Healthy cotwins share gut microbiome signatures with their inflammatory bowel disease twins and unrelated patients

Eelco C. Brand; Dorret I. Boomsma; Gonneke Willemsen; Rinse K. Weersma; Marielle J.L. Romberg-Camps; Dutch TWIN-IBD consortium and the Dutch Initiative on Crohn and Colitis

doi:10.1053/j.gastro.2021.01.030

Healthy cotwins share gut microbiome signatures with their inflammatory bowel disease twins and unrelated patients

Eelco C. Brand, Dorret I. Boomsma, Gonneke Willemsen, Rinse K. Weersma^*, Marielle J.L. Romberg-Camps, Dutch TWIN-IBD consortium and the Dutch Initiative on Crohn and Colitis

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.

METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex- and BMI-matched controls, and 99 unrelated IBD patients. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared between healthy-cotwins, IBD-twins, unrelated IBD patients, and healthy controls with multivariable, i.e. adjusted for potential confounding, generalized linear models.

RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate (FDR)<0.10). Compared to healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy-cotwins, IBD-twins and unrelated IBD patients, respectively (FDR<0.10). Of these, 8/19 (42.1%) and 1/18 (5.6%) species, and 37/105 (35.2%) and 30/153 (19.6%) pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated IBD patients respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example: an increase in propionate degradation and L-arginine degradation pathways.

CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow up studies are needed to infer a causal relationship.

Original language	English
Pages (from-to)	1970-1985
Number of pages	16
Journal	Gastroenterology
Volume	160
Issue number	6
Early online date	19 Jan 2021
DOIs	https://doi.org/10.1053/j.gastro.2021.01.030
Publication status	Published - May 2021

Bibliographical note

Funding Information:
Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands’ Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts.

Funding Information:
Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands.

Funding Information:
The authors thank all participants. They thank Dianne Jansen for her work on isolating microbial DNA from the fecal samples, and Bart M?skens for his help with study visits in the TWIN-study. The authors thank all funding partners for their support in this study. Eelco C. Brand, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis:, Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original, draft: Lead; Writing ? review & editing: Lead; Generation and acquisition of data: Equal). Marjolein A.Y. Klaassen, BSc (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original draft: Lead; Writing ? review & editing: Lead). Ranko Gacesa, PhD (Data curation: Equal; Formal analysis: Supporting; Investigation: Supporting; Methodology: Equal; Writing ? review & editing: Equal). Arnau Vich Vila, PhD (Formal analysis: Supporting; Investigation: Supporting;, Methodology: Supporting; Writing ? review & editing: Equal). Hiren Ghosh, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing ? review & editing: Equal). Marcel R. de Zoete, PhD (Writing ? review & editing: Equal). Dorret I. Boomsma, PhD (Writing ? review & editing: Equal). Frank Hoentjen, MD, PhD (Writing ? review & editing: Equal). Carmen S. Horjus Talabur Horje, MD, PhD (Writing ? review & editing: Equal). Paul C. van de Meeberg, MD, PhD (Writing ? review & editing: Equal). Gonneke Willemsen, PhD (Writing ? review & editing: Equal). Jingyuan Fu, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Cisca Wijmenga, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Femke van Wijk, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Alexandra Zhernakova, MD, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Bas Oldenburg, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Rinse K. Weersma, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal). Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands? Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands.

Publisher Copyright:
© 2021 The Authors

Funding

Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands’ Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands. The authors thank all participants. They thank Dianne Jansen for her work on isolating microbial DNA from the fecal samples, and Bart M?skens for his help with study visits in the TWIN-study. The authors thank all funding partners for their support in this study. Eelco C. Brand, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis:, Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original, draft: Lead; Writing ? review & editing: Lead; Generation and acquisition of data: Equal). Marjolein A.Y. Klaassen, BSc (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original draft: Lead; Writing ? review & editing: Lead). Ranko Gacesa, PhD (Data curation: Equal; Formal analysis: Supporting; Investigation: Supporting; Methodology: Equal; Writing ? review & editing: Equal). Arnau Vich Vila, PhD (Formal analysis: Supporting; Investigation: Supporting;, Methodology: Supporting; Writing ? review & editing: Equal). Hiren Ghosh, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing ? review & editing: Equal). Marcel R. de Zoete, PhD (Writing ? review & editing: Equal). Dorret I. Boomsma, PhD (Writing ? review & editing: Equal). Frank Hoentjen, MD, PhD (Writing ? review & editing: Equal). Carmen S. Horjus Talabur Horje, MD, PhD (Writing ? review & editing: Equal). Paul C. van de Meeberg, MD, PhD (Writing ? review & editing: Equal). Gonneke Willemsen, PhD (Writing ? review & editing: Equal). Jingyuan Fu, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Cisca Wijmenga, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Femke van Wijk, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Alexandra Zhernakova, MD, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Bas Oldenburg, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Rinse K. Weersma, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal). Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands? Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands.

