Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort

Daniel Sprockett; Natalie Fischer; Rotem Sigall Boneh; Dan Turner; Jarek Kierkus; Malgorzata Sladek; Johanna C. Escher; Eytan Wine; Baruch Yerushalmi; Jorge Amil Dias; Ron Shaoul; Michal Kori; Scott B. Snapper; Susan Holmes; Athos Bousvaros; Arie Levine; David A. Relman

doi:10.1093/ibd/izz130

Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort

Daniel Sprockett, Natalie Fischer, Rotem Sigall Boneh, Dan Turner, Jarek Kierkus, Malgorzata Sladek, Johanna C. Escher, Eytan Wine, Baruch Yerushalmi, Jorge Amil Dias, Ron Shaoul, Michal Kori, Scott B. Snapper, Susan Holmes, Athos Bousvaros, Arie Levine, David A. Relman^*

^*Corresponding author for this work

Faculty of Medicine

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

17 Scopus citations

Abstract

Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD and the use of microbiota features as classifiers or predictors of disease remission. Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct random forest models to classify remission or predict treatment response. Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random forest models constructed from microbiota profiles before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683-0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24). Conclusions: MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

Original language	American English
Pages (from-to)	1927-1938
Number of pages	12
Journal	Inflammatory Bowel Diseases
Volume	25
Issue number	12
DOIs	https://doi.org/10.1093/ibd/izz130
State	Published - 1 Dec 2019

Bibliographical note

Funding Information:
From the *Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA; †Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; ‡Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Holon, Israel; §The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; ¶Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland; ‖Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland; **Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; ††Division ofPediatric Gastroenterology and Nutrition, Department ofPediatrics, University ofAlberta, Edmonton, Canada; ‡‡Pediatric Gastroenterology Unit, Soroka University Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; §§Department of Pediatrics, Hospital de Sao Joao, Porto, Portugal; ¶¶Pediatric Gastroenterology Unit, Ruth Children’s Hospital, Rambam Medical Center, Haifa, Israel; ‖‖Pediatric Day Care Unit, Kaplan Medical Center, Rehovot, Israel; ***Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA; †††Division of Gastroenterology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA; ‡‡‡Department of Statistics, Stanford University, Stanford, California, USA; §§§Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ¶¶¶Infectious Diseases Section, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA Supported by: This research was funded by National Science Foundation Graduate Research Fellowship DGE-114747 (D.S.), National Institute of General Medical Sciences of the National Institutes of Health training grant T32GM007276 (D.S.), The Leona M. and Harry B. Helmsley Charitable Trust grant 2014PG-IBD014 (D.A.R.), the Thomas C. and Joan M. Merigan Endowment at Stanford University (D.A.R.), and the Chan Zuckerburg Biohub Microbiome Initiative (D.A.R.).

Publisher Copyright:
© 2019 Crohn's & Colitis Foundation.

Keywords

Antibiotics
Disease remission
Microbiota
Pediatric Crohn's disease
Random forest model

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10.1093/ibd/izz130

Cite this

Sprockett, D., Fischer, N., Boneh, R. S., Turner, D., Kierkus, J., Sladek, M., Escher, J. C., Wine, E., Yerushalmi, B., Dias, J. A., Shaoul, R., Kori, M., Snapper, S. B., Holmes, S., Bousvaros, A., Levine, A., & Relman, D. A. (2019). Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort. Inflammatory Bowel Diseases, 25(12), 1927-1938. https://doi.org/10.1093/ibd/izz130

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title = "Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort",

abstract = "Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD and the use of microbiota features as classifiers or predictors of disease remission. Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct random forest models to classify remission or predict treatment response. Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random forest models constructed from microbiota profiles before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683-0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24). Conclusions: MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.",

keywords = "Antibiotics, Disease remission, Microbiota, Pediatric Crohn's disease, Random forest model",

author = "Daniel Sprockett and Natalie Fischer and Boneh, {Rotem Sigall} and Dan Turner and Jarek Kierkus and Malgorzata Sladek and Escher, {Johanna C.} and Eytan Wine and Baruch Yerushalmi and Dias, {Jorge Amil} and Ron Shaoul and Michal Kori and Snapper, {Scott B.} and Susan Holmes and Athos Bousvaros and Arie Levine and Relman, {David A.}",

