Dr. Sartor blends his internationally recognized expertise in host-microbial interactions and use of gnotobiotic mice with highly complementary cutting-edge experts in genome science (Shehzad Sheik, Terry Furey); molecular microbiology and bioinformatics (Anthony Fodor, Jeremiah Faith, Niels van der Lelie); metabolomics (Kun Lu); molecular predictors of clinical outcomes (Ted Denson, Rebekah Karns) and the considerable resources of Cores A and B to identify key members of protective resident bacterial species that preferentially induce IL-10-associated protective immune responses in novel gnotobiotic and humanized models of chronic experimental colitis and predict clinical outcomes in established cohorts of Crohn?s disease (CD) patients. Hypothesis: Subsets of resident intestinal bacteria activate protective IL10- associated immune responses in LP regulatory B and T lymphocytes and metabolites that mediate mucosal homeostasis and predict disease progression and complications in CD patients. We address this hypothesis through 3 complementary Aims:
Aim 1 : Identify resident bacterial species that selectively induce IL10- producing regulatory LP B and T cells and protect against experimental colitis (supported by Core A). Hypothesis: Subsets of resident bacteria selectively activate IL10-production by LP B and T cells and metabo- lites that mediate mucosal homeostasis. Identified bacterial strains will prevent and reverse chronic exp. colitis.
Aim 2. Identify mechanisms of protection of bacterial species capable of reversing established colitis Hypothesis: Key protective bacterial species activate immunological and metabolic pathways that directly suppress TH1/17 immune responses and pathogenic bacterial subsets to prevent and reverse chronic colitis. 2A. Identify metabolite profiles of protective bacterial strains and test their protective function. 2B. Determine the ability of protective strains to normalize luminal and mucosal dysbiotic bacterial profiles. 2C. Identify protective immunologic pathways induced in IL10+ LP T and B cells by protective bacterial strains.
Aim 3. Determine whether protective bacterial species and LP cell transcriptional signatures predict disease progression and post-operative recurrence in phenotyped adult and pediatric CD cohorts. Hypothesis: Protective bacterial species and IL10-associated transcriptional pathways identified in mice provide novel predictors of disease progression and complications in defined CD patient cohorts. This highly innovative and clinically relevant study will yield unique insights into immunologic, metabolic and microbial mechanisms by which resident bacterial subsets mediate mucosal and microbial homeostasis, predict clinical CD progression, complications and ultimately, characterize novel therapeutic bacterial species.

Public Health Relevance

(PROJECT 2) Abnormal balances of beneficial and detrimental resident intestinal bacteria (dysbiosis) drive the aggressive immune responses of Crohn?s disease and ulcerative colitis, however the function of these dysbiotic bacteria have not been evaluated by detailed mechanistic studies. This project will identify dominant protective resident bacterial species and their ability to predict clinical outcomes, including developing complications, progression of disease and recurrence of disease after intestinal resection, in 2 well characterized, prospectively evaluated Crohn?s disease patient cohorts. A long term goal is to identify and characterize novel resident intestinal bacterial consortia for individualized treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK094779-07
Application #
10018863
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761
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Cronan, Mark R; Matty, Molly A; Rosenberg, Allison F et al. (2018) An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nat Methods 15:1098-1107
Ellermann, Melissa; Sartor, R Balfour (2018) Intestinal bacterial biofilms modulate mucosal immune responses. J Immunol Sci 2:13-18
Pushalkar, Smruti; Hundeyin, Mautin; Daley, Donnele et al. (2018) The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov 8:403-416
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Ho, G-T; Aird, R E; Liu, B et al. (2018) MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol 11:120-130
Keith, Benjamin P; Barrow, Jasmine B; Toyonaga, Takahiko et al. (2018) Colonic epithelial miR-31 associates with the development of Crohn's phenotypes. JCI Insight 3:
Sartor, R Balfour; Wu, Gary D (2017) Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology 152:327-339.e4

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