Renewed interest in the microbiome has yielded numerous intriguing findings about the role of bacterial symbiontsinhumanbiologyanddisease.However,mostofthesefindingsarecorrelativeandassociative;?little is known about microbiota-host interactions at the level of molecular mechanism. Typical approaches to addressthisproblemareone-offeffortsthatattempttofindanindividualmoleculeresponsibleforaphenotype of interest. Here, we propose to upend this paradigm by systematically studying one of the most concrete contributions of the microbiota to human biology: the ?top 100? molecules, by abundance, from the gut community. These molecules vary widely in concentration among individuals, can accumulate in host circulation,andarepresentatlevelsthatmatchorexceedtheconcentrationofatypicalsmallmoleculedrug. Theworkweproposehere?todeterminethebacterialspeciesthatproduceeachofthetop100,andidentify the genes responsible ? will be the first step toward creating a capability to completely specify the molecular outputofthegutcommunity(whichmoleculesareproduced,andwhichothersarenot),aprocesswewillpilot inthecurrentproject. Thisensembleofdozensofhigh-concentrationmolecules?towhichweareexposeddaily?islikelytobea majordriverofhumanbiologyanddisease.Itisnotunreasonabletoimagineafutureinwhicheveryhuman will harbor a ?reprogrammed? (synthetic) gut community whose molecular output has been optimized for diseasetreatmentandprevention. The fields of natural product discovery and microbiome research are dominated by genomics-driven approaches.Thesolutionweproposehererunsentirelycountertothistrend:wewillstartwith1)anempirical approachthatis,inessence,old-fashionedBergey?s-stylemicrobiologyoutfittedwithstate-of-the-artanalytical chemistry.Usingtherichinformationwederivefromempiricalmetabolicprofiling,wewillthen2)usegenetics and biochemistry to identify the genes responsible for synthesizing the top 100, 3) use this information to deviseacomputationalalgorithmthatcanpredictmetabolicoutputdirectlyfrommetagenomicsequencedata, and4)testourpredictionsusingsimplesyntheticcommunities.Ourdatawillcreatearichmetabolicmapofthe top 100, and will enable the construction of transplant-ready synthetic communities that produce custom cocktailsofdesiredmolecules(anddonotproduceundesiredmolecules).

Public Health Relevance

Oneofthemostconcretecontributionsgutbacteriamaketohumanbiologyistoproduceacocktailof smallmolecules,someofwhichareabsorbedathighlevelsintocirculation.Thisproposaldescribesa systematicapproachtoidentifyingwhichbacterialspeciesandgenesareresponsibleformakingeach of the ?top 100? molecules by abundance from the gut bacterial community. Our project will not only lead to a greater understanding of the connection between the human microbiome and human disease, it will also lay the groundwork for a larger effort to specify and optimize the cocktail of biologicallyactivesmallmoleculesproducedbythegutmicrobiota.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1DK113598-04
Application #
9538680
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Karp, Robert W
Project Start
2016-09-08
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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