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 diseases (IBD), a family of idiopathic intestinal disorders with increasing prevalence and limited treatment options. Concordance rates of 30-40% among monozygotic twins in Crohn's disease (CD) implicate gene-environment interactions. Advances in DNA sequencing technologies have enabled 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 (GWAS) and deep genomic sequencing have implicated roughly 200 susceptibility loci that are associated with IBD. Many variants encode for genes involved in microbial recognition and immunity, suggesting host-microbial interactions may regulate the balance between health and disease. Polymorphisms in genes of the autophagy pathway (e.g., ATG16L1), and in bacterial pattern recognition receptors that activate autophagy (e.g., NOD2), represent some of the most significant effect sizes in CD 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 factors in sensing and killing of infectious microbes. Conventional wisdom and current perspectives therefore suggest that CD may be caused by mutations that impair immunity to pathogenic bacteria, leading to chronic exposure to microbial products that promotes uncontrolled inflammation. Herein, we present new findings that beneficial gut bacteria require ATG16L1 and NOD2 to engender anti-inflammatory responses in mouse and human cells, and mice lacking these genes are not protected from experimental colitis by probiotics. Based on this discovery, 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 CD result in defective recognition of beneficial molecules from the microbiome. In other words, the absence of sensing and responding to anti-inflammatory bacterial signals due to defects in ATG16L1 and NOD2 leads to chronic intestinal inflammation. If validated, this innovative hypothesis will define novel functions for primary CD risk factors, embolden new research into understanding IBD etiology, and advance promising microbiome-based therapies for disease.

Public Health Relevance

Inflammatory bowel diseases (IBD) affect 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-environment interactions that regulate intestinal health, advancing research into the etiology of IBD while testing a promising probiotic therapy in mouse and human model systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK078938-07A1
Application #
9333894
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2009-04-01
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Donaldson, G P; Ladinsky, M S; Yu, K B et al. (2018) Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360:795-800
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:
Edelblum, Karen L; Sharon, Gil; Singh, Gurminder et al. (2017) The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability. Cell Mol Gastroenterol Hepatol 4:285-297
Meisel, Marlies; Mayassi, Toufic; Fehlner-Peach, Hannah et al. (2017) Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. ISME J 11:15-30
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
Yang, Yang; Wang, Chunlin; Yang, Qunying et al. (2015) Distinct mechanisms define murine B cell lineage immunoglobulin heavy chain (IgH) repertoires. Elife 4:e09083
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

Showing the most recent 10 out of 31 publications