Liver Flukes and the Microbiota in Cancer

Tumor development is a multifactorial process, influenced by both genetic and environmental pressures. A small number of chronic infectious agents have been designated carcinogenic, including viruses (hepatitis B, C and HPV), bacteria (Helicobacter pylori) and parasites (De Martel et al., 2012De Martel C. et al.Global burden of cancers attributable to infections in 2008: a review and synthetic analysis.Lancet Oncol. 2012; 13 (Available at: http://www.ncbi.nlm.nih.gov/pubmed/22575588): 607-615Summary Full Text Full Text PDF PubMed Scopus (1752) Google Scholar). Further, general microbial dysbiosis can contribute to the development of some cancers (Garrett, 2015Garrett W.S. Cancer and the microbiota.Science (New York, N.Y.). 2015; 348 (Available at: http://www.ncbi.nlm.nih.gov/pubmed/25838377): 80-86Crossref PubMed Scopus (90) Google Scholar), including in the biliary system (Avilés-Jiménez et al., 2016Avilés-Jiménez F. et al.Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma.Clin. Microbiol. Infect. 2016; 22 (178.e11–22, (Available at: http://www.ncbi.nlm.nih.gov/pubmed/26493848))Summary Full Text Full Text PDF PubMed Google Scholar). In the Southeast Asian countries Thailand, Laos, Vietnam, and Cambodia, the liver fluke Opisthorchis viverrini is endemic, and chronic infection with this trematode is a known risk factor for development of the bile duct cancer cholangiocarcinoma (CCA). Understanding how O. viverrini infection contributes to CCA development or progression could lead to new therapeutic interventions for this notoriously hard to treat disease. Multiple O. viverrini infection-induced pathways have been associated with tumorigenesis, including parasite secretion of a growth factor that facilitates wound healing, angiogenesis and cellular proliferation that contributes to transformation of bile duct cholangiocytes (Smout et al., 2015Smout M.J. et al.Carcinogenic parasite secretes growth factor that accelerates wound healing and potentially promotes neoplasia.PLoS Pathog. 2015; 11 (Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4618121&tool=pmcentrez&rendertype=abstract): e1005209Crossref PubMed Google Scholar, Smout et al., 2009Smout M.J. et al.A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells.PLoS Pathog. 2009; 5 (Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2749447&tool=pmcentrez&rendertype=abstract): e1000611Crossref PubMed Scopus (0) Google Scholar) and infection-induced chronic inflammation (Sripa et al., 2012Sripa B. et al.The tumorigenic liver fluke Opisthorchis viverrini–multiple pathways to cancer.Trends Parasitol. 2012; 28 (Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3682777&tool=pmcentrez&rendertype=abstract): 395-407Summary Full Text Full Text PDF PubMed Scopus (307) Google Scholar). This is reminiscent of a growing number of inflammation-driven cancers that involve bacterial dysbiosis (Garrett, 2015Garrett W.S. Cancer and the microbiota.Science (New York, N.Y.). 2015; 348 (Available at: http://www.ncbi.nlm.nih.gov/pubmed/25838377): 80-86Crossref PubMed Scopus (90) Google Scholar). However, the local tissue microbiome has been an understudied component of CCA. Recent studies using a small animal model of O. viverrini-induced CCA demonstrated that fluke infection of Syrian golden hamsters altered commensal bacterial communities in the gastrointestinal tract and allowed translocation of several microbes into bile fluid (Plieskatt et al., 2013Plieskatt J.L. et al.Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome.FASEB J. 2013; 27 (Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3804743&tool=pmcentrez&rendertype=abstract): 4572-4584Crossref PubMed Scopus (104) Google Scholar), indicating that microbial shifts associated with O. viverrini infection may influence CCA. In this issue of EBioMedicine, Chng et al. (Chng et al., 2016Chng K.R. et al.Tissue microbiome profiling identifies an enrichment of specific enteric bacteria In Opisthorchis viverrini associated cholangiocarcinoma.EBioMedicine. 