue damage or infection, the release of histamine causes vasodilation, which allows leukocytes and immunoproteins to move easily to the damaged site and fight infection.

While this immune response is often helpful, hypersensitivity (as in hay fever, asthma or allergies) can cause unnecessary and unpleasant symptoms, such as sneezing, wheezing, itching, swelling, increased heart rate, eye irritations and gastric issues (Thangam et al. 2018). In extreme cases, anaphylaxis occurs, which can be fatal.

Antihistamines work by preventing histamine from binding to the relevant receptor, thus inhibiting the inflammatory response (Thangam et al. 2018). Common antihistamines to treat allergies are H1 antagonists. Antihistamines that block H2R inhibit gastric acid secretion, and would include ulcer treatments.

Histamine, the gut, and the microbiome

High concentrations of histamine are found in the gastrointestinal (GI) tract, so it’s no surprise that this metabolite is involved in many GI processes and disorders. However, there remain gaps in our understanding of how microbiota mediate histamine and histamine receptor activity in the gut. Enzymatic activity, dietary intake and microbial processes can all affect histamine levels. While it can have a protective effect, excess levels of histamine are linked to several mucosal inflammatory disorders, including food allergies, histamine intolerance, irritable bowel syndrome and inflammatory bowel disease (Smolinksa et al. 2013).

More than 20% of the population suffer from gastrointestinal problems (Schnedl et al. 2021). Unfortunately, the etiology and pathophysiology of many of these disorders remains unclear. The DAO pathway is the subject of much interest, given its role in breaking down ingested histamine.

A deficiency of DAO leads to impaired histamine degradation, which causes histamine intolerance (HIT). People with HIT suffer a variety of adverse reactions when they consume histamine-rich foods. This should not be confused with food allergies, though histamine often plays a role there too. Enterochromaffin cells have been shown to affect intestinal food intolerances associated with excessive histamine (Pfangazl et al. 2019).

DAO activity has been found to correspond to mucosal damage in Crohn’s disease, ulcerative colitis and colonic adenoma (Schnedl et al. 2021). A study of patients with gastric cancer found that DAO may be a useful predictor of GI toxicity in response to anticancer drugs (Miyoshi et al. 2015). Histamine also attracts interest as a potential therapeutic target in irritable bowel syndrome (Fabisiak et al. 2017).

Histamine and neurology

In the brain, histamine’s effects are mediated by all four receptors (Panula et al. 2021). H1R and H2R are involved in the wake-sleep cycle. H3R regulates neurotransmission, including serotonin- and glutamate-mediated. H4R is present in cerebral blood vessels and microglia, though its exact role remains undefined. Microglial modulation may be a therapeutic target for disorders such as Parkinson’s disease and multiple sclerosis, where changes have been found in histamine receptor levels (Iida et al. 2022).

High levels of histamine are found in the basal ganglia of people with Parkinson’s disease, with increased concentrations in blood and cerebrospinal fluid (Ayaz et al. 2022). Because histamine receptors play a role in motor functioning, they are a potential therapeutic target (Fang et al. 2021). Studies have shown that antihistamines can have a positive effect on resting tremors. However, first generation antihistamines have also been associated with an increased risk of dementia, which suggests they are not a suitable treatment (Gray et al. 2015).

H4R ligands may have a role in the treatment of neuroimmunological disorders and inflammatory neurodegenerative disorders, though more research is needed (Panula et al. 2021).

Histamine dysregulation is also associated with neuropsychological disorders including Tourette’s syndrome, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia (Carthy et al. 2021).

Histamine and cancer

Histamine’s effect on the regulation and behavior of different immune cells draws attention in the world of oncology. Studies have shown that histamine directly influences carcinogenesis, and thus may be a potential therapeutic target (Sun et al. 2018).

A spatially resolved metabolomics method was used to analyze tumor-associated metabolite and enzyme changes in esophageal cancer tissues (Sun et al. 2018). Histamine was significantly downregulated in cancer tissue, and decarboxylation of histidine was found to be weaker in cancer tissue than in non-cancerous tissues.

