Small Intestinal Microbial Fibre Metabolism: Implications for Celiac Disease

Abstract

Celiac disease (CeD) is an immune-mediated condition driven by gluten; a group of proteins found in wheat, barley, and rye. Developing CeD requires risk genes that allows the immune system to recognize gluten efficiently to generate gluten-specific T cells and autoantibodies. The proinflammatory T cell response, in combination with intestinal epithelial cell (IEC) stress, leads to cytotoxic transformation intraepithelial lymphocytes (IEL) and small intestinal mucosal injury (atrophic enteropathy). The only treatment for CeD is a lifelong gluten-free diet (GFD), although mucosal damage may persist for more than 2 years despite best efforts to exclude gluten. Furthermore, the GFD diet can lead to nutritional deficiencies, such as insufficient dietary fibre, which can affect the composition and function of the intestinal microbiota. Fibre is strongly associated with gastrointestinal and extra-intestinal health, although no study has yet investigated the relationships between fibre consumption, microbial fibre metabolism, particularly in the small intestine, and CeD. Here I show that active and GFD-treated CeD patients had changes in small intestinal microbiota versus healthy controls, with depletion of fibre-degrading taxa, such as Prevotella spp., and of their predicted glycoside hydrolase enzymes. Colonization of germ-free mice with a cocktail of Prevotella spp. increased production of small intestinal short-chain fatty acids (SCFA) to a similar level as specific-pathogen free mice. Gluten-sensitized NOD-DQ8 mice were used to investigate the progression of mucosal recovery on GFD. With no added fibre, immunopathology recovered after 10 weeks of GFD and was shortened to 6 weeks after an inulin-supplemented diet. Mechanistically, inulin-supplemented GFD facilitated small intestinal microbial saccharolytic function and SCFA production. In contrast, HylonVII-supplemented GFD shifted small intestinal microbiota without increasing SCFA. The results support clinical investigations of specific fibre supplements and strategies to enhance microbial fibre degradation activity during a GFD.