Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome

Ruben A.T. Mars; Yi Yang; Tonya Ward; Mo Houtti; Sambhawa Priya; Heather R. Lekatz; Xiaojia Tang; Zhifu Sun; Krishna R. Kalari; Tal Korem; Yogesh Bhattarai; Tenghao Zheng; Noam Bar; Gary Frost; Abigail J. Johnson; Will van Treuren; Shuo Han; Tamas Ordog; Madhusudan Grover; Justin Sonnenburg; Mauro D'Amato; Michael Camilleri; Eran Elinav; Eran Segal; Ran Blekhman; Gianrico Farrugia; Jonathan R. Swann; Dan Knights; Purna C. Kashyap

doi:10.1016/j.cell.2020.08.007

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome

Ruben A.T. Mars, Yi Yang, Tonya Ward, Mo Houtti, Sambhawa Priya, Heather R. Lekatz, Xiaojia Tang, Zhifu Sun, Krishna R. Kalari, Tal Korem, Yogesh Bhattarai, Tenghao Zheng, Noam Bar, Gary Frost, Abigail J. Johnson, Will van Treuren, Shuo Han, Tamas Ordog, Madhusudan Grover, Justin SonnenburgMauro D'Amato, Michael Camilleri, Eran Elinav, Eran Segal, Ran Blekhman, Gianrico Farrugia, Jonathan R. Swann, Dan Knights, Purna C. Kashyap

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

115 Scopus citations

Abstract

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. Video Abstract: [Figure presented]. Integrated and longitudinal multiomic analyses of patients with irritable bowel syndrome reveals a role for the gut microbiota in modulating purine metabolism and influencing host gastrointestinal function.

Original language	English (US)
Pages (from-to)	1460-1473.e17
Journal	Cell
Volume	182
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2020.08.007
State	Published - Sep 17 2020

Bibliographical note

Funding Information:
The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic , Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London ( https://www.imperial.ac.uk/stratigrad/ ) (Y.Y.); Société des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.).

Funding Information:
The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic, Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London (https://www.imperial.ac.uk/stratigrad/) (Y.Y.); Soci?t? des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.). D.K and P.C.K. designed the experiments and the overall data analysis. R.A.T.M. D.K. and P.C.K. wrote the manuscript with input from co-authors. H.R.L. Y.B. and P.C.K. coordinated human subject recruiting and sampling. Y.Y. T.W. and H.R.L. contributed to sample processing data generation and analysis. T.W. X.T. Z.S. T.Z. W.v.T. S.H. Y.Y. and R.A.T.M. analyzed data. S.P. X.T. K.R.K. T.K. M.H. N.B. W.v.T. S.H. R.B. Y.Y. and R.A.T.M. performed data integration. T.O. M.G. M.D. M.C. E.E. E.S. R.B. G. Farrugia, G. Frost, J.S. J.R.S. D.K. K.R.K. and P.C.K directed research and provided critical feedback. T.O. M.G. G. Farrugia, M.C. and P.C.K. performed clinical data analysis. Y.B. and P.C.K. contributed to design and execution of Ussing chamber experiments. P.C.K. is on the Advisory Board of Novome Biotechnologies and is an ad hoc consultant for Pendulum Therapeutics, IP group, and Otsuka Pharmaceuticals. P.C.K. holds patent US20170042860A1 for use of tryptamine producing bacteria (?Methods and materials for using Ruminococcus gnavus or Clostridium sporogenes to treat gastrointestinal disorders?), and P.C.K. and Mayo Clinic have a financial interest related to this research. These interests have been reviewed and managed in accordance with Mayo Clinic Conflict-of-Interest policies. D.B.K. serves as CEO of CoreBiome, a company involved in the commercialization of microbiome analysis and a wholly owned subsidiary of OraSure Technologies. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

bile acids
diet
functional bowel disorders
nucleosides
physiology
secretion
short chain fatti acids
symptom severity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2020.08.007

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Mars, R. A. T., Yang, Y., Ward, T., Houtti, M., Priya, S., Lekatz, H. R., Tang, X., Sun, Z., Kalari, K. R., Korem, T., Bhattarai, Y., Zheng, T., Bar, N., Frost, G., Johnson, A. J., van Treuren, W., Han, S., Ordog, T., Grover, M., ... Kashyap, P. C. (2020). Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome. Cell, 182(6), 1460-1473.e17. https://doi.org/10.1016/j.cell.2020.08.007

