Intestinal Dysbiosis Caused by Epithelial <i>Fabp6</i> Gene Disruption Exacerbates Gut Inflammatory Disease

Ileal lipid binding protein (Ilbp), encoded by <i>Fabp6</i> gene, plays a critical role in intracellular transport of bile acids (BAs) from apical to basolateral side of ileal enterocytes, maintaining BA homeostasis within enterohepatic circulation. However, pathophysiological consequences of Ilbp deficiency remain largely unexplored. Here, we demonstrate that disruption of BA balance, caused by intestinal epithelial cell (IEC)-specific <i>Fabp6</i> gene knockout (<i>Fabp6</i> ^ΔIEC), exacerbates dextran sulfate sodium (DSS)-induced gut inflammation. Fecal microbiota transplantation from <i>Fabp6</i> ^ΔIEC mice to germ free recipient mice replicated the adverse effects observed in <i>Fabp6</i> ^ΔIEC mice, which were mitigated when these mice were co-housed with control (<i>Fabp6</i> ^f/f) mice. Metagenomic analysis identified <i>Ligilactobacillus murinus</i> as a primarily diminished strain in <i>Fabp6</i> ^ΔIEC mice. Oral administration of <i>L. murinus</i> isolated from feces of <i>Fabp6</i> ^f/f mice ameliorated DSS-induced colitis in <i>Fabp6</i> ^ΔIEC mice by restoring epithelial barrier integrity and lowering pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Furthermore, daily administration of taurodeoxycholic acid-one of the BAs reduced in <i>Fabp6</i> ^ΔIEC mice and that promotes the growth of <i>L. murinus</i> in an <i>in vitro</i> growth assay-also exhibited a protective effect against DSS-induced colitis through a similar mechanism. These findings suggest that deficiency of specific BAs due to epithelial <i>Fabp6</i> deletion leads to gut dysbiosis, predisposing the host to inflammatory disease.