Deciphering the role of Enterococcus faecium cytidine deaminase in gemcitabine resistance of gallbladder cancer.

Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.

Metagenomic Analysis of Biliary Microbial Flora in Patients with Gallbladder Cancer or Gallstones-Associated Chronic Cholecystitis.

Biliary dysbiosis is associated with gallbladder cancer (GBC). We aimed to look for biliary bacteria specifically detected in GBC patients. We used 16S rRNA-based metagenomic analysis to elucidate biliary microbiota in 30 GBC and 30 gallstones-associated chronic cholecystitis patients. Relative abundance of five genera, Streptococcus, Enterococcus, Halomonas, Escherichia and Caulobacter was significantly associated with GBC. Of 15-species, 7 were detected significantly higher in GBC, Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Actinomyces bowdenii, Actinomyces israelii, Actinomyces gerencseriae, and Escherichia fergusonii were biosafety level-2 infectious bacteria; other 8 species were biosafety level-1 bacteria. These bacterial species may be involved in pathogenesis of GBC.

Association of Microbial Dysbiosis with Gallbladder Diseases Identified by Bile Microbiome Profiling.

BACKGROUND: Cholecystitis is an important risk factor for gallbladder cancer, but the bile microbiome and its association with gallbladder disease has not been investigated fully. We aimed to analyze the bile microbiome in normal conditions, chronic cholecystitis, and gallbladder cancer, and to identify candidate bacteria that play an important role in gallbladder carcinogenesis. METHODS: We performed metagenome sequencing on bile samples of 10 healthy individuals, 10 patients with chronic cholecystitis, and 5 patients with gallbladder cancer, and compared the clinical, radiological, and pathological characteristics of the participants. RESULTS: No significant bacterial signal was identified in the normal bile. The predominant dysbiotic bacteria in both chronic cholecystitis and gallbladder cancer were those belonging to the Enterobacteriaceae family. Klebsiella increased significantly in the order of normal, chronic cholecystitis, and gallbladder cancer. Patients with chronic cholecystitis and dysbiotic microbiome patterns had larger gallstones and showed marked epithelial atypia, which are considered as precancerous conditions. CONCLUSION: We investigated the bile microbiome in normal, chronic cholecystitis, and gallbladder cancer. We suggest possible roles of Enterobacteriaceae, including Klebsiella, in gallbladder carcinogenesis. Our findings reveal a possible link between a dysbiotic bile microbiome and the development of chronic calculous cholecystitis and gallbladder cancer.

Molecular Mechanisms Contributing Bacterial Infections to the Incidence of Various Types of Cancer.

Cancer causes a major health concern worldwide due to high incidence and mortality rates. To accomplish this purpose, the Scopus, PubMed, and Web of Science databases were searched using the keywords bacteria and cancer. Most of published research addressed several different factors that induced cancer, such as toxins, medications, smoking, and obesity. Nonetheless, few studies are dealing with cancer induction via bacterial infection. In addition, mechanisms of cancer induction via bacterial infections are not well understood. Therefore, in this review, we will shed light on different bacteria that induced cancer via different molecular mechanisms. Among the bacterial infection that induced cancer, Helicobacter pylori was the first recognized bacteria which caused gastric cancer and might be also linked to extragastric cancer in humans. H. pylori has been associated with adenocarcinoma in the distal stomach by its ability to cause severe inflammations. It has been found that inflammations induced cancer via different mechanisms including induction of cell proliferation and production of high levels of free radicals. Recently, free radicals were found to induce and cause various types of cancer. Salmonella typhi has been found to be associated with gallbladder carcinoma (GBC). Also, intercellular infection of lungs with Chlamydia pneumoniae was found to contribute as one of the ethological factors of lung cancer. Moreover, infection of the urinary tract with Staphylococcus aureus, Klebsiella spp., and Proteus mirabilis has been found to cause bladder cancer. These microorganisms produce a high level of N-nitrosamines which are metabolically activated leading to the generation of alkylating agents that damage DNA and other macromolecules. It is concluded that a certain bacterium is linked with induction of a specific type of cancer via different molecular and biochemical mechanisms as discussed in the text in details. This infection could potentially affect human health in different ways. In addition, it is important to know the possible factors involved in cancer induction for better treatment of cancer patients.

Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer.

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention.

The role of H. pylori infection in gall bladder cancer: clinicopathological study.

