Contribution of the Gut Microbiota to Intestinal Fibrosis in Crohn's Disease.

Nobuhiko Kamada,Daisuke Watanabe

doi:10.3389/fmed.2022.826240

Nobuhiko Kamada, Daisuke Watanabe

Open Access

https://doi.org/10.3389/fmed.2022.826240

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Abstract

In Crohn's disease (CD), intestinal fibrosis is a critical determinant of a patient's prognosis. Although inflammation may be a prerequisite for the initiation of intestinal fibrosis, research shows that the progression or continuation of intestinal fibrosis can occur independently of inflammation. Thus, once initiated, intestinal fibrosis may persist even if medical treatment controls inflammation. Clearly, an understanding of the pathophysiological mechanisms of intestinal fibrosis is required to diminish its occurrence. Accumulating evidence suggests that the gut microbiota contributes to the pathogenesis of intestinal fibrosis. For example, the presence of antibodies against gut microbes can predict which CD patients will have intestinal complications. In addition, microbial ligands can activate intestinal fibroblasts, thereby inducing the production of extracellular matrix. Moreover, in various animal models, bacterial infection can lead to the development of intestinal fibrosis. In this review, we summarize the current knowledge of the link between intestinal fibrosis in CD and the gut microbiota. We highlight basic science and clinical evidence that the gut microbiota can be causative for intestinal fibrosis in CD and provide valuable information about the animal models used to investigate intestinal fibrosis.

Highlights

About a third of patients with Crohn’s disease (CD) exhibit a distinct phenotype of intestinal fibrosis and stenosis over a period of 10 years [1]
In CD myofibroblasts, TGF-β3 is significantly reduced, while TGF-β2 is enhanced compared to normal or UC [10]. These results indicate that the differential functional capacity of myofibroblasts in CD may lead to the development of intestinal fibrosis
Flagellin produced by adherent–invasive strains of Escherichia coli (AIEC), a principal component of bacterial flagella, is a key molecule that promotes the expression of interleukin 1 receptor–like 1 (IL1RL1, known as ST2) in intestinal epithelial cells (IECs), which depends on flagellin ligands TLR5 and NLRC4 on IECs [66]

Summary

INTRODUCTION

About a third of patients with Crohn’s disease (CD) exhibit a distinct phenotype of intestinal fibrosis and stenosis over a period of 10 years [1]. IL-17A enhances the production of collagen I and heat shock protein 47 (HSP47) in subepithelial myofibroblasts, which is significantly elevated in the intestinal tissues of patients with active CD [84] In line with these findings, the colonization by adherent-invasive Escherichia coli (AIEC) induces Th17 responses, heightens proinflammatory cytokines and fibrotic growth factors, with transmural inflammation and fibrosis [85]. IL-1α acts as a profibrotic cytokine in other organs, as IL-1α -deficient mice exhibit reduced collagen deposition in response to bleomycin treatment in lung fibroblasts [90] In addition to these mechanisms, intestinal epithelial cells are involved in the pathogenesis of intestinal fibrosis via the machinery of epithelial-mesenchymal transition (EMT).

Animal models of intestinal fibrosis induced by bacterial infection

Findings

CONCLUSION