Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines

Abstract

ObjectiveColorectal 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.DesignThe 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 bothin vitroandin vivo.ResultsMice 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 ofAlistipes onderdonkiiandParabacteroides goldsteinii. Oral supplementation withA. onderdonkiiresulted in a higher rate of leaks in mice, while gavage withP. goldsteiniiimproved 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.ConclusionGut 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.

Basal levels of microbiota-driven subclinical inflammation are associated with anastomotic leak in patients with colorectal cancer

“…Subclinical inflammation is increasingly recognised as a potential driver of poor anastomotic healing in bowel surgery. In keeping with our findings,1 a recent report showed that preoperative levels of circulating white cells were higher in patients that developed AL after colorectal surgery 6. Another study suggested that serum chemokine levels were higher before surgery in patients experiencing AL,7 and more evidence has emerged on the impact of preoperative low-grade inflammation on AL in gastric and oesophageal surgery 8 9.…”

“…Colonic mucosal biopsies were collected during surgery from all patients and the levels of nine cytokines were measured (online supplemental material), confirming higher levels of MIP-1α, MIP-2, MCP-1 and IL-17A/F in patients who later developed AL (figure 1A). This larger cohort also revealed that the basal levels of IL-1β and tumour necrosis factor alpha, which we have previously shown to be increased after surgery in patients with AL,1 were already high before completion of the anastomosis. Proinflammatory IL-5 and interferon-gamma were also increased at baseline.…”

“…As mucosal cytokines cannot be easily assessed in clinical practice, we quantified proinflammatory markers in preoperative faecal samples. Calprotectin is a faecal marker routinely used in patients with inflammatory bowel disease,3 and we have shown that lipocalin-2 (LCN-2) correlates with circulating white blood cells 1. Both markers were increased before surgery in patients with poor healing and leakage after surgery (figure 1B), and significantly correlated with postoperative levels of serum C-reactive protein, a marker routinely measured after surgery for early detection of AL4 (figure 1C,D).…”

“…In our recent publication in Gut ,1 we showed that preoperative gut microbiota was causally linked to the development of anastomotic leak (AL) after colorectal cancer (CRC) surgery. AL results from impaired healing of the colonic wound and leads to the leakage of intestinal content into the abdomen.…”

Microbiome is the key to preventing anastomotic leak in colorectal surgery

“…The study by Hajjar et al provides further evidence that the microbiome represents a critical missing piece in this puzzle because it modulates the innate immune response to anastomotic wound healing 2. The more intriguing observation from this work is that it is possible to transfer a colonic healing phenotype through the transplantation of preoperative faecal samples and even individual bacterial strains.…”