Recent work demonstrated the presence of Helicobacter pylori (H. pylori) in the bile and gallbladder of more than 75 % of patients with gallbladder cancer and more than 50 % of patients with chronic cholecystitis. The aim of the work was to determine the prevalence of H. pylori in the gallbladder of patients operated on for chronic cholecystitis and relating their presence to the precancerous histological changes. In our study, fifty patients were operated on for chronic cholecystitis. The patients were subdivided into two groups (each includes 25 patients): H. pylori-positive group, who had H. pylori in their gallbladder mucosa detected by Giemsa stain, and H. pylori-negative group. The histological findings (mucosal erosions, atrophy, metaplasia, dysplasia, lymphoid infiltration, musculosa hypertrophy, and fibrosis) were compared between the two groups. Comparing the histological findings of the H. pylori-infected gallbladders with the non-infected ones, the gallbladders with mucosal hyperplasia, metaplasia/dysplasia, and lymphoid infiltration showed statistically significant differences, with a P value of 0.028, 0.049, and 0.022, respectively. On the other hand, no statistically significant differences were detected between the two groups in the degree of mucosal erosions (P = 0.299), atrophy, musculosa hypertrophy (P = 1.000), and fibrosis (P = 1.000). These results highlight the role of H. pylori infection in aggravating the mucosal lesions (mucosal hyperplasia, metaplasia, and lymphoid infiltration) of the gallbladder that is considered potentially precancerous.

The footprint of gut microbiota in gallbladder cancer: a mechanistic review.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.

Helicobacter pylori and pathogenesis of gallbladder cancer.

BACKGROUND AND AIM: Gallbladder cancer (GBC) is a rare but leading cause of cancer-related deaths worldwide. The incidence of GBC is increasing at an alarming rate in the Varanasi region, and its etiology remains obscure. METHODS: A total of 108 patients, 54 with GBC and 54 with gallstone diseases (GSD), were examined for Helicobacter pylori (H. pylori) in gallbladder specimens by rapid urease test, biochemical test, histology, culture, serology, polymerase chain reaction (PCR), and partial DNA sequencing. PCR was done using heat shock protein-60 (Hsp60) gene-nested primers. RESULT: Forty (74%) patients with GBC had gallstones. Upon culture, H. pylori colonies were identified in 24 (44%) GBC and 18 (33%) GSD specimens. H. pylori was detected in 20 (37%) GBC and 15 (28%) GSD samples upon histology. Serology was positive in 17 (32%) GBC and 15 (28%) GSD patients. The DNA isolated from GBC and GSD specimens was amplified by PCR with Hsp60-nested primers in 18 (33%) patients with GBC and 15 (28%) with GSD (P > 0.05). These sequences had 98% similarity with the presubmitted Hsp60 sequences of H. pylori in the National Centre for Biotechnology Information's GenBank. CONCLUSION: The results revealed that H. pylori was present in a large population, including both GBC and GSD patients, which indicates its endemic presence in the Varanasi region. Thus, it appears H. pylori might not have a significant role in the etiopathogenesis of GBC in our region.

Helicobacter pylori: association with gall bladder disorders in Pakistan.

Helicobacter species colonise the biliary tract and therefore this study explores the relationship between of Helicobacter pylori and cholecystitis. Bile and gall bladder tissue samples were obtained from 144 patients who underwent cholecystectomy. Of these, 89 had chronic cholecystitis with cholelithiasis, 44 had gall bladder carcinoma and 11 had gall bladder polyps. Histopathology examination included special staining and immunohistochemistry (IHC), while Helicobacter species (H. pylori, H. bilis and H. hepaticus) were detected by the polymerase chain reaction (PCR). Sequencing and BLAST query of PCR products was undertaken and samples were considered to contain H. pylori if both PCR and IHC were positive. Immunohistochemistry for H. pylori was positive in 22 (25%) cases compared to five (9%) in the control group (P=0.02). Testing (PCR) for 16S rDNA was positive in 23 (26%) cases compared to six (11%) controls (P=0.03). Negative PCR results were obtained for H. bilis and H. hepaticus. Twenty-four (89%) were positive by both 16S rDNA PCR and IHC for H. pylori (P<0.001). Both PCR for 16S rDNA and IHC were positive in 21 (24%) cases compared to five (9%) controls (P=0.03). Sequencing of 16S rRNA and glmM PCR products were consistent with H. pylori. In conclusion, H. pylori DNA was demonstrated in cases of chronic cholecystitis and gall bladder carcinoma associated with cholelithiasis, but this association requires further study.

Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development.

