**8. The Helicobacter species and gallbladder cancer**

The *Helicobacter species*, especially *H. pylori*, have been largely implicated in the causation of gastric as well as intestinal cancers by the mechanism of inflammationinduced tumorigenesis and are now being associated with the development of various hepatobiliary cancers [100].

*H. pylori* induces a chronic inflammatory state by resulting in the release of various pro-inflammatory mediators like TNF-α, IL-1, IL-6, and other vasoactive substances [101]. They also prevent cell adhesion and lead to the migration of the mutated epithelial cells [102]. Free radicals produced cause oxidative damage to the biliary epithelium [103]. IL-8 production may also promote inflammation and alter cellular proliferation and apoptosis [87]. The Cag- A protein secreted by *H. pylori* is one of the most extensively studied virulence factors responsible for producing a chronic inflammatory state as seen in gastric epithelial cells and increasing the risk of gallstones [90]. Some strains possess pathogenicity islands which produce a type IV secretion system and also result in a "hummingbird" epithelial phenotype of epithelial cells which are implicated in rival cell death, thus resulting in the death of the normal biliary microbiota and producing a Helicobacter "bloom" [104, 105]. This "bloom" of Helicobacter results in chronic inflammation of the biliary epithelium by the various mechanisms mentioned, leading to dysplasia and subsequent neoplasia.

Since the first evidence of *H. pylori* in gallbladder mucosa in a patient with cholecystitis was detected by Kawaguchi et al. [106] in 1996, ample studies have shown an association of Helicobacter species, especially *H. pylori*, with the formation of gallstones [107–109] which have also been reiterated by recent meta-analyses [110]. Another study by Kuroki et al. [111] reported a higher biliary epithelial proliferation rate in patients infected with *Helicobacter species* as compared to the control group.

*Role of Gut Microbiome and Enteric Bacteria in Gallbladder Cancer DOI: http://dx.doi.org/10.5772/intechopen.104404*

The isolation of bacteria in these studies was done using various next-generation sequencing techniques. These techniques are being utilized to establish an association between the *Helicobacter species* and GBC. While some have shown promising results [112, 113], others have negated this theory [114, 115]. Apart from *H. pylori*, attempt at isolating other enterohepatic strains like *H. bilis*, *H. hepaticus,* and *H. pullorum* have been done in a number of studies [116]. Dewhirst and Fox [117] identified 5 strains of *H. bilis*, 2 strains of *Flexisipira rappini*, and one strain of *H. pullorum* using PCR analysis in patients with gallbladder diseases and GBC. Various studies have demonstrated high positivity of *H. bilis* in patients with biliary tract and gallbladder cancer, suggesting an association of *H. bilis* with GBC [118–120].

There have been several meta-analyses suggesting an association between Helicobacter infection and cancer of the biliary tract with conflicting results [121, 122]. However, a recent meta-analysis has suggested a significant association between *H. pylori* infection and biliary tract cancer [98]. The available research has suggested a strong association between *Helicobacter species* and GBC; however, these studies are largely limited to observational studies or small meta-analyses necessitating the need for a higher level of evidence in order to establish a general consensus.