Funders	Funder number
Artizan Biosciences
Cardiovasculair Onderzoek Nederland	CVON 2012-03, ERC-671274, SPI 92-266
IN CONTROL	024.003.001, CVON2018-27
Netherlands Heart Foundation
Netherlands Heart Foundation CVON	2018-27, ExposomeNL 024.004.017
Netherlands Organization for Health Research and Development
Netherlands Organization for Scientific Research NWO-VIDI	016.178.056
Top Institute Food and Nutrition	GH001
University Medical Center Utrecht
Pfizer
Johnson and Johnson
Celgene
AbbVie
Meso Scale Diagnostics
Stiftelsen Kristian Gerhard Jebsen
Takeda Pharmaceutical Company
Cilag
ZonMw	715772
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	91715377
Ferring Pharmaceuticals

Keywords

Crohn's Disease
Discordant Twin Design
Family Studies
Microbiota
Preclinical
Prediagnostic
Prediction
Ulcerative Colitis

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10.1053/j.gastro.2021.01.030

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Cite this

@article{612e2683873b49f1bb7a85ad9c5c7ee2,

title = "Healthy cotwins share gut microbiome signatures with their inflammatory bowel disease twins and unrelated patients",

abstract = "BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex- and BMI-matched controls, and 99 unrelated IBD patients. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared between healthy-cotwins, IBD-twins, unrelated IBD patients, and healthy controls with multivariable, i.e. adjusted for potential confounding, generalized linear models.RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate (FDR)<0.10). Compared to healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy-cotwins, IBD-twins and unrelated IBD patients, respectively (FDR<0.10). Of these, 8/19 (42.1%) and 1/18 (5.6%) species, and 37/105 (35.2%) and 30/153 (19.6%) pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated IBD patients respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example: an increase in propionate degradation and L-arginine degradation pathways.CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow up studies are needed to infer a causal relationship.",

keywords = "Crohn's Disease, Discordant Twin Design, Family Studies, Microbiota, Preclinical, Prediagnostic, Prediction, Ulcerative Colitis",

author = "Brand, {Eelco C.} and Klaassen, {Marjolein A.Y.} and Ranko Gacesa and {Vich Vila}, Arnau and Hiren Ghosh and {de Zoete}, {Marcel R.} and Boomsma, {Dorret I.} and Frank Hoentjen and {Horjus Talabur Horje}, {Carmen S.} and {van de Meeberg}, {Paul C.} and Gonneke Willemsen and Jingyuan Fu and Cisca Wijmenga and {van Wijk}, Femke and Alexandra Zhernakova and Bas Oldenburg and Weersma, {Rinse K.} and Pieter Honkoop and Jacobs, {Rutger J.} and Ponsioen, {Cyriel Y.} and {de Boer}, {Nanne K.H.} and Alderlieste, {Yasser A.} and {van Herwaarden}, {Margot A.} and {van Tuyl}, {Sebastiaan A.C.} and Lutgens, {Maurice W.} and {Janneke van der Woude}, C. and Mares, {Wout G.M.} and {de Koning}, {Daan B.} and Bosman, {Joukje H.} and Juda Vecht and {de Schryver}, {Anneke M.P.} and {van der Meulen-de Jong}, {Andrea E.} and Pierik, {Marieke J.} and Boekema, {Paul J.} and Verburg, {Robert J.} and Bindia Jharap and Jansen, {Jeroen M.} and Stokkers, {Pieter C.F.} and Rutger Quispel and Nofel Mahmmod and West, {Rachel L.} and Marleen Willems and Minderhoud, {Itta M.} and Fidder, {Herma H.} and {van Schaik}, {Fiona D.M.} and Hirdes, {Meike M.C.} and Boontje, {Nynke A.} and M{\"u}skens, {Bart L.M.} and Romberg-Camps, {Marielle J.L.} and {Dutch TWIN-IBD consortium and the Dutch Initiative on Crohn and Colitis}",

