Inflammatory bowel disease (IBD) represents a serious medical disorder marked by aberrant immune responses within the human gastrointestinal tract, and results in severe clinical outcomes in affected patients. Overwhelming clinical and laboratory research has shown that commensal bacteria, harbored within the intestines of human patients and animals, are the targets of inflammatory responses. Furthermore, many researchers have predicted that members of the gut microflora may modulate the development of IBD, and that certain subsets of symbiotic bacteria may direct protective mucosal immune responses. However, the identity of these beneficial microbes and the molecular mechanisms they employ during protection from disease are largely unknown. We have shown that during symbiosis of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Most significantly, the importance of this process to health is demonstrated by our findings that colonization with B. fragilis protects animals from experimental colitis. Thus, for the first time, a single symbiotic bacterial species has been experimentally demonstrated to direct a beneficial immunologic program during protection from disease. Preliminary data suggest a novel process of intestinal immune regulation and anti-inflammatory responses elicited in the gastrointestinal tract of protected animals. However, the biological mechanisms which govern how B. fragilis promotes health remain almost entirely undefined. Through the merger of immunologic and microbiologic approaches incorporated into a widely-relevant animal model, we seek to identify the immune cells and molecules required to mediate the critical balance between intestinal health and disease during host-bacterial symbiosis.

Public Health Relevance

Inflammatory bowel disease affects millions of people world-wide, causing widespread suffering and mortality. We seek to determine if the beneficial intestinal microorganism, Bacteroides fragilis, can serve as a probiotic to protect laboratory animals from experimental colitis. Based on strong preliminary evidence, we propose this unique microbe can elicit host anti-inflammatory responses to establish intestinal health in animals. Most importantly, this information may potentially provide the basis for development of novel therapeutic treatments for IBD in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078938-04
Application #
8245742
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2009-04-01
Project End
2013-08-31
Budget Start
2012-04-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$345,339
Indirect Cost
$132,167
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
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
Sampson, Timothy R; Mazmanian, Sarkis K (2015) Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17:565-76

Showing the most recent 10 out of 31 publications