Antihistamines have also been associated with improved clinical outcomes in cancer treatment. High histamine levels seem to inhibit the immunotherapy response, suggesting a role for antihistamines as an adjuvant treatment (Hongzhong et al. 2022).

References

Ayaz et al.: Parkinsonism Attenuation by Antihistamines via Downregulating the Oxidative Stress, Histamine, and Inflammation. (2022) ACS Omega | https://doi.org/10.1021/acsomega.2c00145.

Branco et al.: Role of Histamine in Modulating the Immune Response and Inflammation. (2018) Mediators Inflamm | https://doi.org/10.1155/2018/9524075.

Carthy et al.: Histamine, Neuroinflammation and Neurodevelopment: A Review. Front. (2021) Neurosci | https://doi.org/10.3389/fnins.2021.680214.

Cataldi et al.: Histamine receptors and antihistamines: from discovery to clinical applications. (2014) Chem Immunol Allergy | https://doi.org/10.1159/000358740.

Dale et al.: The physiological action of β-iminazolylethylamine. (1910) J Physiol | https://doi.org/10.1113/jphysiol.1910.sp001406.

EHRS (2018) European Histamine Research Society | https://www.ehrs.org.uk.

Fabisiak et al.: Targeting Histamine Receptors in Irritable Bowel Syndrome: A Critical Appraisal. (1917) J Journal of Neurogastroenterology and Motility | https://doi.org/10.5056/jnm16203.

Fang et al.: Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum. (2021) Brain, Behavior, and Immunity | https://doi.org/10.1016/j.bbi.2020.11.036 .

Gray et al.: Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. (2015) JAMA Intern Med | https://doi.org/10.1001/jamainternmed.2014.7663.

Hongzhong et al.: The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. (2022) Cancer Cell | https://doi.org/10.1016/j.ccell.2021.11.002

Huang et al.: Molecular Regulation of Histamine Synthesis. (2018) Front Immunol | https://doi.org/10.3389/fimmu.2018.01392

Iida et al.: Histamine and Microglia. (2022) Curr Top Behav Neurosci | https://doi.org/10.1007/7854_2022_322

Landete et al.: Updated molecular knowledge about histamine biosynthesis by bacteria. (2008) Crit Rev Food Sci Nutr | https://doi.org/10.1080/10408390701639041

Miyoshi et al.: Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs. (2015) Journal of Gastroenterology and Hepatology | https://doi.org/10.1111/jgh.13004

Oda et al.: Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes. (2000) Journal of Biological Chemistry | https://doi.org/10.1074/jbc.M006480200.

Panula et al.: International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. (2015) Pharmacol Rev | https://doi.org/10.1124/pr.114.010249.

Panula et al.: Histamine receptors, agonists, and antagonists in health and disease. (2021) Handb Clin Neurol | https://doi.org/10.1016/B978-0-12-820107-7.00023-9.

Patel et al.: Biochemistry, Histamine. (2022) In: StatPearls [Internet]. Florida: StatPearls Publishing | https://www.ncbi.nlm.nih.gov/books/NBK557790

Pfangazl et al.: Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions. (2019) Am J Physiol Gastrointest Liver Physiol | https://doi.org/10.1152/ajpgi.00261.2018

Reese et al.: Nutrition therapy for adverse reactions to histamine in food and beverages. (2018) Allergol Select | https://doi.org/10.5414/ALP34152

Schnedl et al.: Histamine Intolerance Originates in the Gut. (2021) Nutrients | https://doi.org/10.3390/nu13041262

Sun et al.: Spatially resolved metabolomics to discover tumor-associated metabolic alterations. (2018) PNAS | https://doi.org/10.1073/pnas.1808950116

Smolinska et al.: Histamine and gut mucosal immune regulation. (2013) Allergy | https://doi.org/10.1111/all.12330

Thangam et al.: The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. (2018) Front Immunol | https://doi.org/10.3389/fimmu.2018.01873

