The interplay between a host's genetics, immune system, and intestinal microbial communities is a dynamic force influencing health and disease status. This proposal will assess how genetic variants associated with IBD shape the microbiota and the functional consequences that alter host responses and culminate pathologic inflammation. We focus on autophagy-linked genetic variants to determine whether genetic subsets of Crohn's disease (CD) are associated with specific changes in the luminal microbiome. We will explore microbial community structure, function and metabolism, and the microbiome's interaction with its host in CD. We will leverage the extensive resources and detailed phenotypic information of the IBDGC as well as several other IBD registries (Massachusetts General Hospital, Boston Children's Hospital, and the Ocean State Crohn's and Colitis Area Registry, an inception cohort in Rhode Island) to enroll subjects with ATG16L1, IRGM, and NOD2 disease-associated variants, as well as healthy individuals with and without these risk alleles. Using 16S ribosomal sequencing of luminal samples, we will apply novel biostatistical techniques to associate organisms or clades within the microbiome with CD status and host genetics. Subsequent whole genome sequencing and transcriptomics will allow us to advance beyond categorization of disease-associated bacteria to understand the functional implications of the dysbiosis associated with CD. Utilizing mouse models of the autophagy allele variants, we will confirm the genetic impact of the microbiome by performing association in gnotobiotic mice with the human study samples and investigate the host response to these microbial changes. CD is fundamentally shaped by intestinal microbial factors, which may provoke the disease in individuals with defined genetic risks. The specific roles of organisms or metabolism in the intestinal microbiome during CD remain poorly defined and are emerging frontiers in deciphering the pathophysiology of the disease. The results anticipated from these studies will advance our understanding of CD by determining how the interactions and influences of host genetics, the microbiome and the immune response contribute to Crohn's disease.

Public Health Relevance

This proposal aims to identify microbial factors that contribute to IBD in patients with genetic polymorphisms in autophagy genes. The project is consistent with the goals of the Human Microbiome Project and has the potential to be truly transformative by contributing to a fundamental knowledge gap regarding the cause of IBD. The results could transform our understanding of relationships between microbes and humans and can lead to innovative diagnostic tests and future treatments.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-J (J3))
Program Officer
Karp, Robert W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Broad Institute, Inc.
United States
Zip Code
Franzosa, Eric A; Sirota-Madi, Alexandra; Avila-Pacheco, Julian et al. (2018) Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol :
Graham, Daniel B; Luo, Chengwei; O'Connell, Daniel J et al. (2018) Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes. Nat Med 24:1762-1772
Schirmer, Melanie; Franzosa, Eric A; Lloyd-Price, Jason et al. (2018) Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat Microbiol 3:337-346
Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J (2017) Human genetic variation and the gut microbiome in disease. Nat Rev Genet 18:690-699
Ananthakrishnan, Ashwin N; Luo, Chengwei; Yajnik, Vijay et al. (2017) Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe 21:603-610.e3
Bist, Pradeep; Cheong, Wan Shoo; Ng, Aylwin et al. (2017) E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. Nat Commun 8:15865
Atarashi, Koji; Suda, Wataru; Luo, Chengwei et al. (2017) Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358:359-365
Hall, Andrew Brantley; Yassour, Moran; Sauk, Jenny et al. (2017) A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med 9:103
Vatanen, Tommi; Kostic, Aleksandar D; d'Hennezel, Eva et al. (2016) Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell 165:842-53
Schirmer, Melanie; Smeekens, Sanne P; Vlamakis, Hera et al. (2016) Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell 167:1125-1136.e8

Showing the most recent 10 out of 29 publications