Butyrate and Secondary Bile Acids-Producing Gut Microbes Suppress Insulitis in NOD Mice 2258407

Abstract

Abstract Introduction Gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) such as butyrate and secondary bile acids (SBAs), are key regulators of immune homeostasis. In a pilot study of individuals with type 1 diabetes (T1D), higher circulating SCFA levels were associated with improved glycemic control. Moreover, longitudinal studies have shown that children who later developed multiple islet autoantibodies displayed early alterations in SBA profiles, implicating bile acid dysregulation in T1D pathogenesis. We therefore hypothesize that a defined probiotic consortium capable of producing both butyrate and SBAs will suppress islet autoimmunity and prevent T1D onset. Methods To develop a safe and effective strategy for T1D prevention, we assembled four probiotic consortia comprising six butyrate-producing and eleven SBA-producing bacterial species from the Symbiotic Bacterial Strain Bank. Female NOD mice were orally gavaged with the consortia (∼5 × 108 CFU per species) or saline for four weeks post-weaning. Bacterial colonization was quantified by qPCR two weeks after the final administration, and insulitis severity and immune cell profiles were analyzed at 12 weeks of age. Results Of the species tested, Bacteroides ovatus, Phocaeicola vulgatus, and Anaerostipes caccae successfully colonized the NOD mice. Consortia-treated mice exhibited slightly increased intestinal length at 12 weeks, consistent with reduced gut inflammation. Importantly, insulitis severity was significantly suppressed in treated mice compared with controls. Conclusion Developing probiotic consortia enriched in SCFA- and SBA-producing gut microbes may offer a promising and safe strategy to prevent T1D. Funding Source 2024 Study Abroad Grant, Manpei Suzuki Diabetes Foundation Topic Categories Mucosal and Regional Immunology (MUC)