Rerouted bile acid reduces tumour spread in colorectal cancer mouse model

Bile acid diversion in Roux-en-Y gastric bypass (RYGB) reduces colorectal tumour growth and metastasis independent of weight loss, potentially reshaping future cancer treatment approaches, researchers from the Department of General and Visceral Surgery, Faculty of Medicine, University of Freiburg, Germany, have reported.

Metabolic surgery reduces colorectal carcinogenesis and metastasis due to bile acid diversion (Credit: Rebecca Kesselring/Medical Center University Freiburg, Germany)

More than 2 billion adults worldwide are now overweight or obese, a condition marked by chronic low-grade inflammation and metabolic disruption that can promote tumour growth, increasing the risk of developing at least 15 types of cancer.

Among various weight-loss interventions, bariatric surgery, specifically RYGB, is not only effective in promoting sustained weight reduction but has intriguingly been linked to reduced cancer incidence. Whether these changes alone can slow or prevent colorectal cancer remains a question with critical implications for prevention and treatment.

Previous research has focused on how losing weight with RYGB reshapes cancer outcomes, leaving unanswered questions about biological mechanisms behind RYGB's anticancer correlation.

In their study, the researchers developed a combined mouse model of obesity and colorectal cancer to determine whether bile acid diversion after gastric bypass surgery reduces tumorigenesis and metastasis independent of weight loss.

Mouse experiments were conducted at the University of Freiburg, along with a translational analysis involving 41 patients with stage IV colorectal cancer.

Researchers induced obesity in mice by feeding a high-fat diet for six weeks, gaining around 50% body weight, before performing RYGB or sham surgery. Animals recovered for six additional weeks on either normal chow or continued a high-fat diet until body weight stabilized. Orthotopic colorectal cancer was modelled by implanting genetically engineered tumour organoids under the subserosa of the cecum.

A separate cohort underwent cholecysto-intestinal shunt surgery to divert bile acids without other metabolic alterations. Circulating and focal bile acid profiles were measured by liquid chromatography–tandem mass spectrometry.

Investigators also performed microbiome analysis with 16S ribosomal RNA sequencing and evaluated immune cell composition in tumours by flow cytometry.

Mice that underwent Roux-en-Y gastric bypass developed primary colorectal tumours that were significantly smaller and exhibited almost no liver metastases compared with sham-operated controls. Even when researchers extended tumour development periods to allow increased tumour size, metastases remained disproportionately low in RYGB mice, suggesting that metabolic changes, rather than weight loss alone, drive this anticancer effect.

When bile acid diversion was achieved by cholecysto-intestinal shunt alone, similar suppression of tumour growth and metastasis occurred. Circulating bile acids in gastric bypass animals shifted toward reduced primary bile acids and elevated secondary bile acids, a pattern absent in diet-restricted controls.

Faecal microbiome composition remained largely unchanged after bile diversion, and transplantation of microbiota from treated mice into high-fat diet recipients did not confer anticancer effects.

Analysis of the tumour microenvironment revealed no differences in immune cell populations between groups. In a cohort of patients with colorectal cancer, higher serum concentrations of primary bile acids correlated with shorter time to metastasis. This pinpointed dramatic alterations in bile acid circulation following RYGB surgery as the likely key factor inhibiting tumour progression and metastasis.

Further exploration revealed that gut microbiome alterations or immune system changes were not involved in this observed anticancer effect, leaving a reduced-primary/ elevated-secondary bile-acid profile as the only distinguishable change.

Researchers speculate that this altered bile acid metabolism of increased secondary bile acid and decreased primary bile acid contributes to reduced tumour growth and metastasis, although the precise mechanisms are still unknown.

Even without the specific mechanistic molecular pathway understood, there is potential for clinically relevant manipulation of bile acids in cancer prevention and treatment strategies. The authors suggest that modulating bile acid metabolism could offer nonsurgical cancer treatment options, particularly beneficial for individuals at high risk due to obesity or metabolic dysfunction.

The authors concluded that future research is essential to pinpoint the exact bile acid species and molecular pathways involved, clarifying these details in follow-up studies could reveal previously unexplored molecular targets to reduce metastasis.

The findings were reported in the paper, ‘Metabolic surgery reduces CRC disease progression through circulating bile acid diversion,’ published in Science Translational Medicine. To access this paper, please click here (login maybe required)