Associate Professor Cleveland Clinic Cleveland, Ohio, United States
Introduction/Rationale: Mucosal microbes must be tightly regulated to prevent infection by opportunistic pathogens, promote commensal homeostasis and maintain gut health. B cells maintain microbial homeostasis through local production of antibodies. We previously reported that Myosin 18A (Myo18A), an F-actin-binding unconventional myosin, controls antibody-mediated immunity. B cell-conditional Myo18A-deficient (Myo18A BKO) mice have increased mature splenic B cells antibody-secreting cells, elevated serum IgM and IgG antibodies, development of autoantibodies, and greater B cell differentiation to plasma cells. In this study, we tested the hypothesis that Myo18A deficiency regulates gut homeostasis by altering local antibody production and composition of the gut microbiome.
Methods: We measured fecal IgA and conducted shotgun sequencing on colon-derived fecal samples from control Mb1cre/+ and Myo18A BKO mice followed by meta transcriptomics and metabolic pathway analysis.
Results: Serum and free fecal IgA were decreased and gut microbial diversity altered in Myo18A BKO mice compared to Mb1cre/+ mice. Deletion of Myo18A was associated with enrichment of Erysipelotrichaceae and a decrease in the abundance of Bifidobacterium pseudolongum. As the former is linked to metabolic disorders and inflammatory diseases, and the latter has beneficial roles in health by suppressing diseases such as non-alcoholic fatty liver disease, our data are consistent with poorer gut health in Myo18A BKO mice. Accordingly, Myo18A BKO mice had enlarged livers and significantly higher liver triglyceride levels compared to Mb1cre/+ mice. Analysis of metabolic pathways revealed perturbation of acetate and adenosine metabolism in the fecal environment of Myo18A BKO mice, which further points to an altered gut barrier and pro-inflammatory environment.
Conclusion: Taken together, our results suggest that B cell Myo18A maintains gut health by regulating commensal diversity and metabolic balance.
