miRNA-155 impacts neuroinflammation in a sex-dependent mechanism, dysregulation of the intestinal barrier, and dysbiosis 2258069

Abstract Introduction Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease caused by the host’s immune cells attacking the myelin sheath in the central nervous system (CNS). Recently, MS has been linked to significant modifications in gut microbial taxa and intestinal barrier dysfunction. Additionally, microRNAs (miRs), which are small, noncoding RNA regulatory sequences, influence immune cell differentiation and intestinal permeability. In the context of experimental autoimmune encephalomyelitis (EAE), a model of MS, miRNA-155 is overexpressed. Elevated levels of miRNA-155 have been shown to induce T cell differentiation into pro-inflammatory phenotypes and may also regulate the intestinal epithelial barriers. We hypothesized that increased miRNA-155 expression during EAE could lead to disruptions in the intestinal microenvironment. Methods In this project, we examined how miRNA-155 deficiency affects the MOG35-55 model of EAE in male and female C57BL/6 mice, along with its impact on EAE-induced intestinal barrier disruption and microbial dysbiosis. Results Global miRNA-155 deficiency triggered sex-dependent effects on EAE, with reduced severity in males. Moreover, miRNA-155 deficiency reversed the intestinal barrier disruption caused by EAE induction. Gut microbiota analysis revealed that, compared to wild-type controls, miRNA-155 deficiency resulted in significant alterations in gut bacterial composition, becoming more pronounced upon EAE induction. Furthermore, miRNA-155 was shown to directly modify the composition of bacteria isolated from the gut of healthy mice. Conclusion Our findings suggest early, prior to disease onset, sex-dependent effects on colonic transcriptomics and microbiota profiles in EAE mice, and that miRNA-155 plays a key role in regulating intestinal barrier function and microbiota, contributing to immune regulation in neuroinflammatory diseases. Funding Source Boise State University Topic Categories Mucosal and Regional Immunology (MUC)