期刊
FASEB JOURNAL
卷 34, 期 5, 页码 7089-7102出版社
WILEY
DOI: 10.1096/fj.201902687R
关键词
bile acids; intestinal permeability; microbiome; NAFLD; NASH; tight junction
资金
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK072564, DK061379] Funding Source: Medline
- NIAAA NIH HHS [F31 AA024960, F31AA024960] Funding Source: Medline
- NIDDK NIH HHS [P30 DK034933, K01 DK110264, R01 DK072564, P30 DK120531, R01 DK061379] Funding Source: Medline
There is compelling evidence implicating intestinal permeability in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain poorly understood. Here we examined the role of bile acids (BA) in western diet (WD)-induced loss of colonic epithelial barrier (CEB) function in mice with a genetic impairment in intestinal epithelial barrier function, junctional adhesion molecule A knockout mice, F11r(-/-). WD-fed knockout mice developed severe NASH, which was associated with increased BA concentration in the cecum and loss of CEB function. Analysis of cecal BA composition revealed selective increases in primary unconjugated BAs in the WD-fed mice, which correlated with increased abundance of microbial taxa linked to BA metabolism. In vitro permeability assays revealed that chenodeoxycholic acid (CDCA), which was elevated in the cecum of WD-fed mice, increased paracellular permeability, while the BA-binding resin sevelamer hydrochloride protected against CDCA-induced loss of barrier function. Sequestration of intestinal BAs by in vivo delivery of sevelamer to WD-fed knockout mice attenuated colonic mucosal inflammation and improved CEB. Sevelamer also reduced hepatic inflammation and fibrosis, and improved metabolic derangements associated with NASH. Collectively, these findings highlight a hitherto unappreciated role for BAs in WD-induced impairment of the intestinal epithelial barrier in NASH.
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