Microbial regulation of host nutrient metabolism

Efficient digestion and absorption of dietary nutrients are central to metabolic health, yet the cellular and molecular mechanisms governing these processes – particularly in the small intestine, where most nutrient assimilation occurs – remain incompletely defined. Although microbial fermentation in the colon has been well characterized, how the microbiome shapes small intestinal nutrient handling has been less clear. We first made the landmark discovery that the microbiome stimulates IEC absorption of dietary fats and their subsequent metabolism in the liver, providing new mechanistic insight into how microbiome-diet interactions can regulate host energy balance. Notably, these results from the zebrafish model were subsequently validated in mice, confirming that this important role for microbiome in promoting dietary fat absorption and metabolism is conserved across vertebrate taxa. In mice, we found that this microbial effect is coupled to suppression of fatty acid oxidation and coordinated changes in HNF4A activity and enhancer regulation in IECs, suggesting that microbes enhance net lipid absorption by limiting epithelial lipid catabolism. We further showed that zebrafish possess a distinct ileal region expressing conserved bile salt transport genes and discovered that their bile salts are essential for ileal epithelial differentiation. Extending beyond absorption to nutrient sensing, we also established zebrafish as a model for enteroendocrine cell (EEC) biology and uncovered a microbiome-dependent adaptation to high-fat diet consumption (“EEC silencing”) as well as a conserved EEC–gut–brain signaling axis responsive to specific bacterial metabolites. Our complementary developmental and endocrine analyses have defined peptide hormone diversity, resolved at least six EEC subtypes, and identified transient precursor states within the lineage. Together, this work delineates conserved mechanisms by which the microbiome regulates intestinal lipid assimilation, bile biology, and epithelial nutrient sensing and endocrinology to shape systemic metabolic homeostasis.