Bifidobacterium bifidum Enhances the Intestinal Epithelial Tight Junction Barrier and Protects against Intestinal Inflammation by Targeting the Toll-like Receptor-2 Pathway in an NF-κB-Independent Manner.

Rana Al-Sadi,Shuhong Guo,Thomas Y Ma,Viszwapriya Dharmaprakash,Meghali Nighot,Toan Do,Prashant Nighot

doi:10.3390/ijms22158070

Abstract

Defective intestinal tight junction (TJ) barrier is a hallmark in the pathogenesis of inflammatory bowel disease (IBD). To date, there are no effective therapies that specifically target the intestinal TJ barrier. Among the various probiotic bacteria, Bifidobacterium, is one of the most widely studied to have beneficial effects on the intestinal TJ barrier. The main purpose of this study was to identify Bifidobacterium species that cause a sustained enhancement in the intestinal epithelial TJ barrier and can be used therapeutically to target the intestinal TJ barrier and to protect against or treat intestinal inflammation. Our results showed that Bifidobacterium bifidum caused a marked, sustained enhancement in the intestinal TJ barrier in Caco-2 monolayers. The Bifidobacterium bifidum effect on TJ barrier was strain-specific, and only the strain designated as BB1 caused a maximal enhancement in TJ barrier function. The mechanism of BB1 enhancement of intestinal TJ barrier required live bacterial cell/enterocyte interaction and was mediated by the BB1 attachment to Toll-like receptor-2 (TLR-2) at the apical membrane surface. The BB1 enhancement of the intestinal epithelial TJ barrier function was mediated by the activation of the p38 kinase pathway, but not the NF-κB signaling pathway. Moreover, the BB1 caused a marked enhancement in mouse intestinal TJ barrier in a TLR-2-dependent manner and protected against dextran sodium sulfate (DSS)-induced increase in mouse colonic permeability, and treated the DSS-induced colitis in a TJ barrier-dependent manner. These studies show that probiotic bacteria BB1 causes a strain-specific enhancement of the intestinal TJ barrier through a novel mechanism involving BB1 attachment to the enterocyte TLR-2 receptor complex and activation of p38 kinase pathway.

Highlights

Intestinal epithelial tight junction (TJ) barrier dysfunction has been implicated as an important pathogenic factor of various inflammatory conditions of the gut, including inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and celiac disease [1,2,3,4].Clinical studies in IBD patients have shown that a persistent increase in intestinal permeability following clinical remission is predictive of poor clinical outcome and an early recurrence of the disease [5,6], while normalization of intestinal permeability correlated with a sustained long-term clinical remission
We found that one species, in particular, Bifidobacterium bifidum (BB), caused a marked increase in intestinal TJ barrier function in cell culture and in a live mouse
We examined the effects of Bifidobacterium species on intestinal epithelial TJ barrier function by measuring trans-epithelial resistance (TER) in filter-grown Caco-2 monolayers

Summary

Introduction

Clinical studies in IBD patients have shown that a persistent increase in intestinal permeability following clinical remission is predictive of poor clinical outcome and an early recurrence of the disease [5,6], while normalization of intestinal permeability correlated with a sustained long-term clinical remission. There has been much interest in the role of the intestinal microbiome on IBD and the use of probiotics to modulate and treat intestinal inflammation [9,10]. There is an important unmet need and a gap in scientific knowledge related to the use of probiotic bacterial species that can target and preserve the intestinal epithelial TJ barrier function and prevent and treat intestinal inflammation

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