Microbes that inhabit the mucin layer that separates epithelial surfaces from the bulk of microbial contents of the gastrointestinal tract (GI) play a critical role in maintaining the metabolic and immunological health of their host. For instance, the mucolytic, gram negative, obligate anaerobic bacterium Akkermansia muciniphila is associated with protection from high-fat induced obesity. Concomitantly, the abundance of this microbe decreases in humans on western style diets. Importantly, in mouse models of diet-induced obesity, experimental colonization with A. mucinophila leads to lower rates of weight gain and glucose resistance. In addition, A. muciniphila contributes to dampening inflammation by enhancing mucin production and promoting intestinal barrier integrity through enhanced formation of epithelial cell junctions. Not surprisingly, A. muciniphila is being considered as a potential commercial probiotic. Unfortunately, the molecular mechanisms underlying the interactions between Akkermansia, its host, and associated microbial communities are largely unknown In this application, we propose to apply genetic methods we recently developed to characterize the process of mucin acquisition and degradation by A. mucinipihila, develop new ex vivo colonization models to test the impact of A. muciniphila exposure on epithelial cell physiology and function, and define the role that mucin metabolism plays in Akkermansia colonization of mice and its impact on GI ecology. The proposed work will generate new genetic tools and host model systems with which to understand the molecular basis of how this emerging beneficial microbe exerts its health-promoting effects on its host, and aid in the engineering of A. muciniphila strains with enhanced probiotic functions.

Public Health Relevance

Akkermansia muciniphila is new microbial commensal whose abundance in the gastrointestinal tract (GI) is associated with immunological and metabolic health. The goal of this proposal is to develop novel methods and experimental platforms to define how this microbe colonizes the mucin layer of the GI and exerts its positive influence on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI142376-01
Application #
9652782
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Ranallo, Ryan
Project Start
2018-09-21
Project End
2023-08-31
Budget Start
2018-09-21
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705