Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases

Hao Q Tran,Andrew T Gewirtz,Benoit Chassaing,Ruth E Ley

doi:10.1038/s41467-019-13538-y

Abstract

Alterations in gut microbiota composition are associated with metabolic syndrome and chronic inflammatory diseases such as inflammatory bowel disease. One feature of inflammation-associated gut microbiotas is enrichment of motile bacteria, which can facilitate microbiota encroachment into the mucosa and activate pro-inflammatory gene expression. Here, we set out to investigate whether elicitation of mucosal anti-flagellin antibodies by direct administration of purified flagellin might serve as a general vaccine against subsequent development of chronic gut inflammation. We show, in mice, that repeated injection of flagellin elicits increases in fecal anti-flagellin IgA and alterations in microbiota composition, reduces fecal flagellin concentration, prevents microbiota encroachment, protects against IL-10 deficiency-induced colitis, and ameliorates diet-induced obesity. Flagellin’s impact on the microbiota is B-lymphocyte dependent and, in humans, obese subjects exhibit increased levels of fecal flagellin and reduced levels of fecal flagellin-specific IgA, relative to normal weight subjects. Thus, administration of flagellin, and perhaps other pathobiont antigens, may confer some protection against chronic inflammatory diseases.

Highlights

Alterations in gut microbiota composition are associated with metabolic syndrome and chronic inflammatory diseases such as inflammatory bowel disease
The coating of gut bacteria by flagellin-specific IgA, which normally occurs in homeostasis, suppresses levels of flagellated bacteria and guards against microbiota encroachment, which is thought to play a role in promoting both inflammatory bowel diseases (IBD) and metabolic syndrome[8,12,13,14]
The central hypothesis this study sought to test was whether an administration regimen of purified bacterial flagellin that elicited mucosal anti-flagellin antibodies might suppress levels of flagellated microbes and, serve as a vaccine against chronic intestinal inflammation, which are associated with increased levels of flagellated pathobionts[3,6,9,10]

Summary

Introduction

Alterations in gut microbiota composition are associated with metabolic syndrome and chronic inflammatory diseases such as inflammatory bowel disease. An array of chronic inflammatory diseases are associated with dysbiosis in the intestinal microbiota and a breakdown in the normally mutually beneficial host–microbiota relationship Such diseases include inflammatory bowel diseases (IBD) and diseases characterized by low-grade inflammation, such as metabolic syndrome. The coating of gut bacteria by flagellin-specific IgA, which normally occurs in homeostasis, suppresses levels of flagellated bacteria and guards against microbiota encroachment, which is thought to play a role in promoting both IBD and metabolic syndrome[8,12,13,14]. We describe that repeated systemic administration of purified flagellin elicits a robust anti-flagellin fecal IgA response that serves to reshape microbiota composition, reduces flagellin expression, and protects against experimental colitis and metabolic syndrome

Methods

Results

Conclusion