## 6 Biliary Tract Cancers
### Microbiota in BTC  
Given the fact that bile acids exhibit strong antimicrobial properties, the biliary tract was assumed to be a germ-free environment. However, a study of patients with acute cholangitis or cholecystitis reported occurrence of bacteria in their biliary tracts [91]. It has also been found that microbiota composition can influence BTC development by altering bile acid signaling [125].  
Unfortunately, not much data concerning microbiome are available for biliary tract cancer. The first study of BTC-related microbiota and microbiota was conducted by [PERSON] et al. in 2015 to characterize the differences in the microbiota in the biliary tract of patients with BTC and those with benign biliary pathology (BBP). Studies on the microbiota of patients with BTC and BBP reported that bile tract microbiota differs between two study groups. BTC patients' microbiota was enriched in _Fusobacterium_, _Prevotella_, _Helicobacter_, _Campylobacter_, _Methylophiliaceae_, _Sinobacteriaceae_, _Actinomyces_, _Dialister_, and _Novosphingobum_, with significant abundance of _Fusobacterium_, _Prevotella_, _Helicobacter_, and _Campylobacter_. BPP microbiota was less abundant and differentiated from BTC microbiota, with _Nesterankonia_, _Rothia_, and _Mesorhizobium_ being the most abundant species [126] (Table 6). _Rothia_ is a part of the commensal oral microbiota. _Novosphingobium_ has already been linked to primary liver cirrhosis and cancer. It has been reported that the bacterium induces an autoimmune response in the host organism owing to the similarity between its PDC-E2-like proteins and human pyruvate dehydrogenase [93]. _Methylophilaceae_ and _Nesterenkonia_ have been mostly isolated from soil and lake sediments, and _Mesorhizobium_ exists in symbiosis with plant roots and has been rarely isolated from humans [126; 127]. Other studies suggest that infection with _Helicobacter_ species may represent a risk for BTC as _H. bilis_ and _H. hepaticus_ were reported to increase the chance of biliary tract and gallbladder cancer development [127; 128].  
Studies on the microbiome of patients with BTC and BPP reported that bile tract microbiota differs between two study groups [126; 127; 128; 129].  
Bile samples from 125 patients with various hepato-biliary diseases: 75 with biliary stones, 15 with pancreatico-biliary malignancies, and 4 with primary sclerosis cholangitis. 16S Illumina sequencing [126]; review article [127]; bile samples from from 125 patients with various hepatobiliary diseases: 75 with biliary stones, 15 with pancreatico-biliary malignancies, and 4 with primary sclerosis cholangitis, Helicobacter genus-specific primers [128]; 22 gallbladder and liver biopsy specimens. Helicobacter genus-specific 16S rDNA PCR [129].  
Chronic _Salmonella_ enterica serovar Typhi infection has also been reported to be associated with a significant risk of gallbladder cancer development. [PERSON] et al. has shown on an animal model that chronic infection with _Salmonella typhi_ encourages malignant transformation in predisposed mice. [PERSON] et al. have reported that _Salmonella_ infection enhances activation of mitogen-activated protein kinases (MAPK) and protein Kinase B (AKT) pathways; this can suggest a possible mechanism by which the bacteria influence cancer development, as upregulation of MPK and AKT pathways is frequently observed in human cancers. _Salmonella_ produces about 40 proteins that enable the pathogen to infect host cells. Bacterial proteins SopB, SopE, and SopE2 promote _Salmonella_ uptake by host cells via the initiation of the host MAPK pathway. In addition, SopB protein, secreted in order to prevent fusion of the Salmonella-containing vacuole with lysosomes, also triggers the host MAPK pathway [130].