note = "Funding Information: Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands{\textquoteright} Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Information: Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands. Funding Information: The authors thank all participants. They thank Dianne Jansen for her work on isolating microbial DNA from the fecal samples, and Bart M?skens for his help with study visits in the TWIN-study. The authors thank all funding partners for their support in this study. Eelco C. Brand, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis:, Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original, draft: Lead; Writing ? review & editing: Lead; Generation and acquisition of data: Equal). Marjolein A.Y. Klaassen, BSc (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original draft: Lead; Writing ? review & editing: Lead). Ranko Gacesa, PhD (Data curation: Equal; Formal analysis: Supporting; Investigation: Supporting; Methodology: Equal; Writing ? review & editing: Equal). Arnau Vich Vila, PhD (Formal analysis: Supporting; Investigation: Supporting;, Methodology: Supporting; Writing ? review & editing: Equal). Hiren Ghosh, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing ? review & editing: Equal). Marcel R. de Zoete, PhD (Writing ? review & editing: Equal). Dorret I. Boomsma, PhD (Writing ? review & editing: Equal). Frank Hoentjen, MD, PhD (Writing ? review & editing: Equal). Carmen S. Horjus Talabur Horje, MD, PhD (Writing ? review & editing: Equal). Paul C. van de Meeberg, MD, PhD (Writing ? review & editing: Equal). Gonneke Willemsen, PhD (Writing ? review & editing: Equal). Jingyuan Fu, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Cisca Wijmenga, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Femke van Wijk, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Alexandra Zhernakova, MD, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Bas Oldenburg, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Rinse K. Weersma, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal). Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands? Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = may,

doi = "10.1053/j.gastro.2021.01.030",

language = "English",

volume = "160",

pages = "1970--1985",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "6",

}

TY - JOUR

T1 - Healthy cotwins share gut microbiome signatures with their inflammatory bowel disease twins and unrelated patients

AU - Brand, Eelco C.

AU - Klaassen, Marjolein A.Y.

AU - Gacesa, Ranko

AU - Vich Vila, Arnau

AU - Ghosh, Hiren

AU - de Zoete, Marcel R.

AU - Boomsma, Dorret I.

AU - Hoentjen, Frank

AU - Horjus Talabur Horje, Carmen S.

AU - van de Meeberg, Paul C.

AU - Willemsen, Gonneke

AU - Fu, Jingyuan

AU - Wijmenga, Cisca

AU - van Wijk, Femke

AU - Zhernakova, Alexandra

AU - Oldenburg, Bas

AU - Weersma, Rinse K.

AU - Honkoop, Pieter

AU - Jacobs, Rutger J.

AU - Ponsioen, Cyriel Y.

AU - de Boer, Nanne K.H.

AU - Alderlieste, Yasser A.

AU - van Herwaarden, Margot A.

AU - van Tuyl, Sebastiaan A.C.

AU - Lutgens, Maurice W.

AU - Janneke van der Woude, C.

AU - Mares, Wout G.M.

AU - de Koning, Daan B.

AU - Bosman, Joukje H.

AU - Vecht, Juda

AU - de Schryver, Anneke M.P.

AU - van der Meulen-de Jong, Andrea E.

AU - Pierik, Marieke J.

AU - Boekema, Paul J.

AU - Verburg, Robert J.

AU - Jharap, Bindia

AU - Jansen, Jeroen M.

AU - Stokkers, Pieter C.F.

AU - Quispel, Rutger

AU - Mahmmod, Nofel

AU - West, Rachel L.

AU - Willems, Marleen

AU - Minderhoud, Itta M.

AU - Fidder, Herma H.

AU - van Schaik, Fiona D.M.

AU - Hirdes, Meike M.C.

AU - Boontje, Nynke A.

AU - Müskens, Bart L.M.

AU - Romberg-Camps, Marielle J.L.