Mars, RAT, Yang, Y, Ward, T, Houtti, M, Priya, S, Lekatz, HR, Tang, X, Sun, Z, Kalari, KR, Korem, T, Bhattarai, Y, Zheng, T, Bar, N, Frost, G, Johnson, AJ, van Treuren, W, Han, S, Ordog, T, Grover, M, Sonnenburg, J, D'Amato, M, Camilleri, M, Elinav, E, Segal, E, Blekhman, R, Farrugia, G, Swann, JR, Knights, D & Kashyap, PC 2020, 'Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome', Cell, vol. 182, no. 6, pp. 1460-1473.e17. https://doi.org/10.1016/j.cell.2020.08.007

@article{ba4784cd7c6d478abec155a3ce68c52f,

title = "Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome",

abstract = "The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. Video Abstract: [Figure presented]. Integrated and longitudinal multiomic analyses of patients with irritable bowel syndrome reveals a role for the gut microbiota in modulating purine metabolism and influencing host gastrointestinal function.",

keywords = "bile acids, diet, functional bowel disorders, nucleosides, physiology, secretion, short chain fatti acids, symptom severity",

author = "Mars, {Ruben A.T.} and Yi Yang and Tonya Ward and Mo Houtti and Sambhawa Priya and Lekatz, {Heather R.} and Xiaojia Tang and Zhifu Sun and Kalari, {Krishna R.} and Tal Korem and Yogesh Bhattarai and Tenghao Zheng and Noam Bar and Gary Frost and Johnson, {Abigail J.} and {van Treuren}, Will and Shuo Han and Tamas Ordog and Madhusudan Grover and Justin Sonnenburg and Mauro D'Amato and Michael Camilleri and Eran Elinav and Eran Segal and Ran Blekhman and Gianrico Farrugia and Swann, {Jonathan R.} and Dan Knights and Kashyap, {Purna C.}",

note = "Funding Information: The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic , Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London ( https://www.imperial.ac.uk/stratigrad/ ) (Y.Y.); Soci{\'e}t{\'e} des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.). Funding Information: The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic, Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London (https://www.imperial.ac.uk/stratigrad/) (Y.Y.); Soci?t? des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.). D.K and P.C.K. designed the experiments and the overall data analysis. R.A.T.M. D.K. and P.C.K. wrote the manuscript with input from co-authors. H.R.L. Y.B. and P.C.K. coordinated human subject recruiting and sampling. Y.Y. T.W. and H.R.L. contributed to sample processing data generation and analysis. T.W. X.T. Z.S. T.Z. W.v.T. S.H. Y.Y. and R.A.T.M. analyzed data. S.P. X.T. K.R.K. T.K. M.H. N.B. W.v.T. S.H. R.B. Y.Y. and R.A.T.M. performed data integration. T.O. M.G. M.D. M.C. E.E. E.S. R.B. G. Farrugia, G. Frost, J.S. J.R.S. D.K. K.R.K. and P.C.K directed research and provided critical feedback. T.O. M.G. G. Farrugia, M.C. and P.C.K. performed clinical data analysis. Y.B. and P.C.K. contributed to design and execution of Ussing chamber experiments. P.C.K. is on the Advisory Board of Novome Biotechnologies and is an ad hoc consultant for Pendulum Therapeutics, IP group, and Otsuka Pharmaceuticals. P.C.K. holds patent US20170042860A1 for use of tryptamine producing bacteria (?Methods and materials for using Ruminococcus gnavus or Clostridium sporogenes to treat gastrointestinal disorders?), and P.C.K. and Mayo Clinic have a financial interest related to this research. These interests have been reviewed and managed in accordance with Mayo Clinic Conflict-of-Interest policies. D.B.K. serves as CEO of CoreBiome, a company involved in the commercialization of microbiome analysis and a wholly owned subsidiary of OraSure Technologies. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

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doi = "10.1016/j.cell.2020.08.007",

language = "English (US)",

volume = "182",

pages = "1460--1473.e17",

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T1 - Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome

AU - Mars, Ruben A.T.

