Gluten-free diet exposure prohibits pathobiont expansion and gluten sensitive enteropathy in B cell deficient JH-/- mice

Abstract

In humans, celiac disease (CeD) is a T-cell-driven gluten-sensitive enteropathy (GSE) localized to the small bowel (duodenum). The presence of antibodies specific for gluten- and self-antigens are commonly used diagnostic biomarkers of CeD and are considered to play a role in GSE pathogenesis. Previously, we have described an apparent T-cell-mediated GSE in CD19-/- mice, which develop weak and abnormal B cell responses. Here, we expand on this observation and use a mouse model of complete B cell deficiency (JH-/- mice), to show that absence of a humoral immune response also promotes development of a GSE. Furthermore, 16S analysis of microbial communities in the small intestine demonstrates that a gluten-free diet suppresses the expansion of anaerobic bacteria in the small intestine and colonization of the small intestine by a specific pathobiont. Finally, we also observe that SI enteropathy in mice fed a gluten-rich diet is positively correlated with the abundance of several microbial peptidase genes, which supports that bacterial metabolism of gluten may be an important driver of GSE in our model. Collectively, results from our experiments indicate that JH-/- mice will be a useful resource to investigators seeking to empirically delineate the contribution of humoral immunity on GSE pathogenesis, and support the hypothesis that humoral immunity promotes tolerance to gluten.

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency

“…Previous studies from our lab support that primary antibody deficiency perturbs T cell homeostasis in the small bowel and that this may drive gut inflammation ( 18 , 19 ). Results from our analysis above are consistent with this.…”

“…Thus, these latter differences are largely due to straindependent effects that are not shared drivers of immune dysregulation among mice. Previous studies from our lab support that primary antibody deficiency perturbs T cell homeostasis in the small bowel and that this may drive gut inflammation (18,19). Results from our analysis above are consistent with this.…”

Inborn errors of immunity and related microbiome

“…Mohammed et al. focused on the effect of gluten-free diet (GFD) on microbiota in B cell-deficient mice and found that it suppressed the expansion of anaerobic bacteria in the small intestine and colonization of the small intestine by a specific pathobiont ( 142 ).…”

“…This finding provides new therapeutic perspectives in IgA-deficient patients based on intravenous immunoglobulin supplementation with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID (116). Mohammed et al focused on the effect of gluten-free diet (GFD) on microbiota in B cell-deficient mice and found that it suppressed the expansion of anaerobic bacteria in the small intestine and colonization of the small intestine by a specific pathobiont (142). Furthermore, other studies suggested metabolic byproducts from gut microbiota (e.g., SCFAs) could cause epigenetic modification by affecting the local homeostasis of phagocytes and myelopoiesis in the bone marrow.…”

The interplay between bile acids and mucosal adaptive immunity

“…Previously, we demonstrated that CD19 −/− and JH −/− mice present with SIBO (which we defined as both total increases in bacterial biomass in the SI as well as altered taxonomic composition) [ 41 , 42 ]. We also demonstrated that this was associated with defects in bacterial BA metabolism [ 41 ].…”