Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution?

Abstract

It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to healthy controls. CD patients with gastrointestinal symptoms are also known to have a different microbiota compared to patients with dermatitis herpetiformis and controls, suggesting that the microbiota is involved in disease manifestation. Furthermore, a dysbiotic microbiota seems to be associated with persistent gastrointestinal symptoms in treated CD patients, suggesting its pathogenic implication in these particular cases. GFD per se influences gut microbiota composition, and thus constitutes an inevitable confounding factor in studies conducted in CD patients. To improve our understanding of whether intestinal dysbiosis is the cause or consequence of disease, prospective studies in healthy infants at family risk of CD are underway. These studies have revealed that the CD host genotype selects for the early colonizers of the infant's gut, which together with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of oral tolerance to gluten. Indeed, some CD genes and/or their altered expression play a role in bacterial colonization and sensing. In turn, intestinal dysbiosis could promote an abnormal response to gluten or other environmental CD-promoting factors (e.g., infections) in predisposed individuals. Here, we review the current knowledge of host-microbe interactions and how host genetics/epigenetics and environmental factors shape gut microbiota and may influence disease risk. We also summarize the current knowledge about the potential mechanisms of action of the intestinal microbiota and specific components that affect CD pathogenesis.

Keywords: celiac disease; dysbiosis; gluten-free diet; microbiota.

Figure 1

Proposed model for celiac disease (CD) pathogenesis. Specific host genetic makeup and environmental factors could promote the colonization of pathobionts and reduce symbionts, thus leading to dysbiosis. Dysbiosis may contribute to disrupting the immune homeostasis and gut integrity, thereby favoring CD onset and aggravating the pathogenesis.

Figure 2

Potential mechanisms of action of intestinal microbiota components in CD. Schematic representation of CD pathogenesis and the potential role of intestinal dysbiosis. Some gluten peptides cross the intestinal epithelium and can be deamidated by the tissue transglutaminase (tTG), which increases their ability to bind the HLA-DQ2/8 molecules of antigen-presenting cells and to trigger an adaptive immune response, involving Th1, Th2 and Th17 cells. This leads to the release of pro-inflammatory cytokines (IFN-γ, interleukin (IL)-21, etc.) and the production of CD antibodies. Other gluten peptides activate the innate immune response by interacting with epithelial cells and APCs and, thus, triggering the activation of inflammatory pathways (NFκB) and the production of inflammatory cytokines such as IL-15. In particular, IL-15 increases the expression of the MICA molecule at epithelial cell surface and triggers activation of intraepithelial lymphocytes through engagement of NKG2D, leading to an innate-like cytotoxicity toward epithelial cells and enhanced CD8 T cell-mediated adaptive response, contributing to villous atrophy. The microbiota could contribute to the etiopathogenesis of CD by (2) providing proteolytic activities that influence the generation of toxic and immunogenic peptides from gluten and by mediating host-microbe interactions which could influence (1) the intestinal barrier and (3) immune function (e.g., via regulation of the cytokine network of pro-inflammatory and anti-inflammatory factors). Adapted from [114].