Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease

Rafael Valdés-Mas; Avner Leshem; Danping Zheng; Yotam Cohen; Lara Kern; Niv Zmora; Yiming He; Corine Katina; Shimrit Eliyahu-Miller; Tal Yosef-Hevroni; Liron Richman; Barbara Raykhel; Shira Allswang; Reut Better; Merav Shmueli; Aurelia Saftien; Nyssa Cullin; Fernando Slamovitz; Dragos Ciocan; Kyanna S. Ouyang; Uria Mor; Mally Dori-Bachash; Shahar Molina; Yishai Levin; Koji Atarashi; Ghil Jona; Jens Puschhof; Alon Harmelin; Noa Stettner; Minhu Chen; Jotham Suez; Kenya Honda; Wolfgang Lieb; Corinna Bang; Michal Kori; Nitsan Maharshak; Yifat Merbl; Oren Shibolet; Zamir Halpern; Dror S. Shouval; Raanan Shamir; Andre Franke; Suhaib K. Abdeen; Hagit Shapiro; Alon Savidor; Eran Elinav

doi:10.1016/j.cell.2024.12.016

Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease

Rafael Valdés-Mas
, Avner Leshem
, Danping Zheng
, Yotam Cohen
, Lara Kern
, Niv Zmora
, Yiming He
, Corine Katina
, Shimrit Eliyahu-Miller
, Tal Yosef-Hevroni
, Liron Richman
, Barbara Raykhel
, Shira Allswang
, Reut Better
, Merav Shmueli
, Aurelia Saftien
, Nyssa Cullin
, Fernando Slamovitz
, Dragos Ciocan
, Kyanna S. Ouyang

Uria Mor, Mally Dori-Bachash, Shahar Molina, Yishai Levin, Koji Atarashi, Ghil Jona, Jens Puschhof, Alon Harmelin, Noa Stettner, Minhu Chen, Jotham Suez, Kenya Honda, Wolfgang Lieb, Corinna Bang, Michal Kori, Nitsan Maharshak, Yifat Merbl, Oren Shibolet, Zamir Halpern, Dror S. Shouval, Raanan Shamir, Andre Franke, Suhaib K. Abdeen, Hagit Shapiro, Alon Savidor, Eran Elinav^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

75 Citations (Scopus)

Abstract

Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.

Original language	English
Pages (from-to)	1062-1083.e36
Number of pages	22
Journal	Cell
Volume	188
Issue number	4
Early online date	20 Jan 2025
DOIs	https://doi.org/10.1016/j.cell.2024.12.016
Publication status	Published - 20 Feb 2025

Funding

We thank the Weizmann Institute of Science and DKFZ for their continuous support. We thank Carmit Bar-Nathan, Timur Liwinski, Denise Kviatcovsky, and Roni Cohen for experimental help. We are grateful for the continued support by and partnership with the Leona M. and Harry B. Helmsley Charitable Trust in this and other IBD-focused projects. The project was supported in part by the Israel Science Foundation (E.E., 1197/19). R.V.-M. received a senior postdoctoral fellowship from the Weizmann Institute of Science (WIS). A.L. received an Orion scholarship from the Kahn Foundation. D.Z. is supported by the Young Scientists Fund of the National Natural Science Foundation of China (82100549). S.K.A. is supported by the Israel Ministry of Science and Technology Zvi Yanai Fellowship and by a Council of Higher Education (VATAT) Senor Scientist scholarship. H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. German UC cohort (KINDRED) German Research Foundation (DFG) grants include Excellence Clusters “Inflammation at interfaces” (EXC 306), “Precision Medicine in Inflammation” (PMI; EXC 2167), and Research Unit miTarget (FOR 5042), as well as German Ministry of Education and Research grant 01ZX1606A. K.H. is supported by the AMED Moonshot Program (JP22zf0127007), the AMED NEDDTrim program (JP21ae0121041), the WPI program (MEXT, Japan), and the Grant-in-Aid for Specially Promoted Research (JSPS, 20H05627). E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a Kimmel researcher, a Partner of the Novo Nordisk Foundation Microbiome Health Initiative (MHI), a senior CIFAR fellow, and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2024.12.016

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Valdés-Mas, R., Leshem, A., Zheng, D., Cohen, Y., Kern, L., Zmora, N., He, Y., Katina, C., Eliyahu-Miller, S., Yosef-Hevroni, T., Richman, L., Raykhel, B., Allswang, S., Better, R., Shmueli, M., Saftien, A., Cullin, N., Slamovitz, F., Ciocan, D., ... Elinav, E. (2025). Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease. Cell, 188(4), 1062-1083.e36. https://doi.org/10.1016/j.cell.2024.12.016