Tiligada et al.: Histamine pharmacology: from Sir Henry Dale to the 21st century. (2020) Br J Pharmacol | https://doi.org/10.1111/bph.14524

Yoshimoto et al.: Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus. (2006) PNAS | https://doi.org/10.1073/pnas.0506104103

• History & evolution
• Biosynthesis vs. dietary uptake
• Tryptophan, the microbiome, and host metabolism
• Tryptophan and inflammation
• Tryptophan, serotonin and the gut-brain axis
• Tryptophan and cancer

History & Evolution

1901: discovery (Hopkins et al.1901) | 1908: first synthesis (Ellinger et al. 1908) | 1912: identified as essential amino acid (Hopkins 1912)

Tryptophan (or L-tryptophan) was discovered in 1901 by Hopkins and Cole, who isolated it from milk-derived casein (Hopkins et al. 1901). On first spotting an anomalous color reaction when studying acetic acid, Hopkins was said to have danced a jig and exclaimed, “I have a feeling that if we can find the meaning of a color reaction like that, it may open up a way to new knowledge of the structure of the old protein molecule itself,” (Dale 1948). And he was right: the discovery of tryptophan opened the door to understanding the presence and role of essential amino acids, which form the building blocks of proteins.

A few years later, Ellinger and Flamand reported the first synthesis of tryptophan and identified its structure (Ellinger et al. 1908). Tryptophan was subsequently identified as a precursor to serotonin, melatonin and niacin.

In the 1980s, tryptophan became available as a nutritional supplement because of its role as a precursor to the mood-stabilizing neurotransmitter serotonin. In 1988, tryptophan supplements manufactured using genetically engineered bacterial fermentation were linked to an outbreak of eosinophilia myalgia syndrome (EMS), leading to the supplements being banned by the US Food and Drug Administration between 1989 and 2005 (Allen, J. et al, 2011). Numerous clinical trials have shown no further links between tryptophan supplements and EMS.

Tryptophan has been found beneath the ocean floor, suggesting abiotic formation (Urquhart 2018). Some suggest that this discovery could reveal information about the role of amino acids in early-stage biological life. However, others note that tryptophan’s larger and softer structure indicates later evolution than other amino acids.

Biosynthesis vs. dietary uptake

As an essential amino acid, tryptophan cannot be synthesized within the body. It’s obtained from dietary sources including dairy products, meat and seeds. Some say the tryptophan in turkey triggers the melatonin production that causes people to feel sleepy after a big Christmas or Thanksgiving dinner. In reality, there’s no more tryptophan in turkey than in other meats.

The recommended daily allowance for most adults is around 250–425mg per day, and most people easily exceed this (Richard et al. 2009). Relatively low amounts of tryptophan are stored in tissues, but this isn’t an issue given the amount typically consumed.

Tryptophan, the microbiome, and host metabolism

Catabolism of tryptophan occurs primarily in the gut, triggering the indole, kynurenine and serotonin pathways (Taleb, 2019).

Most tryptophan is transformed in the indole pathway. Intestinal bacteria express the enzyme tryptophanase, leading to the production of indole in the gut. This is metabolized into 3-indolepropionic acid (IPA) which binds to the pregnane X receptor (PXR) in intestinal cells. IPA is absorbed in the intestine and distributed to the brain, where it is associated with neuroprotective properties. Indole can also be metabolized into indole-3-aldehyde (I3A) which triggers immunoprotective effects in the intestine. In the liver, indole may be metabolized into indoxyl sulfate, which can be toxic in high concentrations.

As the rarest of three aromatic amino acids, tryptophan is the only amino acid with a non-polar indole ring. This is used for signaling and helps it to anchor membrane proteins within the cell membrane. Indole is a precursor of metabolites that, as noted, can have both positive and negative effects on the host organism.

The majority of remaining dietary tryptophan is metabolized in the kynurenine pathway. In the immune system and brain this occurs via indoleamine 2,3-dioxygenase (IDO). In the liver, kynurenine is synthesized from tryptophan via tryptophan 2,3-dioxygenase (TDO). The kynurenine pathway is a common target for therapeutic study of several neurological, psychological, inflammatory and immune disorders. This pathway also triggers synthesis of niacin (vitamin B3).

