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The Microbiome and Metabolomics
The microbiome refers to the collection of bacteria that colonize the gut. These microorganisms affect not only the chemistry of the gut, but also the chemistry of other parts of the body. The gut microbiome is thought to influence digestion, development of the immune system, and the immune response against pathogens. Disruption of the microbiome has been associated with increased risk of type II diabetes and may contribute to the pathology of various autoimmune and neurodegenerative diseases. Perhaps more than anything, these findings demonstrate the complexity of the relationship between the gut microbiome and human health and underscore the need to better understand it.
Mass spectrometry metabolomics is one of the key technologies to detect and identify the small molecules produced by the human microbiome, and to understand the functional role of these microbial metabolites. Although sequencing provides insights into the microbiota that are present, metabolomics is a direct readout of the function of a system, making the metabolome the closest reflection of the real-time phenotype, and subsequently, an invaluable tool for advancing our understanding of the gut microbiome and its role in human health and disease.
Gain Deep Phenotypic Insight into the Microbiome Through Metabolomic Profiling
Targeted or shotgun 16S rRNA sequencing is typically used to identify the bacteria species and strains in the gut microbiome. However, this only reveals part of the picture. As key drivers of metabolism, metabolites not only receive inputs from the genome, proteome, and environment, they also represent the terminal step of biological processes, which makes them the closest reflection of an organism’s real-time physiologic status. Given this interconnectivity, evaluating metabolomics alongside other omics is essential to gaining a comprehensive understanding of the gut microbiome and its effects on human physiology. Here, we discuss several case studies that show the benefit of evaluating these datasets alongside one another.
Fetal and Maternal Health
It is thought that exposure to a mother’s diet in utero can impact the composition of the offspring’s gut microbiome and subsequently affect metabolic health into adulthood. However, this hypothesis has not been thoroughly tested. To investigate this idea, one research team fed groups of female mice the following diets from one month before pregnancy up to weaning (postnatal day 21): 1) low sugar, low fat (control), 2) high sugar, low fat, 3) high fat, 4) high fat + flaxseed oil. After weaning, they placed offspring on a low fat, low sugar diet until adulthood. 16S sequencing of fecal DNA samples from mothers at pregnancy day 10 and from offspring at postnatal day 21 and postnatal day 91 was performed. In utero and early life exposure to flaxseed oil was associated with enriched levels of 4-hydroxycinnamate sulfate, catechol sulfate, hippurate, and indolelactate compared to offspring of high fat diet mothers. A maternal high fat diet resulted in long-term metabolic and gut microbiome programming in offspring, which increased the amount of visceral adipose tissue (VAT), and associated inflammation and fibrosis. These traits were not observed in offspring of high fat + flaxseed oil diet mothers. Hippurate supplementation reduced VAT fibrosis. Altogether, these data suggest that detrimental effects of early life exposure to high fat diet can be attenuated by supplementing the maternal diet with omega-3 polyunsaturated fatty acids. Future research should delve deeper into the mechanisms linking maternal nutrition, gut microbiome alterations, and metabolic health. Expanding this work to human models and exploring therapeutic avenues, such as microbial metabolite supplementation, could open new strategies for preventing obesity and metabolic syndrome starting from gestational and early-life stages.
Characterizing the Response to Therapy
The paper studies the effects of statin therapy, which is used to lower cholesterol and reduce the risk of atherosclerotic cardiovascular disease. Statins are one of the most prescribed medications worldwide, and although they effectively reduce the risk of cardiovascular disease for many, they are associated with disrupted metabolic control and increased risk of type II diabetes for a subset of patients. To test the hypothesis that the gut microbiome may play a role in modifying patients’ response to statins, one research group assessed the microbiome composition in two independent cohorts; one healthy cohort that included statin users and non-users, and a cohort of individuals at various stages of cardiometabolic disease progression. They profiled gut microbiota by performing 16S rRNA amplicon and shotgun metagenomic sequencing on stool samples collected from the healthy cohort. Then they identified associations between microbiome features and markers of on-target and adverse effects of statins using blood metabolomics profiling, clinical laboratory tests, and high-level statistical analyses. Heterogeneity in statin responses was consistently associated with variation in the gut microbiome across both cohorts. A gut environment with low bacteria diversity and high levels of Bacteroides was associated with more intense statin responses, both on-target and adverse effects. These results were validated in the cardiometabolic disease cohort. This study shows that monitoring the microbiome may help inform clinical decision making based on the patient’s likely response to statin therapy. It also underscores the insight into the microbiome that metabolomics can provide as a complementary tool to other omics techniques. Moving forward, this research paves the way for more precise approaches in cardiovascular disease treatment, where gut microbiome composition could be used to predict and optimize patient outcomes, reducing trial-and-error in drug prescribing and enhancing long-term health. Future research should focus on clinical interventions that modify the gut microbiome to improve statin efficacy and minimize adverse effects.
