Coeliac disease: beyond genetic susceptibility and gluten. A narrative review

Abstract

Coeliac disease (CD) is an immune-mediated disorder triggered by the ingestion of gluten in genetically susceptible individuals. However, only a small proportion of subjects harbouring CDrelated genetic risk develop the disease. Among the environmental factors that may influence CD risk, pre-and perinatal factors, delivery methods, parental lifestyle, infant feeding practices, seasonality, dietary factors, drug use, childhood infections and variability in gut microbiota are those most widely studied regarding the risk to develop CD. Although for many of these external factors the exact mechanism of action is unknown, most of them are thought to act by disrupting the intestinal barrier, facilitating contact between potential antigens and the immune system effector cells. Management of CD is relatively easy in patients with a definite diagnosis and requires a strict, lifelong, gluten-free diet. Better knowledge of environmental exposures apart from gluten can facilitate understanding of the pathogenesis of the disorder and the wide heterogeneity of its clinical spectrum. The purpose of this review is to discuss current knowledge on environmental CD risk factors, as well as possible interaction between them, on the grounds of the reliable scientific evidence available. KEY MESSAGESThe risk of developing CD is influenced not only by gluten ingestion but also by a number of environmental factors including childhood infections and variability in gut microbiota, preand perinatal factors, infant feeding practices, delivery methods, parental lifestyle, seasonality, dietary factors and drug use, acting mainly by disrupting intestinal permeability. Better knowledge of exposure to these factors can facilitate their identification, and subsequent elimination, in the individual patient.

Fecal Microbiota Signatures in Celiac Disease Patients With Poly-Autoimmunity

“…Our finding about Actinobacteria reduction in PAI-CD patients also deserves attention, since their abundance has been consistently reported as changed in CD patients versus healthy controls (Pes et al, 2019 ). Both GFD and HLA-DQ2 haplotype have been associated with lower abundance of Actinobacteria and its most prevalent genus Bifidobacterium (Cenit et al, 2015 ).…”

“…Several studies reported that gut microbiota variations occur in CD patients, with changes in the relative abundance of certain taxa in comparison to healthy controls (Pes et al, 2019 ). Such differences appear to be related to the GFD in treated CD individuals, beyond the underlying disease, since the different diets act as inevitable confounding factors.…”

“…Alterations of the gut microbiota were reported in CD (Cenit et al, 2015;Pes et al, 2019). However, it is still unclear whether the relationships between CD and microbiota changes include disease promotion, causation or other types of association (Sacchetti and Nardelli, 2020).…”

“…Genetic predisposition, however, is necessary but not sufficient for CD to develop. As for other immune disorders, epidemiological data suggest that CD risk might be influenced by additional environmental factors, enteric infections, and/or use of antibiotics (Pes et al, 2019 ). Given the impact of these conditions on the gut microbial communities, there is a growing interest toward the role of the gut microbiota in CD.…”

The Two Faces of Wheat

“…Thus, the absence of HLA-DQ2/8 is a reliable criterion to exclude CD, but its presence is not sufficient to cause CD. A variety of non-HLA genes, mostly encoding for T cells or APCs, has been associated with CD development, but each of these genes most likely only contributes a small percentage to increase the risk of CD (87). It is interesting to note that there is a significant correlation between the level of wheat consumption, the frequency of HLA-DQ2/8 and the prevalence of CD, but with several outlier populations in regions such as northwestern India, northern Africa, Mexico, Finland, and Russia.…”