Br gnard et al also discovered

Brégnard et al. also discovered that some of the cytoplasmic DNA resulted from enhanced LINE-1 retrotransposition, a phenomenon others have associated with inflammatory diseases (). That inhibitors of reverse transcription diminished cytokine production in the FA nuciferine is compatible with the view that these FA proteins function in some way to constrain endogenous reverse transcriptase activities, preventing accumulation of cytoplasmic nucleic acids thereby suppressing the activation of cytokine gene transcription. Therefore, this new pathway by which the inflammatory response participates in the Fanconi anemia phenotype may hold some therapeutic potential. While more work is required on the precise mechanisms by which FA proteins might constrain cytoplasmic accumulation of endogenous nucleic acids, and while the downsides of reverse transcriptase inhibitors need to be investigated carefully in primary FA cells, the possibility that such agents might inhibit aberrant constitutive activation of the inflammatory response is intriguing and, given the important role this response plays in disease pathogenesis, the use of such agents clinically may have some potential. Because inflammation can result in DNA damage and vice versa, the use of such inhibitors in preclinical models might also permit investigators in the field to sort out the order of events in Fanconi anemia pathogenesis. Conflicts of interest
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 () and parasites (). Further, general microbial dysbiosis can contribute to the development of some cancers (), including in the biliary system (). In the Southeast Asian countries Thailand, Laos, Vietnam, and Cambodia, the liver fluke is endemic, and chronic infection with this trematode is a known risk factor for development of the bile duct cancer cholangiocarcinoma (CCA). Understanding how infection contributes to CCA development or progression could lead to new therapeutic interventions for this notoriously hard to treat disease. Multiple 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 () and infection-induced chronic inflammation (). This is reminiscent of a growing number of inflammation-driven cancers that involve bacterial dysbiosis (). However, the local tissue microbiome has been an understudied component of CCA. Recent studies using a small animal model of -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 (), indicating that microbial shifts associated with infection may influence CCA. In this issue of , Chng et al. () interrogate the microbiome of bile ducts isolated from -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 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 -naïve and -infected CCA bile duct microbiomes, Chng et al. identify microbial alterations that stratify based on status. In -naïve tumor samples, the genus (a pro-inflammatory γ-proteobacter) was enriched. Notably, fluke-infected samples have higher abundance and prevalence of , 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 (). 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.