Wilmanski, T. et. al. Heterogeneity in statin responses explained by variation in the human gut microbiome. Med. 2022 Jun 10;3(6): 388-405. PMID: 35690059.
Characterizing Mechanisms of Disease Pathology
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder and the primary cause of dementia in older adults, affecting over 40 million people globally. Bile acids (BAs) are products of cholesterol metabolism that have important signaling functions. They are produced in the liver and further metabolized by gut bacteria. The microbiome has been implicated in neurodegenerative disorders, and particularly in AD, bile acids seem to be dysregulated, suggesting that the microbiome may play a role in AD pathology. To test this hypothesis, one research group used targeted metabolomics to measure serum levels of 15 primary and secondary BAs in a large cohort of persons with AD, mild cognitive impairment, and age matched healthy individuals. They identified associations between BA profiles and diagnosis, cognition, and AD-related genetic variants. AD patients showed significantly lower amounts of the primary BA cholic acid and increased amounts of the bacterially produced secondary BA, deoxycholic acid and its conjugated forms, glycine and taurine. The ratio of deoxycholic acid and cholic acid was strongly associated with cognitive decline, showing compromised cholic acid metabolism. Several variants of genes related to the immune response that have been implicated in AD were also associated with altered BA profiles. With the help of metabolomics, this study suggests that gut dysbiosis may play a role in AD pathology. These findings call for further research into the therapeutic potential of targeting the gut microbiome and bile acid signaling pathways. Future studies should explore the mechanisms by which microbial and metabolic alterations influence neurodegeneration, examine the causality of these associations, and investigate new treatment avenues aimed at restoring metabolic and microbial balance in AD patients.
Mahmoudian Dehkorki, S. et. al. Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-An emerging role for gut microbiome Alzheimers Dement. 2019 Jan;15(1):76-92. PMID: 30337151
Metabolomics Applications for Microbiome Research
- EBiomarker discovery
- EMechanistic studies
- EDisease pathology and phenotypes
- EResponse to therapy
- EAssociation studies
- EDietary intervention studies
- EFetal and maternal health
- ESignal Transduction
- ETherapeutic modulation of the microbiome
“Mass spectrometry-based metabolomics is one of the key technologies to detect and identify the small molecules produced by the human microbiome, and to understand the functional role of these microbial metabolites.”
Mass spectrometry-based metabolomics in microbiome investigations. Nat Rev Microbiol. 2022;20(3):143-160. doi:10.1038/s41579-021-00621-9
Gut Microbiome Composition Is Associated with Future Development of Crohn’s Disease
Crohn’s disease (CD), a type of inflammatory bowel disease characterized by chronic, relapsing inflammation of the intestine. Although the exact cause of CD is not known, current theories suggest that microbial or environmental factors may trigger gut inflammation in genetically susceptible individuals. This inflammation can lead to long-term intestinal damage. Although the cause of Crohn’s disease (CD) is currently unknown, a growing body of work suggests that microbial or environmental factors induce chronic gut inflammation in genetically susceptible individuals. The composition of the gut microbiome is altered in persons with CD. However, it is unknown if these changes are caused by the onset of disease or are the result of general inflammation and/or drug treatment.
To identify the gut microbiome composition that precedes the onset of CD and test the extent to which the microbiome can predict the risk of developing CD, one research group performed a comprehensive evaluation of the gut microbiomes of a large cohort of healthy first-degree relatives of CD patients. Those in the cohort either eventually developed CD or remained healthy. This study compared the microbiomes of those who developed CD to those who did not. They performed S16 rRNA sequencing, untargeted metabolomics profiling, and assayed biomarkers of gut inflammation then applied a machine learning approach to these datasets to derive a microbiome risk score.
When tested in a validation cohort the risk score identified individuals that developed CD up to 5 years before disease onset (AUC 0.67). The five bacterial taxa that contributed the most to the microbiome risk score were Ruminococcus torques, Blautia, Colidextribacter, Roseburia, and a genus-level group from Oscillospiraceae. Pathway analysis showed the microbiome risk score associated most significantly with the reductive acetyl coenzyme A pathway, and biosynthesis of various fatty acids and amino acids. Altogether, this study demonstrates that gut microbiome composition is associated with future onset of CD, and suggests that the microbiome is a potential contributor to the pathogenesis of CD. Understanding biomarkers associated with the risk of CD and their biology as they relate to disease pathogenesis will be important to developing novel preventative strategies. Future research should explore the integration of microbiome-based risk scores with other biomarkers, genetic data, and lifestyle factors to enhance predictive accuracy. Ultimately, this work paves the way for potential early interventions, such as dietary modifications or microbiota-targeted therapies, to delay or even prevent the onset of Crohn’s disease in at-risk populations.
Garay, J. et. al. Gut microbiome composition is associated with future onset of Crohn’s disease in healthy first-degree relatives. Gastroenterology. 2023 sep;165(3):670-681. PMID: 37263307
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