Metabolomics India 2023

In spite of substantial research funding over the past three decades, the prevalence of complex chronic diseases continues to rise, while identifying early markers, effective treatments, and preventive strategies remains an ongoing challenge. This talk provides a new perspective on complex chronic diseases traditionally studied separately: Alzheimer’s, depression, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, and cancers, by examining them through the prism of metabolomics. The models shown of priming for complex chronic diseases confirm the significance of the gut microbiome for many conditions, reveal new potential druggable targets, and provide a proof-of-principle for the broader use of metabolomics in the study of complex chronic diseases.

Abstract will follow soon

Our study delves into the captivating relationship between neurodegeneration and cancer, with a specific focus on the enigmatic ferroptosis process driven by lipid peroxidation and oxidative stress. We shed light on the multifaceted role of the amyloid precursor protein (APP) beyond Alzheimer’s disease, as oncogene-mediated malignant transformation elevates APP production in cancer cells, granting them survival advantages by evading ferroptosis. Elevated APP levels significantly correlate with adverse outcomes in aggressive tumor types. At the core of the mechanistic puzzle lies the intricate interplay between APP, heme oxygenase-1 (HO-1), and heme levels. The loss of APP triggers HO-1 activation through mitochondrial translocation, leading to the accumulation of the heme-regulated transcription factor BACH1. BACH1 emerges as a master regulator of ferroptosis, orchestrating a multifaceted defense mechanism by dampening cellular responses to oxidative stress and promoting the synthesis of polyunsaturated fatty acids (PUFAs), which provoke ferroptotic cell death. Interestingly, this mechanism exhibits dual effects, as it effectively suppresses tumor growth and metastasis while concurrently exacerbating ischemic injury in neuronal cells. Nevertheless, our study unveils an exciting ray of hope – the potential therapeutic avenue of pharmacologically targeting BACH1. Such intervention potently enhances neuronal ferroptosis inhibition, offering promising prospects for ameliorating outcomes in ischemic stroke. In conclusion, our study provides novel insights into the complex interplay of ferroptosis in both cancer and neurodegenerative diseases. The pivotal roles of APP, heme oxygenase-1, and heme levels illuminate the intricate dynamics governing BACH1 and ferroptosis regulation. APP- and BACH1-dependent pathways emerge as compelling therapeutic targets for manipulating ferroptosis in cancer and mitigating neuronal ischemic injury, paving the way for future interventions to combat these challenging conditions

In the past few decades, there have been enormous advancements in omics technology. Understanding the metabolome enhances our comprehensive understanding of cellular processes and metabolome reprogramming. Revolution in High Resolution Mass Spectrometry (HRMS) has enabled the researchers to detect thousands of metabolites and their quantification simultaneously. These metabolites play a key role in understanding an individual physiological status, disease progression, drug treatments, and pathobiology, thus helping us in identification of perturbed pathways, disease biomarkers, monitoring treatment responses etc. Procuring the clinical samples, sample preparation, metabolite extraction and profiling, LCMS based method optimization, data analysis and biological interpretation is quite challenging and plays crucial factor in batch effect, stability, selectivity, reproducibility and versatility of experimental outcomes. In our Proteomics Lab, IITB we perform metabolomics studies on various brain tumors such as Meningioma and Pituitary Adenomas and also worked on other human diseases such as Chronic obstructive pulmonary disease (COPD) using vibration spectroscopy (Raman and ATR-FTIR) followed by Orbitrap based HRMS metabolic profiling.

