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).
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.
| Fischbach, Michael A (2018) Microbiome: Focus on Causation and Mechanism. Cell 174:785-790 |
| Chen, Y Erin; Fischbach, Michael A; Belkaid, Yasmine (2018) Skin microbiota-host interactions. Nature 553:427-436 |
| Jacobson, Amy N; Choudhury, Biswa P; Fischbach, Michael A (2018) The Biosynthesis of Lipooligosaccharide from Bacteroides thetaiotaomicron. MBio 9: |
| Ridaura, Vanessa K; Bouladoux, Nicolas; Claesen, Jan et al. (2018) Contextual control of skin immunity and inflammation by Corynebacterium. J Exp Med 215:785-799 |
| Horlbeck, Max A; Xu, Albert; Wang, Min et al. (2018) Mapping the Genetic Landscape of Human Cells. Cell 174:953-967.e22 |
| Skye, Sarah M; Zhu, Weifei; Romano, Kymberleigh A et al. (2018) Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res 123:1164-1176 |
| Dodd, Dylan; Spitzer, Matthew H; Van Treuren, William et al. (2017) A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551:648-652 |
