Jamal Green (Mentor: Michael Silverman, MD, PhD)

“Do early life commensal microbes prevent type 1 diabetes?”

Jamal Green, Jean-Bernard Lubin PhD, Sarah Maddux, Tereza Duranova and Michael Silverman 

Type 1 diabetes (T1D) is a debilitating autoimmune disease that affects millions. Unfortunately, the incidence of T1D is rising. The strongest genetic factor in T1D is the MHC class II locus. Some MHC haplotypes are associated with higher risk to T1D, while others provide dominant protection. Yet, the mechanism remains unknown. Recent studies suggest that environmental factors, such as the microbiome, also contribute to the increasing incidence of T1D. While both genetic and environmental factors contribute to the risk of developing T1D, little is known of how MHC II genetic factors interact with microbial factors. The non-obese diabetic (NOD) murine model recapitulates many features of T1D in humans including the dominant protection associated with the MHC class II locus. NOD mice spontaneously develop T1D, but autoimmunity can be prevented by transgenic expression of the MHCII E allele (E.alpha-16/NOD mice).  Recent studies suggest that the early-life microbiota is critical for this protection. To rigorously study the early-life microbiota, we developed a novel consortium of 9 culturable bacteria (PedsCom) that represent over 90% of the bacteria in pre-weaning diabetes-protected E.αlpha-16/NOD mice. To investigate immunomodulatory mechanisms of specific bacteria, we are applying gnotobiotic techniques using the PedsCom consortium and genetic models of disease utilizing NOD and E.αlpha-16/NOD mice. The preliminary data suggest that early life colonization with the PedsCom consortia protects NOD mice from developing diabetes compared to germ-free mice. Furthermore, we demonstrate that specific early life microbes drive distinct adaptive mucosal and systemic immune responses. We aim to identify immunomodulatory commensal bacteria and immune pathways that will be the basis for developing effective preventative therapies for T1D.