Inhibition of oxygen-mediated opportunistic bacteria overgrowth in the ileum alleviates excessive fatty acid absorption against a high-fat diet

High-fat diet-induced gut microbiota disorder leads to excessive fat absorption, especially in the lower part of the small intestine. A critical but unclear aspect is how the interactions between microbial communities and fat absorption. Using a mouse model, we show that prolonged high-fat intake is linked to increased luminal oxygen bioavailability, promoting the overgrowth of oxygen-mediated opportunistic bacteria ( Staphylococcus xylosus ) in the small intestine. S. xylosus effectively produces a saturated medium-chain fatty acid (dodecanoic acid) by its substrate-specific Acyl-CoA thioesterase (ACOT). Moreover, this microbe-derived dodecanoic acid (DA) shows an appropriate amount for activating the intestinal PPARα-CD36 signaling, enhancing the fatty acid uptake. Interestingly, we also show that avenanthramide B (AVN B), a novel antioxidant derived from oat, increases ileal epithelial hypoxia, and selectively inhibits S. xylosus proliferation. This alleviates excessive fat absorption, providing an alternative dietary intervention for treating obesity.