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title = "Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease",

abstract = "Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a {\textquotedblleft}compositional dysbiosis{\textquotedblright} and a concomitant species-specific {\textquotedblleft}functional dysbiosis{\textquotedblright} driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.",

author = "Rafael Vald{\'e}s-Mas and Avner Leshem and Danping Zheng and Yotam Cohen and Lara Kern and Niv Zmora and Yiming He and Corine Katina and Shimrit Eliyahu-Miller and Tal Yosef-Hevroni and Liron Richman and Barbara Raykhel and Shira Allswang and Reut Better and Merav Shmueli and Aurelia Saftien and Nyssa Cullin and Fernando Slamovitz and Dragos Ciocan and Ouyang, \{Kyanna S.\} and Uria Mor and Mally Dori-Bachash and Shahar Molina and Yishai Levin and Koji Atarashi and Ghil Jona and Jens Puschhof and Alon Harmelin and Noa Stettner and Minhu Chen and Jotham Suez and Kenya Honda and Wolfgang Lieb and Corinna Bang and Michal Kori and Nitsan Maharshak and Yifat Merbl and Oren Shibolet and Zamir Halpern and Shouval, \{Dror S.\} and Raanan Shamir and Andre Franke and Abdeen, \{Suhaib K.\} and Hagit Shapiro and Alon Savidor and Eran Elinav",

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Valdés-Mas, R, Leshem, A, Zheng, D, Cohen, Y, Kern, L, Zmora, N, He, Y, Katina, C, Eliyahu-Miller, S, Yosef-Hevroni, T, Richman, L, Raykhel, B, Allswang, S, Better, R, Shmueli, M, Saftien, A, Cullin, N, Slamovitz, F, Ciocan, D, Ouyang, KS, Mor, U, Dori-Bachash, M, Molina, S, Levin, Y, Atarashi, K, Jona, G, Puschhof, J, Harmelin, A, Stettner, N, Chen, M, Suez, J, Honda, K, Lieb, W, Bang, C, Kori, M, Maharshak, N, Merbl, Y, Shibolet, O, Halpern, Z, Shouval, DS, Shamir, R, Franke, A, Abdeen, SK , Shapiro, H , Savidor, A & Elinav, E 2025, 'Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease', Cell, vol. 188, no. 4, pp. 1062-1083.e36. https://doi.org/10.1016/j.cell.2024.12.016

TY - JOUR

T1 - Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease

AU - Valdés-Mas, Rafael

AU - Leshem, Avner

AU - Zheng, Danping

AU - Cohen, Yotam

AU - Kern, Lara

AU - Zmora, Niv

AU - He, Yiming

AU - Katina, Corine

AU - Eliyahu-Miller, Shimrit

AU - Yosef-Hevroni, Tal

AU - Richman, Liron

AU - Raykhel, Barbara

AU - Allswang, Shira

AU - Better, Reut

AU - Shmueli, Merav

AU - Saftien, Aurelia

AU - Cullin, Nyssa

AU - Slamovitz, Fernando

AU - Ciocan, Dragos

AU - Ouyang, Kyanna S.

AU - Mor, Uria

AU - Dori-Bachash, Mally

AU - Molina, Shahar

AU - Levin, Yishai

AU - Atarashi, Koji

AU - Jona, Ghil

AU - Puschhof, Jens

AU - Harmelin, Alon

AU - Stettner, Noa

AU - Chen, Minhu

AU - Suez, Jotham

AU - Honda, Kenya

AU - Lieb, Wolfgang

AU - Bang, Corinna

AU - Kori, Michal

AU - Maharshak, Nitsan

AU - Merbl, Yifat

AU - Shibolet, Oren

AU - Halpern, Zamir

AU - Shouval, Dror S.

AU - Shamir, Raanan

AU - Franke, Andre

AU - Abdeen, Suhaib K.

AU - Shapiro, Hagit

AU - Savidor, Alon

AU - Elinav, Eran

PY - 2025/2/20

Y1 - 2025/2/20

N2 - Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.

AB - Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.

UR - https://www.scopus.com/pages/publications/85217214200

U2 - 10.1016/j.cell.2024.12.016

DO - 10.1016/j.cell.2024.12.016

M3 - Article

C2 - 39837331

AN - SCOPUS:85217214200

SN - 0092-8674

VL - 188

SP - 1062-1083.e36

JO - Cell

JF - Cell

IS - 4

ER -

Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease

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