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Original research
Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines
  1. Roy Hajjar1,2,3,4,
  2. Emmanuel Gonzalez5,6,
  3. Gabriela Fragoso1,4,
  4. Manon Oliero1,4,
  5. Ahmed Amine Alaoui1,2,3,4,
  6. Annie Calvé1,4,
  7. Hervé Vennin Rendos1,4,
  8. Souad Djediai7,
  9. Thibault Cuisiniere1,4,
  10. Patrick Laplante4,8,
  11. Claire Gerkins1,4,
  12. Ayodeji Samuel Ajayi1,4,
  13. Khoudia Diop4,9,
  14. Nassima Taleb2,
  15. Sophie Thérien2,
  16. Frédéricke Schampaert2,
  17. Hefzi Alratrout10,
  18. François Dagbert2,11,
  19. Rasmy Loungnarath2,11,
  20. Herawaty Sebajang2,11,
  21. Frank Schwenter2,11,
  22. Ramses Wassef2,11,
  23. Richard Ratelle2,11,
  24. Eric Debroux2,11,
  25. Jean-François Cailhier4,12,13,
  26. Bertrand Routy4,9,14,
  27. Borhane Annabi7,
  28. Nicholas J B Brereton15,16,
  29. Carole Richard2,11,
  30. Manuela M Santos1,4,12
  1. 1Nutrition and Microbiome Laboratory, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
  2. 2Digestive Surgery Service, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
  3. 3Department of Surgery, Université de Montréal, Montréal, Québec, Canada
  4. 4Institut du cancer de Montréal, Montréal, Québec, Canada
  5. 5Canadian Centre for Computational Genomics, McGill Genome Centre, Department of Human Genetics, McGill University, Montréal, Québec, Canada
  6. 6Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada
  7. 7Molecular Oncology Laboratory, Department of Chemistry, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
  8. 8Axe Cancer, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
  9. 9Laboratory of Immunotherapy and Oncomicrobiome, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
  10. 10(Current address: Department of General Surgery, King Fahd Hospital of the University, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia). Digestive Surgery Service, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
  11. 11Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
  12. 12Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
  13. 13Renal Division, Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
  14. 14Hemato-oncology Division, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, Québec, Canada
  15. 15School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
  16. 16Institut de Recherche en Biologie Végétale, Université de Montréal, Montréal, Québec, Canada
  1. Correspondence to Dr Manuela M Santos, Nutrition and Microbiome Laboratory, Centre de recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM), Montréal H2X 0A9, Québec, Canada; manuela.santos{at}umontreal.ca

Abstract

Objective Colorectal cancer (CRC) is the third most diagnosed cancer, and requires surgical resection and reconnection, or anastomosis, of the remaining bowel to re-establish intestinal continuity. Anastomotic leak (AL) is a major complication that increases mortality and cancer recurrence. Our objective is to assess the causal role of gut microbiota in anastomotic healing.

Design The causal role of gut microbiota was assessed in a murine AL model receiving faecal microbiota transplantation (FMT) from patients with CRC collected before surgery and who later developed or not, AL. Anastomotic healing and gut barrier integrity were assessed after surgery. Bacterial candidates implicated in anastomotic healing were identified using 16S rRNA gene sequencing and were isolated from faecal samples to be tested both in vitro and in vivo.

Results Mice receiving FMT from patients that developed AL displayed poor anastomotic healing. Profiling of gut microbiota of patients and mice after FMT revealed correlations between healing parameters and the relative abundance of Alistipes onderdonkii and Parabacteroides goldsteinii. Oral supplementation with A. onderdonkii resulted in a higher rate of leaks in mice, while gavage with P. goldsteinii improved healing by exerting an anti-inflammatory effect. Patients with AL and mice receiving FMT from AL patients presented upregulation of mucosal MIP-1α, MIP-2, MCP-1 and IL-17A/F before surgery. Retrospective analysis revealed that patients with AL present higher circulating neutrophil and monocyte counts before surgery.

Conclusion Gut microbiota plays an important role in surgical colonic healing in patients with CRC. The impact of these findings may extend to a vast array of invasive gastrointestinal procedures.

  • COLORECTAL SURGERY
  • COLORECTAL CANCER
  • COLONIC MICROFLORA
  • INTESTINAL MICROBIOLOGY
  • INFLAMMATORY MEDIATORS

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Footnotes

  • Twitter @Roy__Hajjar, @GonzalezEmBio, @NJBBrereton, @Nut_Microb_Lab

  • Contributors Conceptualisation: RH, CR, MMS. Methodology: RH, EG, MO, AAA, GF, AC, HVR, SD, TC, PL, CG, ASA, KD, NT, ST, FS, HA, FD, RL, HS, FS, RW, RR, ED, BR, J-FC, BA, NJBB, CR, MMS. Visualisation: RH, EG, TC, MMS. Supervision: CR, MMS. Original draft: RH, MMS. Review and editing: RH, EG, MO, AAA, GF, AC, HVR, SD, TC, PL, CG, ASA, KD, NT, ST, FS, HA, FD, RL, HS, FS, RW, RR, ED, BR, J-FC, BA, NJBB, CR, MMS. Overall supervisor and guarantor: MMS.

  • Funding Canadian Institutes of Health Research grants FRN-159775 and PJT-175181 (MMS). Natural Sciences and Engineering Research Council of Canada grants RGPIN-2018-06442 (MMS). New Frontiers in Research Fund – Exploration grant NFRFE-2020-00991 (MMS, CR). Canadian Society of Colon and Rectal Surgeons operating grant 2019 (CR, RH). Fonds de recherche du Québec – Santé (FRQ-S) and Ministère de la Santé et des Services sociaux Resident Physician Health Research Career Training Program (RH). Canadian Institutes of Health Research Graduate Scholarships program (RH). Institut du cancer de Montréal (Canderel scholarship) (MO, TC, CG, ASA). Fonds de recherche du Québec – Santé (FRQ-S) (Postdoctoral Fellowship) (KD). BA holds a Chair in Cancer Prevention and Treatment at UQAM

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.