Dysregulated inflammation causes numerous diseases that impact millions worldwide. In concert with the human genome, gut bacteria of the microbiome 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. Advances in DNA sequencing technologies have empowered detailed genomic characterization of IBD patients and controls, and numerous studies have chronicled changes in the composition and gene content of the microbiome during disease. Despite a wealth of sequence-based data, few hypothesis-driven studies have described molecular interactions between the microbiome and IBD-related genetic pathways. Genome wide association studies and deep sequencing 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-microbial 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 activate autophagy (e.g., NOD2), represent some of the most significant effect sizes in IBD susceptibility. Further, considerable preclinical 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 infectious microbes. Conventional wisdom and current perspectives 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, we present new findings that beneficial gut bacteria 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 probiotics. We 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. In other words, the absence of sensing and responding to anti-inflammatory bacterial signals may be a risk factor for chronic intestinal inflammation. If validated, this innovative hypothesis will embolden new research into understanding IBD etiology, and advance promising microbiome-based therapies for disease.
Inflammatory bowel disease (IBD) affects 1.5 million people and their families in the United States, with rates of diagnosis on the rise and no effective cures In addition to genetic risk factors, recent research has implicated the gut microbiome as an environmental contributor to IBD. This project will explore fascinating new principles and define mechanisms into gene-environmental interactions that regulate intestinal health, advancing research into the etiology of IBD while testing a promising probiotic therapy in mouse and human models.
| Lee, Yun Kyung; Mehrabian, Parpi; Boyajian, Silva et al. (2018) The Protective Role of Bacteroides fragilis in a Murine Model of Colitis-Associated Colorectal Cancer. mSphere 3: |
| Yoo, Bryan B; Mazmanian, Sarkis K (2017) The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. Immunity 46:910-926 |
| Sharon, Gil; Sampson, Timothy R; Geschwind, Daniel H et al. (2016) The Central Nervous System and the Gut Microbiome. Cell 167:915-932 |
| Donaldson, Gregory P; Lee, S Melanie; Mazmanian, Sarkis K (2016) Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 14:20-32 |
| Chu, Hiutung; Khosravi, Arya; Kusumawardhani, Indah P et al. (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352:1116-20 |
| Yano, Jessica M; Yu, Kristie; Donaldson, Gregory P et al. (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161:264-76 |
| Stefka, Andrew T; Feehley, Taylor; Tripathi, Prabhanshu et al. (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A 111:13145-50 |
| Sharon, Gil; Garg, Neha; Debelius, Justine et al. (2014) Specialized metabolites from the microbiome in health and disease. Cell Metab 20:719-730 |
| Noval Rivas, Magali; Burton, Oliver T; Wise, Petra et al. (2013) A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis. J Allergy Clin Immunol 131:201-12 |
| Chu, Hiutung; Mazmanian, Sarkis K (2013) Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol 14:668-75 |
Showing the most recent 10 out of 18 publications
