Humans harbor a highly diverse and complex population of microorganisms in our gastrointestinal (GI) tracts that appear to have profound influences on the balance between health and disease. Although many recent investigations have focused on sequence-based profiling of microbial communities within the human gut, the mechanistic basis for how these communities are established and maintained is poorly described. We recently reported the first example of a molecular mechanism by which any symbiotic bacteria establishes initial colonization of a mammalian host. Our studies show that Bacteroides fragilis, a numerically prominent gut symbiont of humans, establishes colonization of the mammalian gut by varying its surface capsular polysaccharides (Liu, Lee et al., PNAS, 2008). This organism engenders health during its colonization of animals, as B. fragilis prevents intestinal inflammation caused by enteric pathogens. Therefore, B. fragilis augments our immune system to help fight diseases by infectious agents. Our preliminary data included, in this application, strongly suggest that maintenance of colonization is mediated by mechanisms distinct from initial colonization. Molecules other than capsular polysaccharides are required for stable association of B. fragilis with its host during protection from disease. As colonization of the GI tract by commensal bacteria helps our immune system fight infections, we propose to investigate the molecular mechanisms required during sustained host colonization by B. fragilis. Initially, we will characterize the anatomical niche occupied by B. fragilis within the intestines of experimental animals (Aim 1). Demonstration of a physical interaction between B. fragilis and its host will reinforce the hypothesis that this organism has evolved dedicated molecules that mediate gut colonization. Subsequently, we propose to identify and characterize the molecular machinery required for maintained intestinal colonization (Aim 2). The discovery of molecules that promote host-symbiont interactions will facilitate the development and delivery of novel probiotic therapies for human diseases caused by pathogenic bacteria.

Public Health Relevance

Decades of research in microbiology have identified numerous virulence factors from many diverse pathogens. However, the study of colonization factors employed by commensal bacteria has only recently been investigated. Bacteroides fragilis is an important commensal microorganism of the human gastrointestinal tract, and has emerged as a model symbiont due to its ability to prevent intestinal inflammation. Therefore, just as virulence factors are important for the biology of pathogens, colonization factors are important for symbiotic microbes to exert their profound benefits to their mammalian hosts. The discovery of molecules or molecular pathways that mediate host-symbiont association is a burgeoning and important area of research worthy of study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK083633-01A1
Application #
7790135
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Hamilton, Frank A
Project Start
2010-04-15
Project End
2012-01-31
Budget Start
2010-04-15
Budget End
2011-01-31
Support Year
1
Fiscal Year
2010
Total Cost
$283,500
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Lee, S Melanie; Donaldson, Gregory P; Mikulski, Zbigniew et al. (2013) Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501:426-9
Shen, Yue; Giardino Torchia, Maria Letizia; Lawson, Gregory W et al. (2012) Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12:509-20
Huang, Julie Y; Lee, S Melanie; Mazmanian, Sarkis K (2011) The human commensal Bacteroides fragilis binds intestinal mucin. Anaerobe 17:137-41
Chow, Janet; Tang, Haiqing; Mazmanian, Sarkis K (2011) Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 23:473-80
Round, June L; Lee, S Melanie; Li, Jennifer et al. (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974-7
Lee, Yun Kyung; Mazmanian, Sarkis K (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330:1768-73
Chow, Janet; Lee, S Melanie; Shen, Yue et al. (2010) Host-bacterial symbiosis in health and disease. Adv Immunol 107:243-74