AU - Dutch TWIN-IBD consortium and the Dutch Initiative on Crohn and Colitis

N1 - Funding Information: Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands’ Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Information: Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands. Funding Information: The authors thank all participants. They thank Dianne Jansen for her work on isolating microbial DNA from the fecal samples, and Bart M?skens for his help with study visits in the TWIN-study. The authors thank all funding partners for their support in this study. Eelco C. Brand, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis:, Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original, draft: Lead; Writing ? review & editing: Lead; Generation and acquisition of data: Equal). Marjolein A.Y. Klaassen, BSc (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Equal; Writing ? original draft: Lead; Writing ? review & editing: Lead). Ranko Gacesa, PhD (Data curation: Equal; Formal analysis: Supporting; Investigation: Supporting; Methodology: Equal; Writing ? review & editing: Equal). Arnau Vich Vila, PhD (Formal analysis: Supporting; Investigation: Supporting;, Methodology: Supporting; Writing ? review & editing: Equal). Hiren Ghosh, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing ? review & editing: Equal). Marcel R. de Zoete, PhD (Writing ? review & editing: Equal). Dorret I. Boomsma, PhD (Writing ? review & editing: Equal). Frank Hoentjen, MD, PhD (Writing ? review & editing: Equal). Carmen S. Horjus Talabur Horje, MD, PhD (Writing ? review & editing: Equal). Paul C. van de Meeberg, MD, PhD (Writing ? review & editing: Equal). Gonneke Willemsen, PhD (Writing ? review & editing: Equal). Jingyuan Fu, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Cisca Wijmenga, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Femke van Wijk, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Alexandra Zhernakova, MD, PhD (Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Bas Oldenburg, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal; Generation and acquisition of data: Equal). Rinse K. Weersma, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing ? original draft: Supporting; Writing ? review & editing: Equal). Conflict of interest These authors disclose the following: Eelco C. Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, Netherlands, and is co-applicant on an Investigator-Initiated research grant of Pfizer. Marcel R. de Zoete is supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO, grant 91715377) and the Utrecht Exposome Hub of Utrecht Life Sciences, and a co-founder and consultant of Artizan Biosciences. Frank Hoentjen has received unrestricted grants from Janssen-Cilag, AbbVie, and Takeda; and consulting fees from Celgene and Janssen-Cilag. Jingyuan Fu is funded by the Netherlands Heart Foundation (IN CONTROL, CVON2018-27) and NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). Jingyuan Fu and Alexandra Zhernakova are further supported by a CardioVasculair Onderzoek Nederland grant (CVON 2012-03). Cisca Wijmenga is supported by a Spinoza award (NWO SPI 92-266), an ERC advanced grant (ERC-671274), a grant from the Nederlands? Top Institute Food and Nutrition (GH001), the NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. Femke van Wijk is supported by a VIDI career development grant from The Netherlands Organization for Health Research and Development (ZonMw), unrestricted grants from Pfizer and Regeneron, and has been a consultant for Sanofi. Alexandra Zhernakova is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and the NWO Gravitation grant ExposomeNL 024.004.017. Bas Oldenburg has received unrestricted grants from AbbVie, Janssen, Pfizer, Ferring, dr. Falk, Takeda, and MSD; and served on the advisory board of Janssen, Pfizer, Takeda, and Cablon. Rinse K. Weersma has received unrestricted grants from Takeda, Johnson & Johnson, Tramedico, and Ferring; and served as a consultant for Takeda. The remaining authors disclose no conflicts. Funding Eelco Brand is supported by the Alexandre Suerman program for MD and PhD candidates of the University Medical Center Utrecht, the Netherlands. Publisher Copyright: © 2021 The Authors

PY - 2021/5

Y1 - 2021/5

N2 - BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex- and BMI-matched controls, and 99 unrelated IBD patients. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared between healthy-cotwins, IBD-twins, unrelated IBD patients, and healthy controls with multivariable, i.e. adjusted for potential confounding, generalized linear models.RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate (FDR)<0.10). Compared to healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy-cotwins, IBD-twins and unrelated IBD patients, respectively (FDR<0.10). Of these, 8/19 (42.1%) and 1/18 (5.6%) species, and 37/105 (35.2%) and 30/153 (19.6%) pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated IBD patients respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example: an increase in propionate degradation and L-arginine degradation pathways.CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow up studies are needed to infer a causal relationship.

AB - BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex- and BMI-matched controls, and 99 unrelated IBD patients. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared between healthy-cotwins, IBD-twins, unrelated IBD patients, and healthy controls with multivariable, i.e. adjusted for potential confounding, generalized linear models.RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate (FDR)<0.10). Compared to healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy-cotwins, IBD-twins and unrelated IBD patients, respectively (FDR<0.10). Of these, 8/19 (42.1%) and 1/18 (5.6%) species, and 37/105 (35.2%) and 30/153 (19.6%) pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated IBD patients respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example: an increase in propionate degradation and L-arginine degradation pathways.CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow up studies are needed to infer a causal relationship.

KW - Crohn's Disease

KW - Discordant Twin Design

KW - Family Studies

KW - Microbiota

KW - Preclinical

KW - Prediagnostic

KW - Prediction

KW - Ulcerative Colitis

UR - http://www.scopus.com/inward/record.url?scp=85106069784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85106069784&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2021.01.030

DO - 10.1053/j.gastro.2021.01.030

M3 - Article

C2 - 33476671

SN - 0016-5085

VL - 160

SP - 1970

EP - 1985

JO - Gastroenterology

JF - Gastroenterology

IS - 6

ER -

Healthy cotwins share gut microbiome signatures with their inflammatory bowel disease twins and unrelated patients

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