BACKGROUND: Typhoid (Salmonella typhi and paratyphi) carriers and gall bladder cancer (GBC) are endemic in northern India. Results of previous studies about association of typhoid carriers with GBC are inconsistent. We studied antibodies against Salmonella typhi and paratyphi in serum samples of patients with GBC. METHODS: We performed modified Widal test for antibodies against Salmonella typhi (Vi and O) and Salmonella paratyphi (AO and BO) antigens in patients with GBC (n=100), xanthogranulomatous cholecystitis (XGC, n=24), chronic cholecystitis (CC, n=200) and healthy controls (HC, n=200). RESULTS: Serum antibodies against Salmonella were more frequently positive in GBC (22%) and XGC (29%), particularly in males in age ≥50 years (GBC: 47% and XGC: 50%) vs. HC (0) (p <0.01). Vi antibody was more common in GBC (13%, OR:9.8) and XGC (8%, OR:5.9) than HC (2%). O antibody was more common in GBC (8%, OR: 8.6) and XGC (8%, OR: 9.0) than HC (1%). O antibody was also more common in males with GBC (12%) than CC (1%) and HC (1%) (P=0.02 and p <0.001, respectively). AO (6%) and BO (4%) antibodies were detected in GBC, particularly in males, than HC (0), (p <0.01). Salmonella antibodies were more frequent in GBC with GS than those without GS (50% vs. 20%, OR=3.94, P=0.01). CONCLUSIONS: Salmonella carrier state was more common in GBC and XGC, particularly in elderly males than HC. The Vi antibody was more common in GBC and XGC than HC. Salmonella infection was more common in GBC with GS than those without GS.

Helicobacter species and pathogenesis of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is a rare disease but a leading cause of cancer-related death worldwide. A number of etiological factors have been implicated in the causation of GBC and pathogenic infection by bacteria is one of these. DATA SOURCES: A PubMed search on "helicobacter", "gallbladder cancer", and "biliary tract malignancies" was done on the topic, and the relevant data were collected, reviewed, and analyzed. RESULTS: Helicobacter is an epsilon proteobacterium that infects the mucosal lining of the human gastrobiliary system. Infection with helicobacter is an important risk factor for the development of cancer and the bacterium has been categorized as a group-I carcinogen by the International Agency for Research on Cancer (IARC). These microbes enter the human body by means of contaminated food and water. Thereby they invade the tissues and produce chemical carcinogens that lead to DNA damage and subsequently a series of gene mutations transform normal cells into cancer cells. In this review, we focus our attention on the role of helicobacter in the causation of biliary tract malignancies. CONCLUSIONS: The review attempts to summarize the current available data on the role of helicobacter in the causation of GBC. There are accountable data available to suggest the role of helicobacter species in the causation of GBC although larger studies are urgently required for confirmation.

Salmonella typhi and gallbladder cancer: report from an endemic region.

BACKGROUND: Evidence exists of a link between chronic infection by Salmonella typhi (S. typhi) and the development of gallbladder cancer (GBC), but several studies from endemic regions contradict its role in the etiopathogenesis of GBC. This study used various tools to assess the prevalence of S. typhi in patients with GBC and gallstone disease (GSD) in this region with a high incidence of GBC. METHODS: S. typhi was detected in tissue and bile by PCR and culture and in serum by the Widal test and indirect hemagglutination assay (IHA). PCR with two pairs of S. typhi specific primers (flagellin gene H1d and SOP E gene) could detect 0.6 ng of S. typhi DNA. Fifty-four patients with GBC (cases) were matched with 54 patients with GSD (controls). RESULTS: Of the 54 cases, 24 (44.44%) were positive on the Widal test and 12 (22.22%) on IHA, compared to 13 (24.07%) and 5 (9.26%) respectively in the controls. Eighteen (33.33%) cases showed a positive result on PCR (tissue) and 2 on PCR (bile) vs. none in the controls. Bile culture revealed no Salmonella colonies in either cases or controls. Only 3 cases were positive for Salmonella on tissue culture compared to none in the controls. The sensitivity of PCR (tissue) relative to the Widal test, IHA, culture (bile and tissue) and PCR (bile) was 100% vs. 66.67%, 11.11%, and 11.11%, and the specificity was 83.33% vs. 100%, 100%, and 100%, respectively. CONCLUSIONS: S. typhi is significantly associated with GBC compared to GSD (33% vs. 0%). PCR appears to be the most specific diagnostic tool, the gold standard for S. typhi in tissue samples.

Helicobacter species in cancers of the gallbladder and extrahepatic biliary tract.

