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 #
5R01GM095372-08
Application #
9774069
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Maas, Stefan
Project Start
2011-01-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cornell University
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Kim, Geonho; Huang, Jia Hsin; McMullen 2nd, John G et al. (2018) Physiological responses of insects to microbial fermentation products: Insights from the interactions between Drosophila and acetic acid. J Insect Physiol 106:13-19
Douglas, Angela E (2018) What will it take to understand the ecology of symbiotic microorganisms? Environ Microbiol :
Douglas, Angela E (2018) Which experimental systems should we use for human microbiome science? PLoS Biol 16:e2005245
Sexton, Corinne E; Smith, Hayden Z; Newell, Peter D et al. (2018) MAGNAMWAR: an R package for genome-wide association studies of bacterial orthologs. Bioinformatics 34:1951-1952
Inamine, Hidetoshi; Ellner, Stephen P; Newell, Peter D et al. (2018) Spatiotemporally Heterogeneous Population Dynamics of Gut Bacteria Inferred from Fecal Time Series Data. MBio 9:
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
Koyle, Melinda L; Veloz, Madeline; Judd, Alec M et al. (2016) Rearing the Fruit Fly Drosophila melanogaster Under Axenic and Gnotobiotic Conditions. J Vis Exp :
Chaston, John M; Dobson, Adam J; Newell, Peter D et al. (2016) Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype. Appl Environ Microbiol 82:671-9
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

Showing the most recent 10 out of 30 publications