METABOLOMICS DISTINGUISHES DIET- AND MICROBIOME-DERIVED METABOLITES DURING EPISODES OF INFLAMMATORY BOWEL DISEASE DYSBIOSIS

Gut microbiome dysbiosis, defined as departure from community configurations observed in healthy control subjects, is a characteristic of some but not all patients with Inflammatory Bowel Disease patients. Metabolomic signatures of dysbiosis are more pronounced than taxonomic differences in the gut microbiome, suggesting that key metabolic roles of the gut microbiome may be disrupted in the setting of dysbiosis.

In Phase 1, we analyzed fecal metabolomic data from a controlled feeding and gut microbiome depletion study (Tanes, C. et al. Cell Host & Microbe 2021) to differentiate diet-derived fecal metabolites from those produced or consumed by the gut microbiome. Of 476 named metabolites, we identified 75 metabolites produced by the microbiome and 91 metabolites consumed by the microbiome, controlling for a false discovery rate of 10% (Figure 1). The set of microbiome-derived metabolites included widely recognized compounds such as butyrate and lithocholate, but included other molecules, such as benzoate, that are not normally considered to be microbial products in the gut. In the context of a depleted gut microbiome, we identified 56 metabolites derived from a standardized omnivore diet relative to exclusive enteral nutrition. These included a variety of carnitines and nicotinate, a B vitamin.

In Phase 2, we applied our metabolite classification results to data from the Integrative Human Microbiome Project (HMP2), to determine the diet- and microbiome-derived metabolites that were associated with episodes of dysbiosis (Figure 2). Of the metabolites linked to the microbiome in Phase 1, 74% were significantly increased or decreased in microbiome samples classified as dysbiotic relative to healthy controls. A majority of the diet-derived gut metabolites also differed in dysbiotic samples, including 8 metabolites that our analysis did not categorize as substrates or products of the microbiome.

In total, our comprehensive analysis of untargeted fecal metabolomics data across two studies revealed diet- and microbiome-derived metabolites associated with dysbiosis. Our results both reinforce our current understanding of the biological roles of many gut metabolites and offer an opportunity to re-frame our understanding of others. Future work will focus on identifying the microbes driving variation among dysbiosis-associated metabolites and quantifying the metabolomic consequences of dietary choices by patients with inflammatory bowel disease.