Gut microbiota modulation: the key to improving outcomes after colorectal cancer surgery?

Anastomotic leak is the most feared complication after colorectal surgery, carrying significant clinical implications including abscess formation, faecal peritonitis, sepsis, and multi-organ failure. It extends average in-patient stay from 7 to 19 days and increases in-hospital morbidity and mortality (1). Anastomotic leak also has a long-term impact, and several studies have shown that it is associated with increased local cancer recurrence and reduced disease-free survival (2,3).

In their study, Hajjar et al. (4) began by conducting a retrospective review of cases at their own institution, revealing poorer oncological outcomes in patients who experienced anastomotic leak. While these observations could potentially stem from a delay in initiating adjuvant therapy, various alternative hypotheses are of note, including one suggesting the implantation of exfoliated tumour cells onto the anastomotic site (5). Using a murine model, Hajjar et al. (4) created an anastomosis following caecal colotomy and administered a rectal enema containing CT26 colorectal cancer cells. Their findings revealed that mice with impaired anastomotic healing developed larger anastomotic tumours (suggesting greater implantation of cancer cells in the anastomotic wound), as well as increased haemorrhagic ascites and peritoneal tumours (indicating greater extraintestinal dissemination).

Next, the authors explored the potential involvement of the gut microbiota in this process, building upon previous research showing differences in the microbiome between patients with and without anastomotic leak (6,7). Utilising a murine model, they found that the microbiome of patients with anastomotic leak led to reduced activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway, which is known for its anti-inflammatory effects (8) and its inhibition of colorectal cancer cell proliferation (9).

Finally, Hajjar et al. (4) investigated the therapeutic potential of modulating the microbiome through dietary supplementation with inulin or 5-aminosalicylate (5-ASA). Inulin, a dietary fibre fermented by gut bacteria to produce butyrate, and 5-ASA, a PPAR-γ activator used in inflammatory bowel disease treatment, were administered to mice prior to caecal colotomy and sutured anastomosis. These interventions resulted in smaller local anastomotic tumours, reduced peritoneal disease dissemination, and reduced splenic bacterial levels.

While these findings highlight promising avenues for microbiome-based interventions, they warrant careful interpretation due to the challenges of using animal models to replicate mechanisms of anastomotic leak seen in human patients. First, the animal model used in the study, involved sutured closure of a caecal colotomy with six sutures (instead of the standard eight), suggesting a mechanical rather than bacterial-mediated mechanism underpinning poor anastomotic healing. Second, the microbiomes of humans and mice differ substantially, with variations in the abundance of key phyla and presence of several unique genera (10). Evaluating inulin and 5-ASA in a non-humanised microbiome model raises questions about the translatability of these findings to human patients.

Despite this, these findings add to a growing body of evidence indicating that the microbiome holds considerable promise in preventing anastomotic leakage and, in turn, lowering the likelihood of disease recurrence. Various other perioperative interventions, such as low-fat/high-fibre dietary prehabilitation (11), pre- and pro-biotic supplementation (12), and phosphate supplementation (13), have demonstrated promising effects on the microbiome and anastomotic healing in experimental animal studies. However, the safety and efficacy of these interventions in reducing anastomotic leak remains to be established through rigorous evaluation in clinical trials. As interest in this area grows, there is pressing need for translational research to ascertain whether encouraging pre-clinical data on the microbiome can be replicated in patients undergoing colorectal surgery.

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