2016; 8: 195-202Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar) interrogate the microbiome of bile ducts isolated from O. viverrini-naïve and -infected CCA patients and report a number of distinct features in the bacterial composition of local tissues. All bile duct samples from CCA patients, independent of O. viverrini infection, harbor similar microbial communities comprised of taxa typically found in the gut. Based on comparison of these tumor samples to hepatic and gastric tissues of non-CCA patients, the authors suggest the existence of a bile duct-specific microbial signature. These findings will require verification in a prospective trial with robust matching of donor tissues and higher sample numbers. Despite the gross similarities between O. viverrini-naïve and -infected CCA bile duct microbiomes, Chng et al. identify microbial alterations that stratify based on O. viverrini status. In O. viverrini-naïve tumor samples, the genus Stenotrophomonas (a pro-inflammatory γ-proteobacter) was enriched. Notably, fluke-infected samples have higher abundance and prevalence of Bifidobacteria, which has been previously shown to produce high levels of bile salt hydrolase (BSH) and contribute to elevated levels of carcinogenic bile salt metabolic products (Sagar et al., 2015Sagar N.M. et al.The interplay of the gut microbiome, bile acids, and volatile organic compounds.Gastroenterol. Res. Pract. 2015; 2015 (Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4363917&tool=pmcentrez&rendertype=abstract): 398585Crossref PubMed Scopus (60) Google Scholar). However, in contrast to what has been seen in colon cancer, CCA tumors and adjacent non-cancerous hepatic tissue harbor very similar microbes, indicating that CCA-associated microbiome changes are systemic rather than tumor-specific. Together, the fluke-induced microbial changes reported by Chng et al. add to the growing body of literature demonstrating that helminths can alter the microbiota within mammalian hosts and show that the ability of helminths to modulate bacterial communities extends beyond the gut. A final model is presented to suggest that the altered microbial composition of the O. viverrini-infected bile duct may promote tumor development. Specifically, the authors propose that O. viverrini infection and colonization of bile ducts with Bifidobacteria fosters a carcinogenic microenvironment through bacterial metabolic activity, suggesting that increased accumulation of bile acids and ammonia could enhance inflammation or genomic instability, similar to what has been reported in colitis-associated colorectal cancer (Louis et al., 2014Louis P. Hold G.L. Flint H.J. The gut microbiota, bacterial metabolites and colorectal cancer.Nat. Rev. Microbiol. 2014; 12 (Available at: http://www.ncbi.nlm.nih.gov/pubmed/25198138): 661-672Crossref PubMed Scopus (1541) Google Scholar). Together, the results implicate parasite and host interactions in the dysregulation of local physiology that contributes to carcinogenesis as O. viverrini alters the bile duct environment and promotes the proliferation of a new bacterial player (Bifidobacteria). Although the findings from these patient-based studies are intriguing, many questions regarding the relative contribution and mechanisms by which local microbiome shifts may influence the development or progression of CCA in the context of O. viverrini infection remain to be addressed. We highlight the need for future studies to employ careful sampling design and to analyze microbial data with prudence. In the context of comparing CCA-associated bile ducts to healthy tissues and the potential mechanistic link that underlies O. viverrini infection, dysbiosis, and promotion of a carcinogenic microenvironment, the findings by Chng et al. must be interpreted with caution, as must all associational studies. In particular, the enrichment of specific microbes within human tumors should not be considered causative for tumorigenesis, progression or severity (Garrett, 2015Garrett W.S. Cancer and the microbiota.Science (New York, N.Y.). 2015; 348 (Available at: http://www.ncbi.nlm.nih.gov/pubmed/25838377): 80-86Crossref PubMed Scopus (90) Google Scholar). Nonetheless, the value of patient-based epidemiological studies is the provision of testable hypotheses for basic science experiments to determine the contribution, if any, of noted associations. The manuscript by Chng et al. should entice further investigation of how O. viverrini infection can affect microbial communities, the microbial metabolome, and the local immune microenvironment in CCA development and progression. The authors declare no conflicts of interest. Tissue Microbiome Profiling Identifies an Enrichment of Specific Enteric Bacteria in Opisthorchis viverrini Associated CholangiocarcinomaCholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty primary CCA tumors and matched normals, from both liver fluke (Opisthorchis viverrini) associated (OVa, n = 28) and non-O. viverrini associated (non-OVa, n = 32) cancers, were profiled using high-throughput 16S rRNA sequencing. A distinct, tissue-specific microbiome dominated by the bacterial families Dietziaceae, Pseudomonadaceae and Oxalobacteraceae was observed in bile duct tissues. Full-Text PDF Open Access

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