A small amount of dietary tryptophan is metabolized by tryptophan hydroxylase in the serotonin pathway. Around 95% of the serotonin is found in the gastrointestinal tract (GIT), with a small concentration in the brain (Richard et al. 2009). In the GIT, serotonin acts as an enterosyne, signaling to the enteric nervous system (ENS) and contributing to the gut-brain axis. In the brain, besides its role as a neurotransmitter, serotonin is a precursor of melatonin in the pineal gland.

Tryptophan and inflammation

As a precursor to kynurenine, tryptophan plays a large role in regulating the immune system. Kynurenine and its metabolites are of increasing interest to the study of autoimmune and immune-mediated diseases, such as multiple sclerosis and rheumatoid arthritis.

Metabolomic analysis in both animal and human subjects showed that the kynurenine-tryptophan ratio correlated with levels of inflammatory cytokines that could induce IDO activation (Westbrook et al. 2020). The study suggests that tryptophan metabolism and kynurenine metabolite activity are the molecular mechanism that connects chronic inflammation with frailty and other signs of ageing.

Metabolomics has been used to investigate the role of tryptophan metabolites in gut dysbiosis, which increases susceptibility to liver inflammation (Krishnan et al. 2018).

Tryptophan metabolism has also been identified as a primary pathway affected by COVID-19 infection, using targeted and untargeted metabolomics data (Thomas et al. 2020).

A review of the health benefits of dietary tryptophan and its metabolites found potential therapeutic effects for cardiovascular disease, chronic kidney disease, inflammatory bower disease, multiple sclerosis, microbial infections, mood and cognitive function (Friedman 2018).

While tryptophan supplementation is not recommended for the general population, these studies suggest potential use as a treatment for specific conditions.

Tryptophan, serotonin and the gut-brain axis

On a recent episode of The Metabolomist podcast, Dr Jennifer Kirwan, Head of Metabolomics at the Berlin Institute of Health, shared why tryptophan is her favorite metabolite:

“Tryptophan acts as a direct link between nutrition, the gut microbiome and human health. We’re only just beginning to understand all the roles that tryptophan and its metabolites have in the body… Although we think of serotonin as a neurotransmitter, it actually has a fairly important effect on gut motility. There’s increasing interest in how the gut and brain talk to each other. We don’t yet know the full role of tryptophan and its metabolites in this gut-brain axis, and how it’s impacting our health.”

Serotonin was long thought to be important only in the brain, but as noted by Kirwan, it plays a role throughout the body. It’s a key neurotransmitter at both ends of the gut-brain axis – the central nervous system and the gastrointestinal tract (O’Mahony et al. 2015).

Serotonin is sometimes referred to as the “happy hormone,” as low levels can result in low mood, poor sleep and depression. Research has shown that therapeutic targeting of gut microbiota may improve gut-brain axis disorders (Carpenter 2012). Gut microbiota appear to influence serotonergic signaling in the central nervous system, and alterations in the gut microbiome appear to overlap with changes in serotonergic signaling (O’Mahony et al. 2015).

However, there are mixed views on this subject. Serotonin produced in the gut does not cross the blood-brain barrier: it’s the serotonin synthesized from dietary tryptophan in brain cells that influences mood, depression and anxiety (Bektas et al. 2020). The main mediator of these effects would therefore be the serotonin-modulated ENS, rather than circulating serotonin.

Clinical trials on neurological and psychiatric disorders focus on increasing or reducing tryptophan levels, through supplementation or deprivation. A systematic review and meta-analysis of thirteen studies found a positive correlation between probiotics and kynurenine pathway metabolism, but limited evidence of an effect from prebiotics (Purton et al. 2021).

Tryptophan and cancer

Tryptophan has been shown to be a useful diagnostic marker for some cancers. For example, tryptophan fluorescence has been used to assess colonic neoplasms, while amino acid profiling and combined serum histidine and plasma tryptophan have been shown to facilitate the diagnosis of renal carcinoma (Friedman 2018).

