**9.** *Salmonella typhi* **and gallbladder cancer**

*Salmonella enterica* serovar typhi is a gram-negative, flagellated, rod-shaped bacteria which is the causative agent of typhoid fever. It resides in the gallbladder and results in chronic inflammation of the gall bladder mucosa leading to the formation of gallstones [123]. It also produces a biofilm that prevents it from the anti-bacterial action of the bile and thus results in its persistence in the gallbladder leading to a chronic carrier state.

*Salmonella typhi* has been strongly associated with the development of gallstone disease and chronic infection with *S. typhi* is now being linked to GBC. The earliest evidence dates back to 1964 when Cargill et al. suggested a probable association between chronic typhoid and paratyphoid carriers and GBC [76]. In 1971, Axelrod et al., also reported a similar association between *S. typhi* and GBC. Since then, several studies have reiterated the results [124–126]. There are certain proposed mechanisms by which Salmonella may result in a chronic inflammatory state and subsequent development of cancer. The typhoid toxin is carcinogenic and causes alterations in the cell cycle and DNA damage [127]. AvrA, is an effector protein synthesized by Salmonella pathogenicity island 1 via Type III secretion system which subdues the host inflammatory response and prevents autophagy, thus resulting in the persistence of the bacteria and the chronic carrier state [128, 129].

Typhoid fever and GBC are endemic in the Gangetic belt and the northern states of India which provides strong evidence to suggest an association between *S. typhi* and GBC [7, 130, 131]. A study conducted in Northern India demonstrated that patients with gallbladder cancer had a higher Vi polysaccharide as compared to the control group and the risk of developing GBC in typhoid carrier patients was 8.47 times higher than the non-carrier group, thus concluding the chronic typhoid carrier state as a risk factor for GBC [130]. This has been reinforced by a number of recent studies [127, 132]. Although there is emerging evidence suggesting a positive association between *S. typhi* and GBC but the data is limited, with conflicting results, thus requiring larger epidemiological studies to establish a consensus [99, 133].
