Bile acid toxicity in Paneth cells contributes to gut dysbiosis induced by high-fat feeding.

Hui Zhou,Jun Gao,Allen Lee,Chung Owyang,Guanpo Zhang,Merritt Gillilland,Ji-Yao Li,Xianjun Xu,Shi-Yi Zhou

doi:10.1172/jci.insight.138881

Abstract

High-fat feeding (HFF) leads to gut dysbiosis through unclear mechanisms. We hypothesize that bile acids secreted in response to high-fat diets (HFDs) may act on intestinal Paneth cells, leading to gut dysbiosis. We found that HFF resulted in widespread taxonomic shifts in the bacteria of the ileal mucosa, characterized by depletion of Lactobacillus and enrichment of Akkermansia muciniphila, Clostridium XIVa, Ruminococcaceae, and Lachnospiraceae, which were prevented by the bile acid binder cholestyramine. Immunohistochemistry and in situ hybridization studies showed that G protein–coupled bile acid receptor (TGR5) expressed in Paneth cells was upregulated in the rats fed HFD or normal chow supplemented with cholic acid. This was accompanied by decreased lysozyme+ Paneth cells and α-defensin 5 and 6 and increased expression of XBP-1. Pretreatment with ER stress inhibitor 4PBA or with cholestyramine prevented these changes. Ileal explants incubated with deoxycholic acid or cholic acid caused a decrease in α-defensin 5 and 6 and an increase in XBP-1, which was prevented by TGR5 antibody or 4PBA. In conclusion, this is the first demonstration to our knowledge that TGR5 is expressed in Paneth cells. HFF resulted in increased bile acid secretion and upregulation of TGR5 expression in Paneth cells. Bile acid toxicity in Paneth cells contributes to gut dysbiosis induced by HFF.

Highlights

Chronic high-fat feeding (HFF) may induce gut dysbiosis and alter host homeostasis, resulting in mucosal inflammation and metabolic endotoxemia [1,2,3]
To provide direct evidence that bile acids induce damage in Paneth cells, we showed that there was a decrease in Defa5 and Defa6 gene expression and an increase in X-box–binding protein 1 (XBP-1) gene expression in whole-mount ileal tissue incubated with deoxycholic acid (DCA) (100 μM) (Figure 4A) or CA (100 μM) (Figure 4B) for 24 hours
We demonstrated that TGR5 receptors are expressed by Paneth cells in intestinal ileal crypts

Summary

Introduction

Chronic high-fat feeding (HFF) may induce gut dysbiosis and alter host homeostasis, resulting in mucosal inflammation and metabolic endotoxemia [1,2,3]. In addition to the direct antimicrobial actions, we explored other mechanisms by which bile acids may affect host factors and alter the gut bacterial composition Both primary and secondary bile acids exert their effects by activating nuclear [15] and plasma membrane receptors [16, 17]. We hypothesis that TGR5 receptors are present in Paneth cells This may provide a mechanism by which bile acids regulate intestinal immune function. Zheng et al reported that a HFD caused rapid and significant increases in the intestinal bile acid pool, accompanied by an alteration in bacterial composition [7] This raises the possibility that, in addition to the direct effect of bile acid on intestinal bacteria, bile acids may modulate gut immune function and indirectly alter gut bacterial communities. We hypothesized that bile acids elevated by HFF regulate intestinal Paneth cell function, which may contribute to gut dysbiosis in the ileal mucosa

Results

Discussion

Methods