Association of Chronic Opisthorchis Infestation and Microbiota Alteration on Tumorigenesis in Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a common hepatobiliary cancer in East and Southeast Asia. The data of microbiota contribution in CCA are still unclear. Current available reports have demonstrated that an Opisthorchis viverrini (OV) infection leads to dysbiosis in the bile duct. An increase in the commensal bacteria Helicobacter spp. in OV-infected CCA patients is associated with bile duct inflammation, severity of bile duct fibrosis, and cholangiocyte proliferation. In addition, secondary bile acids, major microbial metabolites, can mediate cholangiocyte inflammation and proliferation in the liver. A range of samples from CCA patients (stool, bile, and tumor) showed different degrees of dysbiosis. The evidence from these samples suggests that OV infection is associated with alterations in microbiota and could potentially have a role in CCA. In this comprehensive review, reports from in vitro, in vivo, and clinical studies that demonstrate possible links between OV infection, microbiota, and CCA pathogenesis are summarized and discussed. Understanding these associations may pave ways for novel potential adjunct intervention in gut microbiota in CCA patients.

Figure 1.

Microbiota alteration contributes to CCA carcinogenesis. Increased levels of commensal Helicobacter spp. during a parasitic OV infection result in chronic inflammation and abnormal cell proliferation of cholangiocytes. (1) Increased levels of conjugated bile acids (TUDCA and GUDCA) within the bile duct lumen from the increases in Helicobacter spp. lead to cholangiocyte inflammation through the NF-kB pathway. Proinflammatory cytokine IL-1, profibrotic cytokine TGF-β, and angiogenetic vascular endothelial growth factor are upregulated in cholangiocytes. (2) Helicobacter spp. can activate the mitogen-activated protein kinase pathway resulting in cholangiocyte proliferation. (3) Helicobacter spp. can dysregulate the cell cycle of cholangiocytes by phosphorylation of the RB, a tumor-suppressing protein, and then release transcription factor E2F resulting in abnormal cholangiocyte proliferation. E2F, E2 factor; GUDCA, glycoursodeoxycholic acid; NF-kB, nuclear factor-kappa B; OV, Opisthorchis viverrini; RB, retinoblastoma; TUDCA, tauroursodeoxycholic acid.

Figure 2.

Association of biliary pathway and host immunity. (1) Primary bile acids (cholic acid and chenodeoxycholic acid) are mainly synthesized and conjugated with glycine and taurine respectively in the liver and are then released into the gastrointestinal tract. (2) In the intestinal lumen, gut microbiota metabolize these primary bile acids to secondary bile acids (deoxycholic and lithocholic acid, respectively). Secondary bile acids can regulate immune response in gut by decreasing proinflammatory cytokines. (3) Subsequently, enterohepatic circulation reabsorbs 95% of bile acids in the terminal ileum, and they are deconjugated in the liver through the portal vein. Nonreabsorbed secondary bile acids (5%) in the terminal ileum will be then excreted in the feces. (4) In the liver, deconjugated secondary bile acids become primary bile acids that could inhibit hepatic tumor growth by the induction of CXCL16-activated NKT cells. (5) However, it is uncertain whether these primary bile acids are able to inhibit tumor growth in the bile duct. CXCL16, C-X-C Motif Chemokine Ligand 16; FXR, farnesoid X receptors; G + PBAR1, G protein-coupled bile acid receptor 1; NKT cells, natural killer T cells.

Figure 3.

Different microbiota populations found in different tissue sites of CCA patients. Samples from different tissue sites illustrate the variations in microbiota profile as shown.