The intestinal epithelium is a critical mucosal barrier that confines the gut microbiota to the lumen, preventing these generally beneficial microbes from invading host tissues and triggering overt inflammation. While gut homeostasis requires this physical separation of the microbiota and host, it also depends on symbiotic interactions between them, which often occur through small molecule metabolites. For instance, by converting indigestible fiber into short-chain fatty acids (SCFA), the microbiota provides colonic epithelial cells with a fuel source to power fatty acid oxidation (FAO) and energy production. Accordingly, intestinal tissues from germ-free mice show signs of energy deprivation, and the clinical significance of this metabolic integration is evident from studies correlating inflammatory bowel disease (IBD) with impaired FAO and changes in microbiota composition. However, the mechanisms by which these alterations could contribute to IBD remain unclear, highlighting the need to understand the pathways linking epithelial cell metabolism with microbial metabolism and whether disruptions in this symbiosis could promote inflammation. In a recent study to investigate metabolic contributions from the microbiota to the host, we performed stable isotope tracing in a mouse model and found that acetylated histones and numerous metabolites in epithelial cells contain microbiota-derived carbon. Treatment with DSS, a chemical irritant that induces inflammation, suppressed the isotopic labeling of molecules bearing fatty acid chains, coinciding with shifts in microbiota composition and decreased expression of genes related to FAO. In ongoing work, we are employing cell and organoid models to trace the anabolic and catabolic pathways by which epithelial cells metabolize microbiota-derived carbon. Overall, we aim to generate mechanistic insight into how metabolic interactions between the gut microbiota and host promote tissue homeostasis and how a disruption in this symbiosis may contribute to the development of IBD.

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