Defective humoral immunity disrupts bile acid homeostasis which promotes inflammatory disease of the small bowel

Ahmed Dawood Mohammed,Lillian M Schoettmer,Zahraa Mohammed,Jason L Kubinak,Ioulia Chatzistamou,Mitzi Nagarkatti,Prakash Nagarkatti,Mireya Arroyo,Amy Jolly,Mary M Roland,Yuan Tian,Khadija Kakar,Andrew Patterson

doi:10.1038/s41467-022-28126-w

Abstract

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. Here, we use a CD19−/− mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in bile acid homeostasis, and gluten-sensitive enteropathy of the small intestine. The gluten-sensitive small intestine enteropathy that develops in CD19−/− mice is associated with alterations to luminal bile acid composition in the SI, marked by significant reductions in the abundance of conjugated bile acids. Manipulation of bile acid availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase activity all influence the severity of small intestine enteropathy in CD19−/− mice. Collectively, results from our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial BA metabolism.

Highlights

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes
Extending upon previous observations reported in the feces of CD19−/− mice[34], we report that outgrowth of anaerobic bacteria (Fig. 1B) and elevated luminal bile acids (BAs) concentrations (Fig. 1C) extends into the small intestine (SI) of these animals
No specific amplicon sequence variant (ASV; a.k.a “species”) within the Lactobacillaceae were significantly enriched in CD19−/− mice (Supplementary Data 2), which implies a general inability to control the outgrowth of Lactobacillaceae family members

Summary

Introduction

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Previous work using immunization models have shown that CD19−/− mice have severe defects in their ability to mount antibody responses against systemically or orally administered T-cell-dependent and T-cell-independent antigens[32,33] Using this model of antibody-deficiency, we have recently reported that CD19−/− mice have lower IgA titers in feces, bind fewer commensal microbes with IgA, and develop gut dysbiosis[34]. These mice develop a gluten-sensitive inflammatory enteropathy restricted to the small intestine (SI) that is associated with defects in lipid metabolism and BA absorption. Using several approaches, we show that adoptive transfer of functional B cells, direct manipulation of BA availability in the gut, and ablation of a key enzyme necessary for bacterial BA biotransformation are all able to modulate the severity of SI enteropathy in CD19−/− mice

Methods

Results

Conclusion