Dietary fat alters goblet cell function and microbial bile acid metabolism to promote intestinal lipid absorption in mice.

Dietary fat reshapes host-microbiota interactions, yet the upstream events that mediate overnutrition-driven microbiome alterations and metabolic dysfunction remain unclear. Here we compared mouse models of diet-induced and genetic obesity using multi-omics to identify the colonic mucus niche as an early, diet-sensitive driver of metabolic dysfunction. Excessive dietary lipids impaired glutamine metabolism and redox homeostasis in goblet cells, thinning the mucus layer and depleting the mucus-adapted symbiont Akkermansia muciniphila while expanding the bile-acid-transforming bacterium Clostridium scindens. Altered bile acid composition along the enterohepatic axis activates FXR-PLIN2 signalling in the small intestine and increases fat absorption. In parallel, enterocytes upregulate the PPARα-dependent uptake pathway that supports luminal lipid entry. Supplementation with glutamine restored goblet cell function and the gut microbiota-derived bile acid pool, thereby reducing intestinal FXR activation and lipid uptake. These findings reveal that dietary fat impairs colonic goblet cell function and reshapes microbial bile acid metabolism, influencing small-intestinal fat absorption.