The Interaction among Microbiota, Immunity, and Genetic and Dietary Factors Is the Condicio Sine Qua Non Celiac Disease Can Develop

Abstract

Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.

Figure 1

The complex interconnection among immune system, microbiota, and environmental factors (including dietary food antigens and/or infection) in the pathogenesis of celiac disease. (a) Steady-state condition. Dietary antigens and physiologic microbiota are in symbiotic relationship with host mucosal cells; thereby a harmonized balance between pro- and anti-inflammatory factors is achieved (homeostasis). (b) Inflammation or infection. The breakdown of the normal microbial community contributes to dysbiosis. In CD patients, gluten derived peptides are recognized by antigen presenting cells, with T-cells response. Deaminated gluten peptides are presented to T-cells with subsequent release of proinflammatory cytokines. In this way, Tregs are suppressed. This fact leads to a break of balance with consequent epithelial cell damage.