The Microbiome Activates CD4 T-cell–mediated Immunity to Compensate for Increased Intestinal Permeability

Abstract

Background & AimsDespite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens.MethodsAcute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability.ResultsAcute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression.ConclusionsIncreased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion.

Segmented filamentous bacteria‐induced immune responses: a balancing act between host protection and autoimmunity

“…For example, SFB‐induced immunity can protect the host against the intestinal bacterial pathogens Citrobacter rodentium and Salmonella typhimurium . Additionally, Th17 cell responses induced by SFB were found to be sufficient to overcome intestinal permeability defects and maintain protection against acute enteric infection with Toxoplasma gondii or Salmonella typhimurium . SFB colonization is also able to confer protection against Salmonella enteritidis in rats, enteropathogenic Escherichia coli in rabbits as well as the protozoan pathogen Entamoeba histolytica in mice .…”

Intestinal dysbiosis and hormonal neuroendocrine secretion in the fibromyalgic patient

“…An alteration or a malfunction of the epithelium leads to intestinal hypertrophy, which is difficult to treat. The presence of eubiosis reduces the prob-ability of intestinal bacterial invasion in case of damage to the epithelial barrier through the release of inflammatory mediators 12 and immune mediators such as IL-17A, an interleukin involved in the differentiation of CD4 + cells 13 . Bacterial alteration, with concomitant increase in LPS, negatively affect the function of the intestinal epithelial barrier 14 .…”

Effects of moderate, voluntary ethanol consumption on the rat and human gut microbiome

“…), alter immune response and gut permeability (Edelblum et al . ) and even induce cancer (Yu et al . ).…”