Abstract: The composition and function of the human intestinal microbiota is tightly linked to diverse aspects of host biology. Several diseases, including obesity and inflammatory bowel diseases, have been associated with altered microbiota composition. While much research is currently aimed at a genomic definition of the microbiota in both healthy and diseased states, there is a paucity of studies aimed at understanding this community at a mechanistic and ecological level, and how changes in its function and composition directly impact host biology. The question of whether disease-associated alterations in microbiota composition are a cause or symptom of disease is difficult to address due to the current lack of tools that allow us to test the effect of perturbations in microbiota structure and function on the host in a controlled experimental setting. And once we are able to identify a pathologic microbiota definitively, how will we return it to a healthy state? The goal of this research proposal is to identify small molecules that can alter the microbiota at the level of function and composition, providing (i) tools to aid investigation of altered microbiotas in model organisms and (ii) a model pipeline for identifying a new class of therapeutics that targets the intestinal microbiota. The ability to monitor host responses in gnotobiotic mice colonized with a normal human gut microbiota provides an unprecedented capacity to search for compounds that will be useful in human medicine. While others have speculated on the promise of targeting the microbiota to manipulate human health, specific plans of how this would be achieved are lacking. This proposal lays out a plan to screen for compounds that target specific taxa of the microbiota, characterize the targeted microbiota in vivo, and determine the impact on host biology. Public Health Relevance: A dense and complex community of microbes resides within each person's gastrointestinal tract and plays many important roles in our health, including aiding in our absorption of energy and nutrients from the foods we eat. In rare instances, members of this community can promote diseases, such as inflammatory bowel diseases (e.g. Crohn's disease or ulcerative colitis), demonstrating the precarious nature of our relationship with some of our microscopic associates. The goal of this research project is to identify small molecules that can be used as therapeutic agents to intentionally alter the composition and function of disease-associated gut microbes and thereby improve human health.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD006515-01
Application #
7853143
Study Section
Special Emphasis Panel (ZGM1-NDIA-O (02))
Program Officer
Basavappa, Ravi
Project Start
2009-09-30
Project End
2014-06-30
Budget Start
2009-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$2,400,000
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Whitaker, Weston R; Shepherd, Elizabeth Stanley; Sonnenburg, Justin L (2017) Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut Microbiome. Cell 169:538-546.e12
Earle, Kristen A; Billings, Gabriel; Sigal, Michael et al. (2015) Quantitative Imaging of Gut Microbiota Spatial Organization. Cell Host Microbe 18:478-88
Ferrari, Roberto; Gou, Dawei; Jawdekar, Gauri et al. (2014) Adenovirus small E1A employs the lysine acetylases p300/CBP and tumor suppressor Rb to repress select host genes and promote productive virus infection. Cell Host Microbe 16:663-76
Sonnenburg, Erica D; Sonnenburg, Justin L (2014) Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab 20:779-86
Macadangdang, Benjamin R; Oberai, Amit; Spektor, Tanya et al. (2014) Evolution of histone 2A for chromatin compaction in eukaryotes. Elife 3:
Sonnenburg, Erica D; Sonnenburg, Justin L (2014) Gut microbes take their vitamins. Cell Host Microbe 15:5-6
Marcobal, A; Kashyap, P C; Nelson, T A et al. (2013) A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice. ISME J 7:1933-43
Marcobal, Angela; Barboza, Mariana; Sonnenburg, Erica D et al. (2011) Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe 10:507-14
Sonnenburg, Justin L; Fischbach, Michael A (2011) Community health care: therapeutic opportunities in the human microbiome. Sci Transl Med 3:78ps12
Fischbach, Michael A; Sonnenburg, Justin L (2011) Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 10:336-47

Showing the most recent 10 out of 11 publications