Intestinal Symbionts in Immune Regulation and Autoimmune Disease

Abstract

The intestinal microbiota regulates many aspects of host immunity, among other fundamental physiological processes. Imbalances in the gut flora have been linked to a variety of inflammatory and autoimmune disorders. We examined the role of intestinal symbionts in calibrating immune responses via two approaches, by 1) assessing the impact of individual bacterial species or their gene products on immune cell populations, and 2) defining elements of the gut microbiota that associate with disease status in type-1 diabetes (T1D). In the first approach, we systematically characterized the immunomodulatory capacity of individual human symbionts. Our screen revealed that a majority of microbes had phylogeny-independent, specialized, complementary and redundant effects on host transcriptional and immune parameters. Most immune cells were not drastically altered by individual bacteria, with the exception of Rorγ-expressing Foxp3+ regulatory T (Treg) cells. To identify microbial factors capable of modulating Rorγ+ Tregs, we explored the association between bacterial gene expression and extent of Rorγ+ Treg induction, which yielded candidate genes for future validation. In the second approach, we examined the role of the microbiota in the non-obese diabetic (NOD) mouse model of T1D. One avenue of investigation explored the basis of heightened T1D susceptibility in female NOD mice compared to males. Hypothesizing that male mice harbored protective symbionts, we identified endogenous bacteria that were overrepresented in males versus females and that tracked with resistance to T1D in both genders. To test the prophylactic capacity of single microbes, we isolated these symbionts from male cecal material. We then assessed their impact on T1D development by orally inoculating them into NOD mice, but observed no substantial modification of disease. Secondly, the major histocompatibility class II (MHC-II) locus represents a significant genetic determinant of T1D, which may nevertheless be influenced by the microbiota. In a collaborative study, we observed subtle disparities in the microbiota of NOD mice that inherited, or not, the dominantly protective Eα16 MHC-II allele. We further investigated its impact on microbiota-specific immunoglobulin A responses. Our findings underscore the complex individual and synergistic effects exerted by intestinal symbionts on the immune system and in the setting of autoimmunity.