The precise etiologies of the multiple disorders collectively known as inflammatory bowel disease (IBD) remain unknown. Despite identification of >100 human genetic polymorphisms that are thought to play a role, an unexplained facet of genetic predisposition to IBD is that it typically explains only a fraction of disease risk. The existence of modifying factors has thus been invoked to explain the weakly penetrant disease development. Environmental factors?including diet and the dense community of gut microbes (microbiota)?have been prominent suspects. However, the functional interconnections between these potential contributors remain unknown. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced and metabolically characterized commensal bacteria, we have begun to elucidate the mechanistic interactions between dietary fiber, the gut microbiota and the colonic mucus barrier, which serves as a primary defense against encroachment by intestinal bacteria. During dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of the mucus layer. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. More strikingly, when this same synthetic microbiota is assembled in mice deficient in interleukin 10 (IL-10), a cytokine for which loss of function defects have been associated with human IBD, animals develop lethal spontaneous inflammation in the absence of C. rodentium, but only on a low fiber diet. Our work has therefore revealed functional interconnections between diet, gut microbiota, mucosal barrier function and spontaneous IBD development. Our central hypothesis is that there is a dynamic balance between fiber- and mucus- degrading bacteria, such that in low fiber conditions the mucus layer is increasingly eroded resulting in a temporal disease progression involving host or microbial changes and that this can be ameliorated by preventative or therapeutic fiber consumption. The proposed work will extend the findings outlined above by first measuring the respective contributions of mucin-degrading bacteria and their functions towards eroding the mucosal barrier and precipitating inflammation. Following this, we will measure the impact of different types of dietary fibers, along with their dosing and consumption schedules, that are required to treat or prevent inflammation. Finally, we will perform time course experiments with microbial, immunological and mucosal barrier readouts to determine how disease progression in this model?which occurs over the course of several weeks?is driven by changes in the homeostasis between gut microbes and the host. We anticipate that our findings will provide detailed functional insight into the constellation of genetic and environmental triggers that conspire to precipitate IBD symptoms. As such, they will provide paths to future research in humans, which are built on a foundation of functional knowledge of fiber-microbiota interactions gathered in a tractable model.

Public Health Relevance

We have shown that the absence of sufficient dietary fiber triggers an increase in the abundance of mucus degrading bacteria in the colon, leading to erosion of the protective mucus layer and higher susceptibility to development of inflammatory bowel disease (IBD). The goal of the proposed work is to determine the host and bacterial mechanisms involved in disease development and the appropriate types, amounts and consumption habits of dietary fibers that can be introduced to restore a normal mucus barrier in the gut. This knowledge will be used to improve gastrointestinal health and treat or prevent chronic disease such as IBD and colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK118024-02
Application #
9737929
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2018-07-03
Project End
2022-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109