Tryptophan metabolism has also been associated with tumor cell malignancy and restriction of antitumor immunity, though clinical trials targeting the tryptophan-kynurenine-aryl hydrocarbon receptor (AhR) axis with immunotherapy have been inconclusive (Peyraud et al. 2022).

Drug development in oncology mostly focuses on inhibiting enzymatic activity in the kynurenine pathway, for example, with IDO1 and TDO inhibitors.

Want to learn more? Watch the webinar (external link to youtube) on tryptophan metabolism or study tryptophan metabolism in your own samples.

Learn more about the roles of tryptophan in complex chronic diseases such as cancer, Alzheimer’s disease, depression, inflammatory bowel disease, multiple sclerosis and diabetes in our whitepaper “Complex chronic diseases have a common origin”.

References

Allen J. et al.: Post-epidemic eosinophilia myalgia syndrome associated with L-Tryptophan. (2011) Arthritis and Rheumatism | http://doi.org/10.1002/art.30514

Bektas A. et al.: Does Seratonin in the intestines make you happy? (2020) Turk Journal Gastroenterology | http://doi.org/10.5152/tjg.2020.19554

Carpenter S.: That gut feeling. (2012) Monitor on Psychology | https://www.apa.org/monitor/2012/09/gut-feeling

Dale H.: Frederick Gowland Hopkins 1861-1947 (1948) Obituary Notices of Fellows of the Royal Society | https://doi.org/10.1098/rsbm.1948.0022

Ellinger A. et al.: Uber syntetisch gewonnes tryptophan und einige seiner derivate. (1908) Hoppe-Selye’s Z Physiol Chemistry |

Friedman, M.: 2018. Analysis, Nutrition, and Health Benefits of Tryptophan. (2018) International Journal of Tryptophan Research | http://doi.org/10.1177/1178646918802282

Hopkins F.: Feeding experiments illustrating the importance of accessory factors in normal dietaries. (1912) The Journal of Physiology | https://doi.org/10.1113/jphysiol.1912.sp001524

Hopkins F. et al.: A contribution to the chemistry of proteids. (1901) The Journal of Physiology | https://doi.org/10.1113/jphysiol.1901.sp000880

Krishnan S. et al.: Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. (2018) Cell Reports | https://doi.org/10.1016/j.celrep.2018.03.109

O’Mahony S. et al.: Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. (2015) Behavioural Brain Research, | https://doi.org/10.1016/j.bbr.2014.07.027

Peyraud F. et al.: Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives. (2022) Frontiers in Immunology | https://doi.org/10.3389/fimmu.2022.807271

Purton T. et al.: Prebiotic and probiotic supplementation and the tryptophan-kynurenine pathway: A systematic review and meta analysis. (2021) Neuroscience & Biobehavioral Reviews | https://doi.org/10.1016/j.neubiorev.2020.12.026

Richard D. et al.: 2009. L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. (2009) International Journal of Tryptophan Research | http://doi.org/10.4137/ijtr.s2129

Taleb S.: Tryptophan Dietary Impacts Gut Barrier and Metabolic Diseases. (2019) Frontiers in Immunology | https://doi.org/10.3389/fimmu.2019.02113

Thomas T. et al.: COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. (2020) JCI Insight | https://doi.org/10.1172/jci.insight.140327

Urquhart J.: Lost City’ seabed rocks hold clues to Earth’s first amino acids. (2018) | Available at: https://www.chemistryworld.com/news/evidence-emerges-from-the-deep-of-earths-first-amino-acids-/3009746.article

Westbrook R. et al.: Kynurenines link chronic inflammation to functional decline and physical frailty. (2020) JCI Insight | https://doi.org/10.1172/jci.insight.136091

Irritable bowel syndrome (IBS) is a commonly diagnosed gastrointestinal disorder, with a global prevalence of 11%. It is characterized by a complex interplay of pathophysiological factors including genetics, nervous system and gut microbiota. Similarly, patients complaint about various symptoms like abdominal pain, bloating, diarrhea, cramps and constipation. In the absence of an established biomarker to distinguish these common symptoms from other gastrointestinal conditions, patients often undergo expensive and invasive investigations to exclude inflammatory organic causes.

