**11. Therapeutic perspective: "microbial therapeutics"**

There is a complex interplay between the human body and its microbiome. While a normal gut flora is essential for homeostasis, dysbiosis may lead to a multitude of diseases. Several mechanisms associated with carcinogenesis are now being utilized in its prevention. GBC has been associated with chronic inflammation and chronic typhoid carrier state; thus, many animal models have been developed to study the role of antibiotics in the eradication of Salmonella, thereby reducing the chances of development of GBC. But the results have been conflicting [128] and Cholecystectomy remains the only definitive treatment for eradication of the carrier state of Salmonella [128]. There was

a rise in the number of prophylactic cholecystectomies owing to this but it also saw an increase in the number of colorectal malignancies due to gut bacterial dysbiosis, thereby emphasizing their role in the development of cancer [141].

The role of the gut microbiome in the maintenance of homeostasis encouraged the researchers to utilize their potential in the therapeutic management of the disease. Microbiome therapeutics consist of additive therapy, subtractive therapy, and modulatory therapy. Additive therapy with genetically engineered or natural probiotic agents has shown some benefit in colorectal cancer and is now being utilized in GBC. There is emerging evidence regarding the association of probiotics and dietary changes with a decreased incidence of gallstone disease, thereby reducing the chances of GBC, thus additive therapy with natural or genetically engineered probiotic organisms may prove beneficial. However, there is still a dearth of evidence in this aspect [142, 143]. Subtractive therapy is being utilized by genetically engineered *E. coli* strains with a cloned antibiofilm protease Deg P gene or a cloned Lysine and Pyosin gene which results in inhibition of growth of pathogenic bacteria in the gut, thereby preventing dysbiosis [144, 145]. *E. coli* strains with a cloned antibiotic Microcin H47 gene may also help in inhibiting and displacing Salmonella from the gut [146]. These two methods can be utilized in patients with a Chronic salmonella carrier state and may be used as an alternative to Cholecystectomy. This may also reduce the incidence of GBC in these patients. Apart from this, genetically engineered bacteria are also being used to test the effect and toxicity profile of chemotherapy [147, 148], develop cancer vaccines and targeted biological therapies [149].