In recent years, groundbreaking advances in the fields of metabolomics and microbiome research have provided invaluable insights into the intricate mechanisms underlying disease pathogenesis. Metabolomics, the systematic study of small molecule metabolites, and microbiome analysis, which explores the complex ecosystem of microorganisms inhabiting the human body, have emerged as powerful tools to unravel the multifaceted interactions between host and microbial metabolism. This interdisciplinary approach has revolutionized our understanding of the role played by microbial communities In in health and disease. Metabolomics, through its ability to comprehensively analyze the dynamic metabolite profiles in biological systems, offers a unique perspective on the intricate interplay between host physiology and the microbial environment. By characterizing the specific metabolic pathways activated or perturbed during disease states, metabolomics provides crucial insights into potential biomarkers for early disease detection and targeted therapies. Concurrently, the human microbiome, encompassing an astounding array of bacteria, viruses, fungi, and other microorganisms, has emerged as a key determinant of human health and disease. The symbiotic relationship between the host and the microbiome profoundly influences various physiological processes, including immune function, nutrient absorption, and drug metabolism. This talk delves into the synergistic convergence of metabolomics and microbiome research and highlights their collaborative impact on disease pathogenesis. By shedding light on the intricate interactions between host metabolism and the microbiome, this emerging field of study offers a promising avenue to elucidate novel therapeutic targets and ultimately improve health outcomes for a diverse range of diseases.

Type 2 Diabetes mellitus (T2DM) is a progressive metabolic disorder that can develop into life-threatening complications such as diabetes-associated kidney (DKD) and cardiovascular (DCD) diseases. Although several metabolomics-based studies have been reported on T2DM, no new blood tests have been developed for the severity of diabetes or its complications. Here we present our results with metabolite signatures as biomarker rather than individual metabolites. Blood samples were drawn from a cohort of Indian patients from four groups: healthy volunteers, and the T2DM, DKD, and DCD. The study was approved by the Institute Ethics Committee. Untargeted metabolomics was performed using LCMS and GCMS and the data was processed using our own, AI/ML-based software platform. We identified over 200 metabolites that were significantly altered in T2DM, DKD, and DCD conditions compared to the healthy group. Metabolites from different classes including acylcarnitines, glucogenic amino acids, cholines, fatty acids, bile acids and several uremic toxins were significantly altered in T2DM, DKD and DCD patients compared to the healthy group. Importantly, a subset of patients showed significantly greater change in a number of metabolites, which led us to the analysis of metabolite signatures. To exemplify, the signature of uremic toxins was dramatically altered in a subset of DKD patients who had an advanced disease. Further, the signature of uremic toxins was also altered in a subset of T2DM patients, who should be monitored for asymptomatic, early stage DKD. Another important signature was that of acyl carnitines, many of which get downregulated in a subset of diabetics, which may indicate possible mitochondrial dysfunction. Further, sugars other than glucose show alterations, which may have implications in certain complications of diabetes. We will also discuss our LCMS data analysis pipeline that makes use of deep neural networks to reduce noise, redundant features and provide clean, reliable and quantifiable data thus resulting in significant saving of time required for data analysis.

The SARS-CoV-2 is a single-stranded RNA virus that enters the human system through the nasal and buccal cavity region and interacts with the oral microbiome. The human oral microbiome consists of several bacterial, viral, and fungal species and the interaction between these microbial species and the Covid-19 virus needs to be studied and analyzed to understand the effects of the virus on the microbial community. Our hypothesis states that SARS-CoV-2 enters the oral cavity and interacts with several microbial species, which in turn creates dysbiosis in the microbial ecosystem. This interaction between the microbes and the Covid virus may also be very specific in nature resulting in elevated symptoms in chronic patients of specific age groups.

In the domain of systems medicine and biotechnology, elucidating the genotype-phenotype interplay relies on a genome-scale metabolic framework. Genome-scale Metabolic models (GEMs) serve as foundational tools, enabling comprehensive analyses of genetic perturbations, metabolic engineering, and disease mechanisms. Integrating omics data into GEMs enhances predictive accuracy, while innovative approaches like the translation of transcription data into biologically relevant gene sets further refine metabolic predictions. This study leverages context-specific GEMs to illuminate the intricate connections between genotype and phenotype in diverse applications. Machine learning-driven classification based on unique metabolic fingerprints reveals distinct features across applications, shedding light on the nuanced landscape of systems medicine and biotechnology. These insights bridge genetic and phenotypic realms, paving the way for precision interventions and transformative advancements.

Metabolomics as a holistic analysis of metabolites provides functional insights into biological systems including dynamic description signatures useful for the risk stratification, early diagnostics, therapy monitoring or theranostics. Both in health and disease metabolomics goes beyond genetic coding further to the impact of life style, environment and interventions on metabolic pathways. Key elements for good metabolomics study will be presented.