A research group in Canada, led by Dr. Stephen Vanner, addressed this diagnostic challenge by looking for metabolic patterns that would differentiate IBS from other chronic functional gastrointestinal disorders.

Urinary metabolites of IBS patients were compared with those of healthy controls, and with those of patients with ulcerative colitis (UC) in remission. IBS could be clearly separated from UC by 14 metabolites containing amino acids and organic acids. Notably, the established predictive model showed very high quality with an area under the curve of 0.99. Furthermore, some metabolites, including histamine, correlated with the severity of IBS. The metabolic pattern also separated IBS patients from healthy controls. Differences in organic acids and lipid levels, which might be related to dietary intake and changes in the gut microbiota were revealed. Interestingly, different IBS subtypes also showed indications that dietary patterns and microbiota could influence disease phenotype. However, these differences were not sufficient to distinguish between the forms of IBS.

To sum up, this study paves the way for a non-invasive diagnosis of IBS by distinct metabolic patterns. Furthermore, it gives insights into the pathophysiology of IBS, which could point to promising treatment options for IBS. If. It is suggested that differences in the metabolic profiles of IBS in comparison to UC patients and healthy controls might derive from alterations in the gut microbiota. Hence, targeting microbial compositions by dietary or therapeutical interventions might have potential for treatment of IBS.

If you are interested in biomarker discovery in easy accessible biological materials using metabolomics, please contact us.

Keshteli AH, Madsen KL, Mandal R, Boeckxstaens GE, Bercik P, Palma G de et al.: Comparison of the metabolomic profiles of irritable bowel syndrome patients with ulcerative colitis patients and healthy controls: new insights into pathophysiology and potential biomarkers. (2019) Alimentary Pharmacology and Therapeutics | https://doi.org/10.1111/apt.15141

Gallstones are the most prevalent disease of the gallbladder and one of the leading causes of hospitalization worldwide. If the limit of solubilization capacity of the bile is reached, precipitation of bile components like cholesterol and calcium salts to crystals occurs. However, the factors and mechanism leading to the aggregation of these precipitations to larger gallstones are still not completely understood.

Prof. Martin Herrmann and his team from the University Hospital Erlangen in Germany revealed that chromatin, externalized by certain immune cells, plays a role in the aggregation of bile precipitations to gallstones.

Analysis of gallstones showed the presence of neutrophil-derived enzymes and extracellular DNA, indicating the interaction of gallstone components and neutrophil extracellular traps (NETs). The shell-like structure of gallstones suggests episodic growth, where calcium and cholesterol crystals aggregate during NET formation. Based on the fact that macropinocytosis is a key mechanism of NET formation, crystal uptake could be shown to cause lysosomal leakage, which results in decondensation and externalization of neutrophil DNA.

Furthermore, in vivo experiments in mice showed that deficiency in neutrophil activity and chromatin decondensation impairs the development of gallstones, while the bile composition was not affected. Importantly, pharmacological targeting of neutrophil activity or NET formation by small molecules blocked gallstone formation and growth.

This study provides profound evidence that gallstone development can be reduced through pharmacological interference with neutrophils and the corresponding NET formation. The findings pave the way for promising therapeutic approaches to prevent gallstone formation and growth.

If you are interested in exploring cholesterol metabolism and bile acid composition in health and disease, take a look at our quantitative metabolomics solutions.

Muñoz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N, Krenn V, Biermann M, Podolska MJ, Hahn J, Knopf J, Maueröder C, Paryzhak S, Dumych T, Zhao Y, Neurath MF, Hoffmann MH, Fuchs TA, Leppkes M, Schett G, Herrmann M: Neutrophil Extracellular Traps Initiate Gallstone Formation. (2019) Immunity | https://doi.org/10.1016/j.immuni.2019.07.002