MUCOSA-ADHERENT BACTERIA REGULATE THE HEALING OF COLONIC ANASTOMOTIC WOUNDS IN COLORECTAL CANCER SURGERY
Roy Hajjar*2,1, Emmanuel Gonzalez3, Gabriela Fragoso2, Manon Oliero2, Ahmed A. Alaoui2,1, Annie Calvé2, Hervé Vennin Rendos2, Souad Djediai4, Thibault Cuisiniere2, Patrick Laplante2, Claire Gerkins2, Ayodeji S. Ajayi2, Khoudia Diop2, Nassima Taleb2, Sophie Thérien2, Frédéricke Schampaert2, Hefzi Alratrout5, François Dagbert5, Rasmy Loungnarath5, Herawaty Sebajang5, Frank Schwenter5, Ramses Wassef5, Richard Ratelle5, Éric Debroux5, Jean-François Cailhier2,1, Bertrand Routy2,1, Borhane Annabi4, Nicholas J. Brereton1, Carole S. Richard5,1, Manuela M. Santos2,1
1Surgery, Universite de Montreal, Laval, QC, Canada; 2Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, QC, Canada; 3McGill University, Montreal, QC, Canada; 4Universite du Quebec a Montreal, Montreal, QC, Canada; 5Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada
Introduction: Anastomotic leak (AL) is a major complication in colorectal cancer (CRC) surgery, and is associated with increased mortality and morbidity. Recent evidence has suggested that the gut microbiota may be involved in the healing of colonic anastomoses in patients undergoing surgery for CRC. Data on the causal link between the pre-operative gut microbiota and AL in CRC patients remains scant. Our objective was to further characterize this link.
Methods: We collected fecal samples before surgery and mucosal samples during surgery in CRC patients undergoing a colorectal resection with anastomosis. The gut microbiota in these samples was analyzed using the Anchor 16 pipeline. The preoperative microbiota of patients with and without AL was transplanted into mice that then underwent a surgical colonic anastomosis. The fecal and mucosal microbiota of these mice was analyzed as well. Bacteria correlated with healing parameters, and showing different levels between patients with and without AL, were isolated, and supplemented to mice that were then subjected to colonic surgery. Their mechanism of action on key repair mechanisms was assessed in vitro.
Results: The pre-operative microbiota of patients with AL led to poor anastomotic healing in mice, to a poorly restored gut barrier function with higher bacterial translocation, and to a weakened anastomotic wound matrix with lower collagen and fibronectin. Differences in the composition of the gut microbiota of patients with and without AL were detected before surgery. These differences were transferable to mice by fecal microbiota transplantation, with 24 differentially abundant species. Two bacterial strains were strongly correlated with healing parameters, and whose role in intestinal health was unknown. These strains were isolated and labeled Pg kh35 and Ao kh33. When supplemented to mice, Pg Kh35 improved anastomotic healing, strengthened the wound matrix and restored the gut barrier, while supplementation with Ao kh33 had a deleterious effect. Most importantly, both were detected in the mucosa of mice and patients, after the administration of antibioprophylaxis and bowel preparation, and their levels were different between patients that later did or did not develop AL. Mechanistically, Pg kh35 exerted a beneficial effect by secreting a compound that upregulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) in the colon, which promotes repair and alleviates inflammation, while Ao kh33 had the opposite effect.
Conclusion: The preoperative microbiota of patients with CRC is causally linked to the risk of developing AL. We unveiled how several mucosal bacteria, that are resistant to the preoperative bowel decontamination, may influence anastomotic healing. These findings pave the way toward clinical trials in which the gut microbiota may be modulated before surgery to improve outcomes.
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