Exploring the gut–biliary microbiome axis in Opisthorchis viverrini-associated cholangiocarcinoma: An overlooked pathogenic interface

Dear Editor, Cholangiocarcinoma (CCA), an aggressive malignancy of the biliary tract, remains a lethal cancer with poor prognosis and limited therapeutic options. Among its etiological factors, liver fluke infection—particularly with Opisthorchis viverrini—has been classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC).[1] The geographic correlation between opisthorchiasis and CCA incidence in the Lower Mekong Basin is well established, and public health efforts have focused on reducing infection through food hygiene and anthelminthic treatment. Despite these efforts, the exact mechanisms underlying fluke-induced carcinogenesis are not fully elucidated. The classical model centers on mechanical damage and chronic inflammation, but this alone may not sufficiently explain neoplastic progression. We propose that microbiome dysbiosis—both intestinal and biliary—may act as a critical and overlooked intermediate in this pathway. THE MICROBIOME AS A MEDIATOR OF CARCINOGENESIS The human biliary system was historically considered sterile, but culture-independent techniques have revealed a complex microbial ecosystem within bile, influenced by both gut translocation and local environmental factors.[2] In O. viverrine infection, several factors may contribute to microbial shifts: Disruption of bile flow and ductal architecture by parasite-induced inflammation Immune modulation and increased permeability of the gut epithelium Altered bile acid profiles that selectively support certain bacteria Such dysbiosis can result in enrichment of pathobionts capable of generating genotoxic compounds (e.g., nitrosamines), pro-inflammatory cytokines, and reactive oxygen species, all of which can promote DNA damage, epithelial proliferation, and tumor initiation.[3,4] EVIDENCE FROM HUMAN AND ANIMAL STUDIES Multiple recent studies have demonstrated the presence of altered microbiomes in the bile and gut of CCA patients, particularly in those with fluke infection. Table 1 summarizes key studies linking microbiome shifts with fluke-associated CCA.Table 1: Summary of studies on microbiome dysbiosis in Opisthorchis viverrini infection and cholangiocarcinomaIMPLICATIONS FOR SCREENING AND PREVENTION We propose that profiling the gut and biliary microbiome in fluke-endemic regions could serve two purposes: Biomarker Development: Specific microbial signatures may indicate early neoplastic changes or high-risk individuals before imaging can detect tumors. Microbiome-based Interventions: Modulating the microbiome via dietary interventions, pre/probiotics, or microbiota transplantation may mitigate inflammation and tumor-promoting signals. These approaches are especially attractive in low-resource settings, where traditional cancer surveillance is often unavailable. Recommendations for future research We call for a concerted research agenda that includes: Longitudinal studies on microbiome changes during fluke infection and CCA progression Integration of metagenomics, metabolomics, and host transcriptomics Controlled trials of microbiome-modulating therapies in at-risk populations Such efforts will bridge parasitology and precision oncology in a novel, interdisciplinary framework. CONCLUSION O. viverrini-induced CCA remains a major burden in Southeast Asia. As conventional mechanisms offer only a partial explanation, we advocate for a paradigm shift incorporating the gut–biliary microbiome axis as a key component of carcinogenesis. Addressing this dimension may unlock new frontiers in early detection and personalized prevention strategies for fluke-associated cancers. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.