G Protein-Coupled Receptor 109A and Host Microbiota Modulate Intestinal Epithelial Integrity During Sepsis

Guangxin Chen,Xin Ran,Shoupeng Fu,Yuhang Li,Bai Li,Liwei Xie,Bingxu Huang,Wei Wang,Dewei He,Liqiang Jiang,Juxiong Liu,Bingdong Liu

doi:10.3389/fimmu.2018.02079

Abstract

The intestinal epithelial barrier is important to mucosal immunity, although how it is maintained after damage is unclear. Here, we show that G protein-coupled receptor 109A (GPR109A) supports barrier integrity and decreases mortality in a mouse cecum ligation and puncture (CLP) sepsis model. Data from 16S RNA sequencing showed that the intestinal microbiota of WT and Gpr109a−/− mice clustered differently and their compositions were disrupted after CLP surgery. GPR109A-deficient mice showed increased mortality, intestinal permeability, altered inflammation, and lower tight junction gene expression. After eliminating the intestinal flora with antibiotics, all experimental mice died within 48 h of CLP surgery. This demonstrates the critical role of the gut microbiota in CLP-induced sepsis. Importantly, mortality and other pathologies in the model were decreased after Gpr109a−/− mice received WT gut microbiota. These findings indicate that GPR109A regulates the gut microbiota, contributing to intestinal epithelial barrier integrity and decreased mortality in CLP-induced sepsis.

Highlights

Sepsis is a frequent cause of mortality in intensive care units and is one of the 10 most common causes of death worldwide [1,2,3]
We examined the colon and ileum using hematoxylin and eosin (HE)-stained specimens (Figure 1G), revealing that G protein-coupled receptor 109A (GPR109A) offered a protection against tissue damage during cecum ligation and puncture (CLP)-induced sepsis in the intestinal epithelium
The protective effects of the intestinal epithelium barrier are central to the prevention and treatment of sepsis.GPR109A have been demonstrated plays an important role in maintaining intestinal epithelium barrierand inhibiting inflammationby us and others [21, 40]

Summary

Introduction

Sepsis is a frequent cause of mortality in intensive care units and is one of the 10 most common causes of death worldwide [1,2,3]. Sepsis is often associated with impairment of the intestinal epithelial barrier. This increases intestinal permeability, causing the contents of intestinal lumen, including the microbiota, to leak out of the intestine, resulting in multiple organ failure or even death in the most extreme cases [8,9,10]. The protective effects of the intestinal epithelial barrier are essential for the prevention and treatment of sepsis

Methods

Results

Conclusion