Perturbation to the human gut microbial community is associated with various gastro-intestinal diseases and metabolic ill-health, especially obesity, but the complexity of this system is hampering the development of reliable microbiological therapies, e.g. probiotics. The naturally simple gut microbial community in Drosophila fruit flies offers a superb model for the overall research goal to determine the mechanistic basis of interactions between gut microbiota and host metabolic health. Building on evidence that the gut microbiota protects Drosophila against hyperlipidemia and hyperglycemia, the first aim of this project is to identify the microbial fermentation products of gut microbiota that protect the host against excessive energy storage (i.e. high levels of lipid, glycogen and sugars), by identifying the metabolites released from microbial communities that reduce energy storage indices; these functional metabolites likely include the products of polymicrobial metabolism.
The second aim will test the hypothesis (based on preliminary data) that microbial-mediated reduction in energy storage is promoted by enhanced mobilization of free sugar, lipid and glycogen in the gut epithelium. The metabolic response of the host to the gut microbiota and their metabolic products will be quantified by isotopic analysis of dietary glucose metabolism in flies colonized with different microorganisms, and the role of candidate metabolic enzymes in reducing energy storage will be identified by RNAi-expression knockdown in the fly gut. These data will inform the third aim, to establish the mechanistic basis of the efficacy of probiotic Lactobacillus to reduce energy storage in flies associated with unmanipulated microbiotas that vary in capacity to reduce energy storage. Using metabolic modeling informed by transcriptomic and metabolomic data, the metabolic reactions and pathways (in the host and microbiota) that mediate microbiota-mediated reduction in energy storage will be identified; and the contribution of metabolic function, abundance and persistence of orally-administered Lactobacillus in the gut to probiotic-mediated protection against hyperglycemia and hyperlipidemia will be determined. Overall, this project will identify microbial products and host metabolic responses that underpin gut microbiota-mediated protection against hyperglycemia and hyperlipidemia, key indices of human metabolic disease, with quantitative metabolic models that can be extrapolated to the mammalian system; and provide a systematic understanding of the metabolic and population processes shaping the efficacy of Lactobacillus (widely used as probiotic in human foods) for metabolic health. It will also provide a Drosophila model for probiotic research that can be extended beyond study of the impacts of interactions with gut microbiotas of different composition in this project to address other critically-important variables, including host genotype and diet.

Public Health Relevance

Gut microorganisms are an important determinant of gut health in humans and other animal hosts. The proposed study will determine the impact of microbial communities of systematically- varied composition and complexity on gut function. This research will identify the interactions between the gut and microbes that shape metabolic health, especially fat and circulating sugar contents, and generate a tractable research model for probiotic therapies to resolve clinical conditions associated with dysfunctional gut microbial communities.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM095372-05A1
Application #
9173272
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Reddy, Michael K
Project Start
2011-01-01
Project End
2020-08-31
Budget Start
2016-09-23
Budget End
2017-08-31
Support Year
5
Fiscal Year
2016
Total Cost
$315,519
Indirect Cost
$115,519
Name
Cornell University
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Winans, Nathan J; Walter, Alec; Chouaia, Bessem et al. (2017) A genomic investigation of ecological differentiation between free-living and Drosophila-associated bacteria. Mol Ecol 26:4536-4550
Kim, Geonho; Huang, Jia Hsin; McMullen 2nd, John G et al. (2017) Physiological responses of insects to microbial fermentation products: Insights from the interactions between Drosophila and acetic acid. J Insect Physiol :
Dobson, Adam J; Chaston, John M; Douglas, Angela E (2016) The Drosophila transcriptional network is structured by microbiota. BMC Genomics 17:975
Dobson, Adam J; Chaston, John M; Newell, Peter D et al. (2015) Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster. Nat Commun 6:6312
Wong, Adam C-N; Luo, Yuan; Jing, Xiangfeng et al. (2015) The Host as the Driver of the Microbiota in the Gut and External Environment of Drosophila melanogaster. Appl Environ Microbiol 81:6232-40
Dobson, Adam J; Chaston, John M; Newell, Peter D et al. (2015) Corrigendum: Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster. Nat Commun 6:7296
Douglas, Angela E (2015) Multiorganismal insects: diversity and function of resident microorganisms. Annu Rev Entomol 60:17-34
Huang, Jia-Hsin; Jing, Xiangfeng; Douglas, Angela E (2015) The multi-tasking gut epithelium of insects. Insect Biochem Mol Biol 67:15-20
Huang, Jia-Hsin; Douglas, Angela E (2015) Consumption of dietary sugar by gut bacteria determines Drosophila lipid content. Biol Lett 11:20150469
Chaston, John M; Dobson, Adam J; Newell, Peter D et al. (2015) Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype. Appl Environ Microbiol 82:671-9

Showing the most recent 10 out of 26 publications