Metabolomics Consortium Collaborative Webinar Series

Understanding the chemical biology of the gut-liver axis with metabolomics

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Speakers

The vast number of microbes (10 to 100 trillion) that comprise the mammalian microbiota serves numerous beneficial

functions for the host that includes stimulation of immune development and competitive exclusion of pathogenic

microorganisms. Exogenously administered viable bacteria –probiotics- can dampen inflammation, improve barrier function

and promote reparative responses in vitro, and have shown promise as therapy in inflammatory and developmental

disorders of the intestinal tract. Abnormalities of the microbiota are associated with inflammatory bowel disease (IBD) and

other allergic, systemic immune, and infectious disorders (e.g., asthma, juvenile-onset diabetes, multiple sclerosis) and

metabolic disorders (adult-onset diabetes, nonalcoholic steatohepatitis, and obesity). Thus, there is an increasing need to

understand the mechanistic basis for microbiota in human disease. High throughput sequencing platforms allow

species-level identification of complex communities associated with clinical phenotypes but do not provide insight into

mechanisms by which bacteria can influence physiological and pathological processes. Advances in metabolomic analyses

have enabled considerable progress in the study of host-microbial interactions.  In our collaborations, we identified a

small molecule activator of the Nrf2 liver antioxidant system, 5-methoxyindoleacetic acid, is produced by human commensal

bacteria and protects against oxidative stress (1).  In an ongoing untargeted LC-MS analysis of hepatic tissue in germ-free

and conventionalized animals, we identified delta-valerobetaine (VB) as the top microbial metabolite present in liver and liver

mitochondria.  VB was found to decrease cellular carnitine, inhibit mitochondrial fatty acid oxidation, and increased central

adiposity in mice. VB was also found to be elevated with obesity in humans.   These studies illustrate the considerable value

of metabolomics to complement genetic and molecular methods to address mechanisms underlying human health and disease.