Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease

Haim Leibovitzh¹, Sun-Ho Lee¹, Mingyue Xue², Juan Antonio Raygoza Garay¹, Cristian Hernandez-Rocha¹, Karen L Madsen³, Jonathan B Meddings⁴, David S Guttman⁵, Osvaldo Espin-Garcia⁶, Michelle I Smith², Ashleigh Goethel², Anne M Griffiths⁷, Paul Moayyedi⁸, A Hillary Steinhart¹, Remo Panaccione⁹, Hien Q Huynh¹⁰, Kevan Jacobson¹¹, Guy Aumais¹², David R Mack¹³, Maria T Abreu¹⁴, Charles N Bernstein¹⁵, John K Marshall⁸, Dan Turner¹⁶, Wei Xu⁶; CCC GEM Project Research Consortium; Williams Turpin¹, Kenneth Croitoru¹⁷

Affiliations

¹ Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
² Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
³ University of Alberta, Edmonton, Alberta, Canada.
⁴ Department of Medicine, Cumming School of Medicine, Calgary, Alberta, Canada.
⁵ Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada; Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada.
⁶ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁷ IBD Center, The Hospital for Sick Children, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Medicine, McMaster University, Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada.
⁹ Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Division of Gastroenterology and Nutrition, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹¹ Canadian Gastro-Intestinal Epidemiology Consortium, Toronto, Ontario, Canada; British Columbia Children's Hospital, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
¹² Department of Medicine, Hôpital Maisonneuve-Rosemont, Montreal University, Montreal, Quebec, Canada.
¹³ Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Division of Gastroenterology, Crohn's and Colitis Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
¹⁵ University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre and Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁶ The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁷ Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: ken.croitoru@sinaihealth.ca.

PMID: 35850197
DOI: 10.1053/j.gastro.2022.07.004

Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease

Haim Leibovitzh et al. Gastroenterology. 2022 Nov.

. 2022 Nov;163(5):1364-1376.e10.

doi: 10.1053/j.gastro.2022.07.004. Epub 2022 Jul 16.

Authors

Affiliations

¹ Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
² Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
³ University of Alberta, Edmonton, Alberta, Canada.
⁴ Department of Medicine, Cumming School of Medicine, Calgary, Alberta, Canada.
⁵ Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada; Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada.
⁶ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁷ IBD Center, The Hospital for Sick Children, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Medicine, McMaster University, Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada.
⁹ Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Division of Gastroenterology and Nutrition, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹¹ Canadian Gastro-Intestinal Epidemiology Consortium, Toronto, Ontario, Canada; British Columbia Children's Hospital, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
¹² Department of Medicine, Hôpital Maisonneuve-Rosemont, Montreal University, Montreal, Quebec, Canada.
¹³ Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Division of Gastroenterology, Crohn's and Colitis Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
¹⁵ University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre and Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁶ The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁷ Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: ken.croitoru@sinaihealth.ca.

PMID: 35850197
DOI: 10.1053/j.gastro.2022.07.004

Abstract

Background & aims: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease.

Methods: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function.

Results: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R² = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6).

Conclusions: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.

Keywords: Gut Microbiota; Healthy Relatives of Patients With Crohn’s Disease; Intestinal Permeability; Machine Learning.

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Revisiting the Stool Microbiome: Intestinal Paracellular Permeability Connection.
Kaunitz JD, Hollander D. Kaunitz JD, et al. Gastroenterology. 2023 May;164(6):1024-1025. doi: 10.1053/j.gastro.2022.12.011. Epub 2022 Dec 20. Gastroenterology. 2023. PMID: 36549372 No abstract available.
Intestinal Permeability Improvement With Nutritional Therapy Is Associated With Specific Microbiome Profiles and Functional Pathways in Pediatric Crohn's Disease.
Verburgt CM, Sigall Boneh R, Dunn K. Verburgt CM, et al. Gastroenterology. 2023 May;164(6):1025-1026. doi: 10.1053/j.gastro.2022.12.010. Epub 2022 Dec 20. Gastroenterology. 2023. PMID: 36563912 No abstract available.

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Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease

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Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease

Authors

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Abstract

Comment in

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Medical

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