Could the microbiome hold the key to diagnosing and treating biliary tract cancer?

By Dr. Priyom Bose, Ph.D.Oct 24 2023Reviewed by Benedette Cuffari, M.Sc.

A recent study published in the journal Microorganisms explores the microbiome composition in patients with biliary tract cancer.

Study: Interplay between the Human Microbiome and Biliary Tract Cancer: Implications for Pathogenesis and Therapy. Image Credit: MR.AUKID PHUMSIRICHAT / Shutterstock.com

Biliary tract cancer

Biliary tract cancer comprises a wide range of invasive adenocarcinomas, including gallbladder carcinoma and cholangiocarcinoma. Cholangiocarcinoma, often associated with a poor prognosis, can be further classified as intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma.

The incidence rate of biliary tract cancer varies according to geographical regions and subgroups. In recent years, the global prevalence of ICC has increased from 0.44 to 1.18 cases per 100,000 individuals. Unlike ICC, extrahepatic cholangiocarcinoma has modestly increased from 0.95 to 10.2 for every 100,000 individuals over a 40-year period.

Epidemiological studies have identified multiple risk factors associated with the incidence of cholangiocarcinoma. Some of these risk factors include hepatolithiasis, choledocholithiasis, primary sclerosing cholangitis, cholelithiasis, and bile duct cysts.

Biliary tract cancer and the microbiome

Thousands of microorganisms are present in different organs, including the stomach, skin, liver, and intestines, all of which influence various physiological functions, including immune regulation.

Previous studies have indicated that the gastrointestinal microbiome can correlate with manifestations of cancer and metabolic disorders. Likewise, next-generation sequencing (NGS) technology has highlighted an association between biliary tract cancer and the microbiome.

Compared to healthy individuals, patients with biliary tract cancer exhibit increased levels of Enterobacteriaceae and decreased levels of Faecalibacterium, Clostridia, and Coprococcus.

Fecal samples of biliary tract cancer patients have also revealed high levels of Enterobacteriaceae. In fact, about 50% of Enterobacteriaceae species identified in the bile samples of patients were similar to strains identified from the fecal sample at the operational taxonomic unit (OTU) level.

Previous studies have observed a relationship between gut dysbiosis and the incidence of ICC, possibly due to the connection between gut microbiota, cytokine profiles, and bile acid. Patients with ICC exhibit significant α- and β-diversity as compared to patients with liver cirrhosis hepatocellular carcinoma and healthy individuals.

ICC has been associated with higher levels of Lactobacillus, Actinomyces, Alloscardovia, and Peptostreptococcaceae. Significantly higher glycoursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA) plasma-stool ratios have also been observed in ICC. Dietziaceae, Pseudomonadaceae, and Oxalobacteraceae have also been detected in the bile duct tissues.

Genomic studies have indicated the presence of Streptococcus, Enterococcus, Bacteroides, Klebsiella, and Pyramidobacter within the biliary microflora. These bacteria play a significant role in the onset of cholangiocarcinoma; therefore, these microbes could be used as a biomarker for the condition.

Extrahepatic cholangiocarcinoma has been associated with a reduced level of Nesterenkonia but an abundance of Methylophilaceae, Prevotella, Fusobacterium, Actinomyces, Helicobacter pylori, and Novosphingobium.

Prolonged inflammation plays a critical role in the development of gallbladder cancer, which also influences the biliary tract. The risk of gallbladder cancer increases in the presence of bacterial infections, which could induce chronic inflammation, carcinogenic toxin, and metabolite production. 

Fusobacterium nucleatum and Escherichia coli are dominant species identified in the bile of gallbladder cancer patients. The presence of Salmonella typhi in the gallbladder may also influence the onset of gallbladder cancer.

The impact of host microbes in the diagnosis and treatment of biliary tract cancer

Although immunotherapy is a common approach to treating malignant tumors, its efficacy is significantly affected by intestinal flora and environmental factors. Many studies have shown that the gut microbiome influences the response to immune checkpoint inhibitors (ICI). These studies have also highlighted the association between gut microbiome and tumor immune resistance.

The strategic use of probiotics to regulate ICI could play an effective role in controlling harmful bacteria with carcinomic potential. Early clinical trial reports have indicated a modest response rate of immune checkpoint therapy (ICT) in cholangiocarcinoma.

Taxonomic screening is an important strategy to identify biomarkers that can be used to assess clinical responses to immunotherapies. Altering gut microbial composition and diversity could be an effective strategy to modulate responses to cancer immunotherapy. 

The liver-bile acid-microbiota axis plays a crucial role in gastrointestinal carcinogenesis. Thus, distinct changes in plasma bile acid concentrations could be used as potential diagnostic biomarkers to distinguish cholangiocarcinoma from benign biliary diseases and healthy individuals.