Date of Award
Medical Doctor (MD)
ALTERATION IN THE GUT MICROBIOME INFLUENCES DIABETES DEVELOPMENT IN AID-DEFICIENT NOD MICE.
Kristina M. Brown, Ningwen Tai, Jian Peng, Qiyuan Tan, Yangyang Li, F. Susan Wong, and Li Wen. Section of Endocrinology, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT.
Activation-induced cytidine deaminase (AID) plays a role in the pathogenesis of type 1 diabetes (T1D) but this relationship has not been fully elucidated. We hypothesize that the gut microbiome modulates the effect of AID deficiency on T1D pathogenesis. We studied T1D development in AID deficient (AID-/-) non obese diabetic (NOD) mice in different housing conditions: 1. “Co-housing (CH)”: AID-/- NOD mice housed with AID sufficient (AID+/+) NOD mice and 2. “Non co-housing (NCH)”: AID-/- NOD mice housed with AID-/- NOD mice. We screened for glycosuria weekly and blood glucose ≥250mg/dl confirmed T1D. Since mice have coprophagia behavior, CH can influence mucosal immunoglobulins (Igs) and gut microbiome. To examine alteration of gut microbiome, we sequenced bacterial DNA from fecal samples. We used quantitative PCR (qPCR) to determine expression levels of intestinal anti-microbial peptides. We tested the stimulatory effect of gut bacteria from AID-/- NOD and AID+/+ NOD mice on T lymphocytes. We found that CH AID-/- NOD mice developed significantly accelerated T1D while NCH AID-/- NOD mice were significantly protected from T1D. NCH AID-/- NOD mice were also found to have a significantly reduced phylum of Bacteroidetes compared to NCH AID+/+ NOD mice. Reg3b and RELMb, anti-microbial peptides, were significantly increased in the small intestine of NCH AID-/- NOD mice. Thus, high levels of anti-microbial peptides may alter the composition of gut microbiome and contribute to T1D protection. Notably, CD8+ T cells of CH AID-/- NOD mice were significantly more activated and produced significantly more IFNγ when stimulated by gut bacteria. Thus, the gut microbiome in CH AID-/- NOD mice may promote an over-responsive immune system, contributing to accelerated T1D. Our results provide important new knowledge about the role of AID in the pathogenesis of T1D development, mediated by gut microbiome and mucosal immunity.
Brown, Kristina Marie Kelly, "Alteration In The Gut Microbiome Influences Diabetes Development In Aid-Deficient Nod Mice." (2020). Yale Medicine Thesis Digital Library. 3886.