AU - Yang, Yi

AU - Ward, Tonya

AU - Houtti, Mo

AU - Priya, Sambhawa

AU - Lekatz, Heather R.

AU - Tang, Xiaojia

AU - Sun, Zhifu

AU - Kalari, Krishna R.

AU - Korem, Tal

AU - Bhattarai, Yogesh

AU - Zheng, Tenghao

AU - Bar, Noam

AU - Frost, Gary

AU - Johnson, Abigail J.

AU - van Treuren, Will

AU - Han, Shuo

AU - Ordog, Tamas

AU - Grover, Madhusudan

AU - Sonnenburg, Justin

AU - D'Amato, Mauro

AU - Camilleri, Michael

AU - Elinav, Eran

AU - Segal, Eran

AU - Blekhman, Ran

AU - Farrugia, Gianrico

AU - Swann, Jonathan R.

AU - Knights, Dan

AU - Kashyap, Purna C.

N1 - Funding Information: The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic , Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London ( https://www.imperial.ac.uk/stratigrad/ ) (Y.Y.); Société des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.). Funding Information: The authors would like to thank Lyndsay Busby for secretarial assistance and J.M. Nielsen for help with figures. This work was supported by NIH grant DK114007 (P.C.K.); the Center for Individualized Medicine, Mayo Clinic, Rochester, MN (P.C.K.); the Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.); the STRATiGRAD PhD training program of Imperial College London (https://www.imperial.ac.uk/stratigrad/) (Y.Y.); Soci?t? des Produits Nestle (J.R.S.); Imperial College NIHR BRC (J.R.S.); and NIH grant R35-GM128716 (R.B.). D.K and P.C.K. designed the experiments and the overall data analysis. R.A.T.M. D.K. and P.C.K. wrote the manuscript with input from co-authors. H.R.L. Y.B. and P.C.K. coordinated human subject recruiting and sampling. Y.Y. T.W. and H.R.L. contributed to sample processing data generation and analysis. T.W. X.T. Z.S. T.Z. W.v.T. S.H. Y.Y. and R.A.T.M. analyzed data. S.P. X.T. K.R.K. T.K. M.H. N.B. W.v.T. S.H. R.B. Y.Y. and R.A.T.M. performed data integration. T.O. M.G. M.D. M.C. E.E. E.S. R.B. G. Farrugia, G. Frost, J.S. J.R.S. D.K. K.R.K. and P.C.K directed research and provided critical feedback. T.O. M.G. G. Farrugia, M.C. and P.C.K. performed clinical data analysis. Y.B. and P.C.K. contributed to design and execution of Ussing chamber experiments. P.C.K. is on the Advisory Board of Novome Biotechnologies and is an ad hoc consultant for Pendulum Therapeutics, IP group, and Otsuka Pharmaceuticals. P.C.K. holds patent US20170042860A1 for use of tryptamine producing bacteria (?Methods and materials for using Ruminococcus gnavus or Clostridium sporogenes to treat gastrointestinal disorders?), and P.C.K. and Mayo Clinic have a financial interest related to this research. These interests have been reviewed and managed in accordance with Mayo Clinic Conflict-of-Interest policies. D.B.K. serves as CEO of CoreBiome, a company involved in the commercialization of microbiome analysis and a wholly owned subsidiary of OraSure Technologies. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/9/17

Y1 - 2020/9/17

N2 - The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. Video Abstract: [Figure presented]. Integrated and longitudinal multiomic analyses of patients with irritable bowel syndrome reveals a role for the gut microbiota in modulating purine metabolism and influencing host gastrointestinal function.

AB - The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. Video Abstract: [Figure presented]. Integrated and longitudinal multiomic analyses of patients with irritable bowel syndrome reveals a role for the gut microbiota in modulating purine metabolism and influencing host gastrointestinal function.

KW - bile acids

KW - diet

KW - functional bowel disorders

KW - nucleosides

KW - physiology

KW - secretion

KW - short chain fatti acids

KW - symptom severity

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M3 - Article

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VL - 182

SP - 1460-1473.e17

JO - Cell

JF - Cell

IS - 6

ER -

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome

Abstract

Bibliographical note

Keywords

UN SDGs

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