Helicobacter species have been found in human bile and biliary tract (BT) tissue and are suspected to cause BT diseases, including gallbladder and extrahepatic cancers, collectively referred to in this work as BT cancers. We conducted a literature review of the epidemiological evidence linking the presence of Helicobacter species in bile or BT biopsies to BT cancers and benign diseases. Reports showed great variability with respect to study methods. Nine studies of BT cancers were identified, all with 30 or fewer BT cancers; eight included cancer-free control subjects and used polymerase chain reaction (PCR) as a means of Helicobacter species detection. In four of these studies, Helicobacter species were detected in patients with BT cancer significantly more frequently than in controls, at least when controls without BT diseases were used. In two studies, no Helicobacter species were detected in either cases or controls. Helicobacter species were also often detected in benign BT diseases such as gallstone disease or chronic cholecystitis. As our current knowledge relies on a few small studies that showed substantial differences, larger studies and more standardised protocols for detecting DNA and antibodies against Helicobacter species are needed to investigate a potential association with BT cancer.

Low prevalence of Helicobacteraceae in gall-stone disease and gall-bladder carcinoma in the German population.

Colonisation of the hepatobiliary system with bile-resistant Helicobacter spp. has been proposed as a novel risk-factor in the pathogenesis of gall-bladder carcinoma (GBC). There are reports that biliary Helicobacter colonisation is frequent in countries with a high incidence of gall-bladder carcinoma. However, the prevalence of Helicobacteraceae in the gall-bladders of patients with GBC in Germany, a region with a low incidence of GBC, is unknown. Therefore, gall-bladder tissue from 99 patients who had undergone cholecystectomy was tested, including 57 cases of gall-stone disease (GSD), 20 cases of GBC, and 22 control patients. The presence of Helicobacter spp. was investigated by culture, immunohistochemistry and a group-specific PCR targeting the 16S rRNA gene of all currently known Helicobacteraceae. Of the 99 cases investigated, only one patient with GSD was PCR-positive for Helicobacteraceae. For this individual, sequence analysis of the 16S rRNA gene showed that it had homology closest to the 16S rRNA sequence of Helicobacter ganmani. Helicobacteraceae were not detected by culture or immunohistochemistry. The low prevalence of Helicobacteraceae in the gall-bladders investigated suggests that Helicobacteraceae do not play a predominant role in the pathogenesis of GSD and GBC in the German population. The low prevalence could be a possible explanation for a relatively low incidence of GBC in the German population, despite the fact that GSD, the major risk-factor for GBC, is highly prevalent.

Role of bile bacteria in gallbladder carcinoma.

BACKGROUND/AIMS: Long standing calculus disease has been observed to be a risk factor for gallbladder carcinoma. However it is possible that calculi may be incriminated by some means other than just chronic irritation. Calculi may induce an element of stasis, promoting chronic infection leading to increased turnover of primary bile acids to secondary bile acids, which are known tumor promoters and initiators. This study aimed to find the prevalence of biliary microflora in gallbladder carcinoma and association of gallbladder carcinoma with chronic bacterial infection and bile acid profile. METHODOLOGY: Bile culture was done in 390 patients divided into 3 groups--gallbladder carcinoma 65 (17%), cholelithiasis 125 (32%) and control group 200 (51%). Serum samples were analyzed for presence of Vi antibody for chronic typhoid carrier state and bile acid analysis was done in 10 patients in each group. RESULTS: 116 (30%) patients had culture positive bile. Significantly higher number of patients with gallbladder carcinoma 40 (65%) had culture positive bile as compared to cholelithiasis 52 (42%) and control 24 (12%). Vi Antibodies suggestive of chronic typhoid carrier state were found to be significantly higher in the gallbladder carcinoma group 20 (31%) as compared to controls 22 (11%) (OR 3.596, p < 0.05) however, the difference was statistically insignificant in the cholelithiasis group 12 (11%) (OR 0.859, p > 0.05). There was a 6.84 times higher risk of developing gallbladder carcinoma in culture positive cholelithiasis patients and 5.14 times if both Vi antibody and cultures were positive. Bile analysis showed primary bile acids cholic acid and chenodeoxycholic acid to be lower while secondary bile acids deoxycholic acid and lithocholic acid to be more in the gallbladder carcinoma group (7.268 mg/mL, 9.183 mg/ mL, 14.468 mg/mL, 3.312 mg/mL respectively) than cholelithiasis (17.50 mg/mL, 13.80 mg/mL, 6.07 mg/ mL, 2.05 mg/mL) and control group (19.85 mg/mL, 16.53 mg/mL, 2.71 mg/mL, 1.128 mg/mL respectively). The difference was statistically significant. CONCLUSIONS: Chronic bacterial infection of bile leading to production of carcinogenic precursors might be one of the etiological factors in the pathogenesis of gallbladder carcinoma and hence a target for its prevention.

Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma.

