Perioperative selective decontamination of the digestive tract (SDD) decreases tumor cell adhesion in
the liver post-operatively.
Nuray Gül1, SSimran Grewal1,2, Rens Braster1, Stephan Pouw1, Marijn Bögels1,2, Nimrat Grewal1,2, Rob
Beelen1, Jaap Bonjer2, Marjolein van Egmond1,2
1Department
of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the
Netherlands
2Department
of Surgery, VU University Medical Center, Amsterdam, the Netherlands
Abstract
Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal cancer
(CRC). However, we previously demonstrated that abdominal surgery paradoxically led to enhanced adhesion
of tumor cells in the liver vasculature, which can grow out into metastases. Furthermore, previous studies
demonstrated that patients with anastomotic leakage after resection of the tumor had poorer long term
survival. Moreover, we showed in a rat model that colectomy resulted in bacterial translocation, suggesting
that bacterial contamination due to resection of primary CRC may have a negative impact on metastases
development and long-term patient outcome.
Therefore, the aim of this study was to investigate the impact of selective decontamination of the digestive
tract (SDD) prior to colectomy on surgery-induced liver metastases outgrowth. SDD is an infection prophylaxis
regimen consisting of polymyxine B sulfate, tobramycin, and amphotericin B to eradicate potential pathogenic
aerobic gram-negative bacteria from the gastrointestinal tract, while leaving the normal anaerobobic flora
undisturbed. The study was performed in a rat colon carcinoma model and SDD prophylaxis was given 5 days
pre-operative in drinking water. Rectal swabs were taken to evaluate the effect of SDD on gram-negative
bacterial load. Rats underwent a sham operation (laparotomy), partial colectomy, or anaesthesia alone, after
which fluorescently-labeled tumor cells were injected into the portal circulation. All rats were sacrificed 2 hours
post-operatively, liver samples were taken, and the number of adhered tumor cells was determined with
fluorescence microscopy.
Pre-operative SDD decreased the amount of gram negative bacterial load in the gastrointestinal tract.
Endothelial continuity was investigated by analysis of the tight junction molecule Claudin-5. Liver vessel
integrity in rats with SDD intake, was less disrupted compared to the rats without SDD. This indicates that
SDD prophylaxis prevents loss of cell-cell contact after abdominal surgery, preventing exposure of the
extracellular matrix with adhesion molecules.
SDD intake did not decrease the number of adhered tumor cells in the liver in the control and laparotomy
groups. Importantly, tumor cell adhesion was significantly decreased in rats that underwent a partial colectomy
after SDD intake.
In conclusion, our results support that exposure to bacterial products after colectomy contributes to
development of surgery-induced liver metastases, which can be reduced by a SDD antibiotic regime preoperatively. We therefore anticipate that SDD of patients undergoing CRC resection will significantly improve
their prognosis.