Background: The microbes residing in and on the human body influence host health and disease in part due to their metabolism of xenobiotics (foreign compounds like host-targeted drugs, antibiotics, and dietary components). Yet microbial xenobiotic metabolism remains an underexplored aspect of pharmacology and nutrition, with the bacterial groups and metabolic pathways responsible often unknown. We are addressing this critical knowledge gap through the use of methods for the single cell analysis of gut microbial communities, metagenomic sequencing of microbial community DNA and RNA, and gnotobiotics (germ-free and colonized mice). Ultimately, we aim to obtain a more comprehensive view of human metabolism, yielding fundamental insights into host-microbial interactions and supporting translational efforts to predict and manipulate the metabolic activities of our resident gut microbes.
Major goals: (i) elucidate the microbial mechanisms that influence xenobiotic metabolism; (ii) determine how microbial communities adapt during exposure to xenobiotics; (iii) test the relative importance of host, microbial, and environmental factors in shaping the fate of xenobiotics.
Project 1) The bacterial inactivation of cardiac drugs. We are studying the inactivation of the cardiac drug digoxin (used to treat heart failure and arrhythmia) by the gut bacterium Eggerthella lenta via the reduction of digoxin’s α,β-unsaturated lactone ring. Previously, we discovered two bacterial cytochromes—the cardiac glycoside reductase (cgr) operon—that are induced by digoxin, unique to E.lenta strains capable of reduction, and predictive of digoxin reduction during the in vitro incubation of the human fecal microbiome. Experiments in gnotobiotic mice (germ-free animals colonized with reducing or non-reducing strains of E.lenta) revealed that rational dietary manipulations, namely increased protein intake, could lessen the microbial inactivation of digoxin.
Current work in the our group is focused on further elucidating the genetic and biochemical mechanisms responsible, uncovering the selection pressures that maintain the cgr operon in vivo, and using this system as a model to dissect host-microbial interactions that shape the fate of these and other xenobiotics.
Project 2) Dietary antimicrobial compounds. Many edible plants produce potent antimicrobial compounds as a defense against predation from bacteria and fungi. When these plant foods are eaten raw, these compounds could theoretically exert effects on the gut microbiota. We are using conventionally raised and gnotobiotic mice to study the impact of diets that vary in their antimicrobial loads as a result of cooking or supplementation. Our preliminary results suggest that dietary compounds can damage gut microbes, reshaping gut microbial ecology in a manner that limits host energy gain. These results encourage a view beyond therapeutics in considering the impact of xenobiotic compounds on host-microbial interactions.
David, L.A., Maurice, C.M., Carmody, R.N., Gootenberg, D.B., Button, J.E., Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y., Fischbach, M.A., Biddinger, S.B., Dutton, R.J., and P.J. Turnbaugh*. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563 (2014).
Haiser, H.J., Gootenberg, D.B., Chatman, K., Sirasani, G., Balskus, E.P., and P.J. Turnbaugh*. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295-298 (2013). PMCID: PMC3736355
Maurice, C.F., Haiser, H.J., and P.J. Turnbaugh*. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39-50 (2013). [Cover article] PMCID: PMC3552296
Liou, A.P., Paziuk, M., Leuvano, J.M., Turnbaugh, P.J.*, and L.M. Kaplan. Shifts in the gut microbiota contribute to reduced host weight and adiposity after Roux-en-Y gastric bypass in mice. Sci. Transl. Med. 5, 178ra41 (2013). PMCID: PMC3652229
Turnbaugh, P.J., Hamady, M., Yatsunenko, T., Cantarel, B.L., Duncan, A., Ley, R.E., Sogin, M.L., Jones, W.J., Roe, B.A., Affourtit, J.P., Egholm, M., Henrissat, B., Heath, A.C., Knight, R., and J.I. Gordon.A core gut microbiome in obese and lean twins. Nature 457, 480-484 (2009). PMCID: PMC2677729
Turnbaugh, P.J., Ley, R.E., Mahowald, M., Magrini, V., Mardis, E.R., and J.I. Gordon. An obesity-associated microbiome with increased capacity for energy harvest. Nature 444, 1027-1031 (2006). [Cover article] PMID: 17183312