Intestinal Dysbiosis Caused by Epithelial Fabp6 Gene Disruption Exacerbates Gut Inflammatory Disease

Abstract

Ileal lipid binding protein (Ilbp), encoded by Fabp6 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 Fabp6 gene knockout (Fabp6 degrees IEC), exacerbates dextran sulfate sodium (DSS)-induced gut inflammation. Fecal microbiota transplantation from Fabp6 degrees IEC mice to germ free recipient mice replicated the adverse effects observed in Fabp6 degrees IEC mice, which were mitigated when these mice were co-housed with control (Fabp6f/f) mice. Metagenomic analysis identified Ligilactobacillus murinus as a primarily diminished strain in Fabp6 degrees IEC mice. Oral administration of L. murinus isolated from feces of Fabp6f/f mice ameliorated DSS-induced colitis in Fabp6 degrees IEC mice by restoring epithelial barrier integrity and lowering pro-inflammatory cytokines IL-1(3, IL-6 and TNF-a. Furthermore, daily administration of taurodeoxycholic acid-one of the BAs reduced in Fabp6 degrees IEC mice and that promotes the growth of L. murinus in an in vitro 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 Fabp6 deletion leads to gut dysbiosis, predisposing the host to inflammatory disease.