Role of the gut microbiota in the pathogenesis of coeliac disease and potential therapeutic implications

Abstract

Purpose: Although genetic predisposition and exposure to dietary gluten are considered necessary triggers for the development of coeliac disease, alterations in the gut microbial composition may also contribute towards the pathogenesis of coeliac disease. This review aims to provide an overview of the available data on the potential mechanisms through which the gut microbiota plays a role in the causation of coeliac disease and to discuss the potential therapeutic strategies that could diminish the consequences of microbial dysbiosis.

Method: A search of the literature was performed using the PubMed, Embase, and JSTOR databases; relevant articles were included.

Results: Recent studies in patients with coeliac disease have reported an increase in the relative amounts of gram negative bacterial genera such as Bacteroides, Prevotella, and Escherichia, and reduced amounts of protective anti-inflammatory bacteria such as Bifidobacteria and Lactobacilli. Dysbiotic microbiota may lead to a dysregulated immune response that may contribute to the pathogenesis of coeliac disease. In infancy, antibiotic use and certain infant feeding practices may lead to alterations in the developing gut microbiota to influence the immune maturation process and predispose to coeliac disease.

Conclusion: The induction of the intestinal immune system and gluten intolerance may be influenced by the relative abundance of certain microbiota. Factors such as infant feeding practices, diet, antibiotics, and infections, may be involved in the development of coeliac disease due to their influence on gut microbial composition. The efficacy of potential modulators of the gut microbiota such as probiotics, prebiotics, and fecal microbial transplant as adjunctive treatments to gluten-free diet in coeliac disease is unproven and requires further investigation.

Keywords: Coeliac disease; Dysbiosis; Metagenomics; Microbiota.

Fig. 1

Flowchart of the Study selection for literature review

Fig. 2

The immune response in coeliac disease pathogenesis is mediated by both B cell and T cell response. The intestinal microbiota, both commensals microbes and pathobionts, might contribute to the development of coeliac disease by influencing the gluten peptide digestion, stimulation of DC and T_Reg cells, epithelial cell stress, intestinal permeability modulation, and pro-inflammatory cytokines production. Microbial flagellin or LPS can stimulate AMPs from epithelial cells and release of mucins from goblet cells. The translocated gluten peptides in the lumen of the small intestine are first deamidated by the tissue TG2 in the lamina propria and are then taken up by the dendritic cells to trigger the proinflammatory gluten-specific CD4 + T-cell response in the mesenteric lymph nodes. The activated CD4 + T-cell prime the B-cells to produce different types of antibodies such as anti-gliadin, anti-TG2 IgA antibodies and also stimulate the gluten-specific TH1 cell to produce IL-21 and IFN-γ cytokines to cause intestinal inflammation in genetically predisposed hosts. Activation of the innate immune response is a key initial step in coeliac disease. Increased epithelial stress due to microbial dysbiosis or ingested gluten peptides can trigger stress molecules on epithelial cells (HLA-E, MICA/B) and induce IL-15 production from epithelial cells. In the presence of IL-15, CD8 + IELs can induce epithelial lesions via production of different cytotoxic molecules (perforin or granzymes). DC dendritic cells, T_Reg cells T Regulatory cells, IL interleukin, TG2 transglutaminase 2, IgA immunoglobulin A, IFN interferon, LPS lipopolysaccharides, SCFAs short-chain fatty acids, TNF tumor necrosis factor, Th T helper, HLA human leukocyte antigen, TLR toll-like receptors, IEL intraepithelial lymphocytes, NKG2C natural killer group 2C receptor, NKG2D natural killer group 2D receptor