Cancer is fueled by deregulation of signaling pathways in control of cellular growth and proliferation. These pathways are also targeted by infectious pathogens en route to establishing infection. Gallbladder carcinoma (GBC) is frequent in the Indian subcontinent, with chronic Salmonella enterica serovar Typhi infection reported as a significant risk factor. However, direct association and causal mechanisms between Salmonella Typhi infection and GBC have not been established. Deconstructing the epidemiological association between GBC and Salmonella Typhi infection, we show that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids, and fibroblasts, with TP53 mutations and c-MYC amplification. Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella enterica effectors secreted during infection, is critical to both ignite and sustain transformation, consistent with observations in GBC patients from India. Collectively, our findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of GBC.

Review article: Helicobacter species and hepatobiliary diseases.

Helicobacter species, which may colonize the biliary tract, have been implicated as a possible cause of hepatobiliary diseases ranging from chronic cholecystitis and primary sclerosing cholangitis to gall-bladder carcinoma and primary hepatic carcinomas. Research in this area has been limited by the lack of a gold standard in the diagnosis of these organisms in bile. Most published data to date have been based on molecular techniques that detect the DNA of Helicobacter species in bile, rather than evidence of viable organisms in bile. Helicobacter species have not been shown to induce histological injury to the biliary epithelium or liver parenchyma. The strongest association of the presence of these organisms in bile is with cholestatic conditions. This article reviews the literature on this newly developing field as it has evolved historically, taking pertinent methodological issues into account.

Chronic typhoid carriage and carcinoma of the gallbladder.

Chronic microbial infections and/or their carrier state have been reported to be associated with particular cancers. Since typhoid infections and carcinoma of the gallbladder (the site where salmonella usually persists) are endemic in northern India, it was considered important to explore the relationship between the two. In the present study, a total of 1001 bile specimens collected from cases of carcinoma of the gallbladder (28), cholelithiasis (56) and individuals without biliary pathology (17) were subjected to aerobic cultures that had been enriched for salmonella. Salmonella typhi and S. paratyphi-A could be detected in a significantly higher (P < 0.05) number in patients with carcinoma of the gallbladder as compared with cholelithiasis and control groups. The existence of such an association indicates that detection and eradication of typhoid carriers may lead to a decrease in the incidence of carcinoma of the gallbladder along with typhoid fever.

[Bacteriological studies on the bile in different conditions of surgical interest]. / Indagini batteriologiche sulla bile in differenti condizioni di interesse chirurgico

A bacteriological study was carried out on bile taken, during the course of surgery, from 235 patients suffering from a wide variety of diseases, both benign and malignant, concerning the bile ways. The investigation, initially directed to the aerobic bile flora, was afterwards extended to include germs growing in strict anaerobiosis. The highest incidence of bactibilia was found in repeat operations for post-operative stenosis of the hepatocholedochus, followed by neoplasias of the gall-bladder or main bile duct, and calculosis of the gall-bladder. For germs growing in compulsory anaerobiosis the responses to the cultural test were all negative, while in two cases microaerophilic streptococci were isolated. Finally the results of the antibiograms made on the isolated microbial species are reported.

Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer.

BACKGROUND: Carcinoma of the gall-bladder is the fifth commonest gastrointestinal tract cancer and is endemic in several countries. An association of chronic typhoid carriage and carcinoma of the gall-bladder has been reported. AIM: To clarify whether chronic Salmonella typhi carrier state is associated with carcinoma of the gall-bladder. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents, Cochrane library, Google Scholar, Science Direct and Web of Science. Original data were abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Of the articles selected, only 17 studies met full criteria for analysis. The overall OR for chronic S. typhi carrier state was 4.28(95% CI: 1.84-9.96). Most of the studies were from South Asia especially India and China. When a subgroup analysis was performed according to region, a significant association was observed in South-East Asia (OR: 4.13, 95% CI: 2.87-5.94, P value <0.01). Chronic S. typhi carrier state was associated with carcinoma of the gall-bladder based on detection methods of S. typhi antibody levels (OR: 3.52, 95% CI: 2.48-5.00, P value <0.01) and even more so on culture (OR: 4.14, 95% CI: 2.41-7.12, P value <0.01). The association was prominent in controls without gallstones (OR: 5.86, 95% CI: 3.84-8.95, P value <0.01) when compared with controls with gallstones (OR: 2.71, 95% CI: 1.92-3.83, P value <0.01). CONCLUSIONS: Chronic S. typhi carrier state is an important risk factor among patients with carcinoma of the gall-bladder. Given the high risk associated with this carrier state, management options should include either elective cholecystectomy or careful monitoring using ultrasound.