The differential influence of commensal and pathogenic flagella on intestinal barrier function

Abstract It is well known that accumulated changes in microbiota composition over several decades have contributed to an increase in non-communicable chronic diseases. While much effort has been devoted toward achieving a consensus on the microbes, and their products, driving this increase, inconsistent results suggest more research is required to understand the disparity in observed outcomes. Previous work from our lab identified a consortium of commensal Clostridia that alone was sufficient to preserve intestinal barrier integrity and prevent sensitization to food allergens in mice by inducing IL-22. Further investigation determined that members of this consortium display flagella. When isolated, these commensal flagella (Fla-C) exhibited TLR5-dependent IL-22 induction at a magnitude comparable to flagellin from SalmonellaTyphimurium (Fla-ST). However, mice treated with Fla-C maintained intestinal barrier function significantly more effectively than Fla-ST or negative control PBS-treated mice as measured by a serum FITC-dextran permeability assay. This was accompanied by a striking difference in the expression of Reg3 antimicrobial peptides and IL-17; all of which were significantly increased by treatment with Fla-ST when compared to Fla-C. Sequencing of Clostridia consortium-derived flagellated isolates revealed flagellin genes with unique hypervariable regions when compared to fliC from S. Typhimurium. These results highlight the distinct impacts of commensal and pathogenic flagella and suggest an important role for flagellated commensal bacteria in the maintenance of intestinal epithelial barrier function. Supported by a grant from National Institutes of Health (RO1 AI06302)