Abstract
Great progress has been made in understanding gut microbiomes’ products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
| Original language | English |
|---|---|
| Pages (from-to) | 3441-3456.e19 |
| Journal | Cell |
| Volume | 185 |
| Issue number | 18 |
| DOIs | |
| State | Published - 1 Sep 2022 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 Elsevier Inc.
Funding
This work is supported by the NIH Pioneer award IDP1DK113643 (J.D.R.), Stand Up to Cancer Convergence Award 3.14.16 probing the cancer-microbiome connection (J.D.R.), Ludwig Cancer Research (J.D.R.), NIH grant R35GM128813 (M.W.), Princeton Catalysis Initiative (M.W.), Eric and Wendy Schmidt Transformative Technology Fund (M.W), NIH grant 1R01AA029124 (C.J.), and the Pew Biomedical Scholars Program (M.S.D). M.G. is funded by a Harold W. Dodds Fellowship. F.C.K is funded by EMBO ALTF 601-2018. J.G.L. is funded by a National Science Foundation Graduate Research Fellowship (2017249408). Y.-C.J.L. is funded by the High Meadows Environmental Institute at Princeton University through the generous support of the William Clay Ford, Jr. ’79 and Lisa Vanderzee Ford ’82 Graduate Fellowship fund and by a training grant from the National Institute of General Medicine Sciences (T32GM007388). M.D.N. is supported by NIH 5T32CA257957. We thank Sheng Hui, Michel Nofal, Yihui Shen, Lingfan Liang, Won Dong Lee, and other Rabinowitz lab members for their input and advice. We thank Seema Chatterjee for the assistance with DNA extraction. We thank Michael Stadlmeier, Thao Nguyen, and Alex Johnson for the assistance with proteomics. We thank Wei Wang and the Lewis-Sigler Institute sequencing core facility for assistance with HT sequencing. X.Z. and J.D.R. came up with the general approach. X.Z. performed most of the experiment and data analysis. C.J. worked intensively with X.Z. to develop the experimental strategy. M.W. designed and enabled the proteomic measurements. X.X. wrote the MATLAB code. M.G. F.C.K. and M.D.N. contributed to proteomics method development. J.G.L. and M.S.D. provided microbiome expertise and performed 16S rRNA gene amplicon sequencing. Y.-C.J.L. performed in vitro bacterial culture studies. A.R. assisted with isotope tracing. L.W. performed ammonia measurement. X.Z. C.J. and J.D.R. wrote the paper. All the authors discussed the results and commented on the paper. J.D.R. is a member of the Rutgers Cancer Institute of New Jersey and the University of Pennsylvania Diabetes Research Center; a co-founder and stockholder in Empress Therapeutics and Serien Therapeutics; and an advisor and stockholder in Agios Pharmaceuticals, Bantam Pharmaceuticals, Colorado Research Partners, Rafael Pharmaceuticals, Barer Institute, and L.E.A.F. Pharmaceuticals. M.S.D. is a member of the scientific advisory boards of DeepBiome Therapeutics and VastBiome. This work is supported by the NIH Pioneer award IDP1DK113643 (J.D.R.), Stand Up to Cancer Convergence Award 3.14.16 probing the cancer-microbiome connection (J.D.R.), Ludwig Cancer Research (J.D.R.), NIH grant R35GM128813 (M.W.), Princeton Catalysis Initiative (M.W.), Eric and Wendy Schmidt Transformative Technology Fund (M.W), NIH grant 1R01AA029124 (C.J.), and the Pew Biomedical Scholars Program (M.S.D). M.G. is funded by a Harold W. Dodds Fellowship . F.C.K is funded by EMBO ALTF 601-2018 . J.G.L. is funded by a National Science Foundation Graduate Research Fellowship ( 2017249408 ). Y.-C.J.L. is funded by the High Meadows Environmental Institute at Princeton University through the generous support of the William Clay Ford, Jr. ’79 and Lisa Vanderzee Ford ’82 Graduate Fellowship fund and by a training grant from the National Institute of General Medicine Sciences ( T32GM007388 ). M.D.N. is supported by NIH 5T32CA257957 . We thank Sheng Hui, Michel Nofal, Yihui Shen, Lingfan Liang, Won Dong Lee, and other Rabinowitz lab members for their input and advice. We thank Seema Chatterjee for the assistance with DNA extraction. We thank Michael Stadlmeier, Thao Nguyen, and Alex Johnson for the assistance with proteomics. We thank Wei Wang and the Lewis-Sigler Institute sequencing core facility for assistance with HT sequencing.
| Funders | Funder number |
|---|---|
| Alex Johnson | |
| Barer Institute | |
| DeepBiome Therapeutics | |
| High Meadows Environmental Institute at Princeton University | |
| Princeton Catalysis Initiative | 1R01AA029124 |
| University of Pennsylvania Diabetes Research Center | |
| VastBiome | |
| National Science Foundation | 2017249408 |
| National Institutes of Health | IDP1DK113643 |
| National Institute of General Medical Sciences | R35GM128813, T32GM007388, 5T32CA257957 |
| Pew Charitable Trusts | |
| European Molecular Biology Organization | ALTF 601-2018 |
| Ludwig Institute for Cancer Research |
Keywords
- diet
- host-microbiome interactions
- isotope tracing
- metabolism
- metabolomics
- methodology
- mice
- microbiome
- nutrient
- proteomics