The Microbiome Mediates Protections from Colitis Through Pathways Linked to IBD

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PROJECT SUMMARY/ABSTRACT Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. In concert with the human genome, the intestinal microbiota regulate development and function of the immune system, modulating the balance between pro- and anti-inflammatory responses. A considerable body of evidence based on preclinical and clinical research suggests that gut microbes play a critical role in inflammatory bowel disease (IBD), a family of idiopathic intestinal disorders with increasing prevalence and limited treatment options. Concordance rates of 30-40% among monozygotic twins implicate gene-environment interactions. Genome wide association studies have implicated roughly 200 susceptibility loci that are significantly associated with IBD. Many variants encode for genes involved in microbial recognition and immunity, suggesting host-microbe interactions may regulate the balance between immune health and inflammatory disease. Polymorphisms in genes of the autophagy pathway (e.g., ATG16L1), and in pattern recognition receptors that are associated with autophagy (e.g., NOD2), represent some of the most significant effect sizes in IBD susceptibility. Further, considerable research has focused on investigating the function of Atg16L1 and NOD2 in mouse models and human cells, and identified a role for both gene products in sensing and killing pathogenic microbes. Current understanding therefore suggest that IBD may be caused by mutations that impair immunity to pathogenic bacteria, leading to chronic exposure to microbial products that activates uncontrolled inflammation. Herein, I present new findings that beneficial gut bacteria such a Bacteroides fragilis require Atg16L1 and NOD2 to promote anti-inflammatory responses in mouse and human cells, and mice deleted in these genes are not protected from colitis by B. fragilis. I propose a novel, non-redundant role for genes previously implicated in recognition and killing of pathogenic bacteria—namely, mutations in genetic pathways linked to IBD result in defective recognition of beneficial molecules from the microbiome. My hypothesis is that genetic defects in Atg16L1 may lead to IBD by not `sensing' and responding to the protective signals of beneficial gut bacteria. I will test my hypothesis in three Specific Aims, which include: 1) defining the cellular pathway(s) required for immune regulation by B. fragilis; 2) Determining Atg16L1 mechanism of action during regulatory T cell induction by B. fragilis; 3) Establishing whether NOD2 is required for mediating the beneficial effects of B. fragilis in mouse and human systems. In other words, the absence of sensing and responding to anti-inflammatory bacterial signals may be a risk factor for chronic intestinal inflammation. The training (K99) phase of this award will be mentored by Dr. Sarkis Mazmanian, and will facilitate the transition of my research program towards an independent investigator (R00).