note = "Funding Information: From the *Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA; †Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; ‡Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Holon, Israel; §The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; ¶Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children{\textquoteright}s Memorial Health Institute, Warsaw, Poland; ‖Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland; **Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children{\textquoteright}s Hospital, Rotterdam, the Netherlands; ††Division ofPediatric Gastroenterology and Nutrition, Department ofPediatrics, University ofAlberta, Edmonton, Canada; ‡‡Pediatric Gastroenterology Unit, Soroka University Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; §§Department of Pediatrics, Hospital de Sao Joao, Porto, Portugal; ¶¶Pediatric Gastroenterology Unit, Ruth Children{\textquoteright}s Hospital, Rambam Medical Center, Haifa, Israel; ‖‖Pediatric Day Care Unit, Kaplan Medical Center, Rehovot, Israel; ***Division of Gastroenterology, Hepatology, and Nutrition, Boston Children{\textquoteright}s Hospital, Boston, Massachusetts, USA; †††Division of Gastroenterology, Brigham and Women{\textquoteright}s Hospital, and Harvard Medical School, Boston, Massachusetts, USA; ‡‡‡Department of Statistics, Stanford University, Stanford, California, USA; §§§Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ¶¶¶Infectious Diseases Section, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA Supported by: This research was funded by National Science Foundation Graduate Research Fellowship DGE-114747 (D.S.), National Institute of General Medical Sciences of the National Institutes of Health training grant T32GM007276 (D.S.), The Leona M. and Harry B. Helmsley Charitable Trust grant 2014PG-IBD014 (D.A.R.), the Thomas C. and Joan M. Merigan Endowment at Stanford University (D.A.R.), and the Chan Zuckerburg Biohub Microbiome Initiative (D.A.R.). Publisher Copyright: {\textcopyright} 2019 Crohn's & Colitis Foundation.",

year = "2019",

month = dec,

day = "1",

doi = "10.1093/ibd/izz130",

language = "American English",

volume = "25",

pages = "1927--1938",

journal = "Inflammatory Bowel Diseases",

issn = "1078-0998",

publisher = "Oxford University Press",

number = "12",

}

Sprockett, D, Fischer, N, Boneh, RS, Turner, D, Kierkus, J, Sladek, M, Escher, JC, Wine, E, Yerushalmi, B, Dias, JA, Shaoul, R, Kori, M, Snapper, SB, Holmes, S, Bousvaros, A, Levine, A & Relman, DA 2019, 'Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort', Inflammatory Bowel Diseases, vol. 25, no. 12, pp. 1927-1938. https://doi.org/10.1093/ibd/izz130

TY - JOUR

T1 - Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort

AU - Sprockett, Daniel

AU - Fischer, Natalie

AU - Boneh, Rotem Sigall

AU - Turner, Dan

AU - Kierkus, Jarek

AU - Sladek, Malgorzata

AU - Escher, Johanna C.

AU - Wine, Eytan

AU - Yerushalmi, Baruch

AU - Dias, Jorge Amil

AU - Shaoul, Ron

AU - Kori, Michal

AU - Snapper, Scott B.

AU - Holmes, Susan

AU - Bousvaros, Athos

AU - Levine, Arie

AU - Relman, David A.

N1 - Funding Information: From the *Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA; †Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; ‡Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Holon, Israel; §The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; ¶Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland; ‖Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland; **Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; ††Division ofPediatric Gastroenterology and Nutrition, Department ofPediatrics, University ofAlberta, Edmonton, Canada; ‡‡Pediatric Gastroenterology Unit, Soroka University Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; §§Department of Pediatrics, Hospital de Sao Joao, Porto, Portugal; ¶¶Pediatric Gastroenterology Unit, Ruth Children’s Hospital, Rambam Medical Center, Haifa, Israel; ‖‖Pediatric Day Care Unit, Kaplan Medical Center, Rehovot, Israel; ***Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA; †††Division of Gastroenterology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA; ‡‡‡Department of Statistics, Stanford University, Stanford, California, USA; §§§Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ¶¶¶Infectious Diseases Section, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA Supported by: This research was funded by National Science Foundation Graduate Research Fellowship DGE-114747 (D.S.), National Institute of General Medical Sciences of the National Institutes of Health training grant T32GM007276 (D.S.), The Leona M. and Harry B. Helmsley Charitable Trust grant 2014PG-IBD014 (D.A.R.), the Thomas C. and Joan M. Merigan Endowment at Stanford University (D.A.R.), and the Chan Zuckerburg Biohub Microbiome Initiative (D.A.R.). Publisher Copyright: © 2019 Crohn's & Colitis Foundation.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD and the use of microbiota features as classifiers or predictors of disease remission. Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct random forest models to classify remission or predict treatment response. Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random forest models constructed from microbiota profiles before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683-0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24). Conclusions: MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

AB - Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD and the use of microbiota features as classifiers or predictors of disease remission. Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct random forest models to classify remission or predict treatment response. Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random forest models constructed from microbiota profiles before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683-0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24). Conclusions: MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

KW - Antibiotics

KW - Disease remission

KW - Microbiota

KW - Pediatric Crohn's disease

KW - Random forest model

UR - http://www.scopus.com/inward/record.url?scp=85075093409&partnerID=8YFLogxK

U2 - 10.1093/ibd/izz130

DO - 10.1093/ibd/izz130

M3 - Article

C2 - 31276165

AN - SCOPUS:85075093409

SN - 1078-0998

VL - 25

SP - 1927

EP - 1938

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

IS - 12

ER -

Treatment-specific composition of the gut microbiota is associated with disease remission in a pediatric crohn's disease cohort

Abstract

Bibliographical note

Keywords

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