TLR4 Deficiency Affects the Microbiome and Reduces Intestinal Dysfunctions and Inflammation in Chronic Alcohol-Fed Mice.

Carlos M. Cuesta,María Pascual,Juan R. Ureña-Peralta,Francisco García-García,Irene Rodríguez-Navarro,Consuelo Guerri,Raúl Pérez-Moraga

doi:10.3390/ijms222312830

Abstract

Chronic alcohol abuse causes an inflammatory response in the intestinal tract with damage to the integrity of the mucosa and epithelium, as well as dysbiosis in the gut microbiome. However, the role of gut bacteria in ethanol effects and how these microorganisms interact with the immune system are not well understood. The aim of the present study was to evaluate if TLR4 alters the ethanol-induced intestinal inflammatory response, and whether the response of this receptor affects the gut microbiota profile. We analyzed the 16S rRNA sequence of the fecal samples from wild-type (WT) and TLR4-knockout (TLR4-KO) mice with and without ethanol intake for 3 months. The results demonstrated that chronic ethanol consumption reduces microbiota diversity and causes dysbiosis in WT mice. Likewise, ethanol upregulates several inflammatory genes (IL-1β, iNOS, TNF-α) and miRNAs (miR-155-5p, miR-146a-5p) and alters structural and permeability genes (INTL1, CDH1, CFTR) in the colon of WT mice. Our results further demonstrated that TLR4-KO mice exhibit a different microbiota that can protect against the ethanol-induced activation of the immune system and colon integrity dysfunctions. In short, our results reveal that TLR4 is a key factor for determining the gut microbiota, which can participate in dysbiosis and the inflammatory response induced by alcohol consumption.

Highlights

The gut microbiota is a highly complex ecosystem made up of millions of microorganisms that inhabit in the gastrointestinal tract
Ethanol Treatment Upregulates Inflammation in the Intestinal Genes Associated with the Previous studies have demonstrated that ethanol treatment can damage the intestinal epithelium and cause dysbiosis [24]
The present findings demonstrated that chronic alcohol abuse modified the expression of genes intelectin 1 (ITLN1) and CFTR in WT mice intestines with minor changes in Toll-like receptor 4 (TLR4)-KO compared to the untreated control mice

Summary

Introduction

The gut microbiota is a highly complex ecosystem made up of millions of microorganisms that inhabit in the gastrointestinal tract Most of these bacteria belong to the phyla Firmicutes (Gram-positive) and Bacteroidetes (Gram-negative) [1], and they produce numerous metabolites capable of influencing the host’s physiology. Microbial ecology stability is good; alterations to bacterial composition or activity can result in changes that may lead to an imbalance between pathogenic and beneficial microorganisms by triggering a process known as dysbiosis [6,7,8] This pathological state is capable of inducing several diseases that impact the whole body, including brain cognitive and behavioral functions [9,10,11]

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