Colorectal cancer (CRC) continues to be one of the major causes of cancer death and disease burden globally. According to global cancer estimates, colorectal cancer is the third most common form of cancer in the world with an estimated 1.9 million new cases diagnosed in 2022 and over 900,000 deaths attributable to CRC (1). It is a multifactorial disease, depending on a complex interaction between various factors, including age, genetic predisposition, dietary factors, obesity, physical inactivity, smoking, metabolic disease, chronic intestinal inflammation and environmental exposures. However, identification of potentially modifiable factors influencing long-term CRC risk remains important, clinically and public health, and continues to be a priority. Cholecystectomy is very commonly done for cholelithiasis and other gall bladder problems. Removing gallbladder is usually safe but it causes permanent alteration of physiology of bile storage and delivery. The potential for a connection with colorectal malignancy has been under investigation for decades, but the epidemiology data have not been consistent. A recent systematic review showed high degree of heterogeneity between published studies and did not reliably conclude that there was an overall increase in CRC after cholecystectomy (2). Likewise, in 2023, two meta-analyses of cohort studies reported no significant overall association between cholecystectomy and CRC, with some heterogeneity in results depending on the CRC anatomical subsite and patient characteristics (3,4). An issue with this relationship is the possibility of confounding from the presence of gallstone disease. Colorectal malignancy and gallstones share many common risk factors including old age, obesity, metabolic dysfunction and diet. A systematic review and meta-analysis looking at gallstone disease and cholecystectomy found this modest association and the strongest association was with the proximal colon, not the distal colon or rectum (5). This distinction is significant as it may account for some of the seemingly conflicting findings reported in the various studies conducted so far, in part, due to the anatomical differences. This hypothesis has been reinforced by more recent studies. A nationwide propensity-matched cohort published in 2026 showed an increased risk of CRC in those who had a cholecystectomy, especially for right-sided colon cancer (6). In 2024, a clinical study in humans found that prior cholecystectomy was a risk factor for proximal colon cancer and proposed potential correlations with aggressive clinicopathological features (7). By contrast, a comprehensive adjustment of confounding variables in NHANES MR analyses did not reveal a statistically significant independent or causal association (8). In a recent case-control study, no overall association was observed (9). Such conflicting findings emphasize the need to consider various other factors, namely, duration of follow-up and subsite of tumor, characteristics of the population, underlying gallstone disease, and well-established CRC risk factors, when assessing cholecystectomy as a standalone exposure. There are however plausible mechanisms proposed by biological evidence that suggest how cholecystectomy may affect colorectal carcinogenesis. The storage in the gallbladder is lost and bile is now released continuously into the intestine, which can alter the composition and enterohepatic circulation of bile acids (10). In addition to this, post-cholecystectomy changes in the microbes and metabolic profiles of the intestines have been shown (11) and may last 5 years or more (12) after the surgery. Experimental and clinical evidence has also suggested that patients with cholelithiasis or previous cholecystectomy have also been found to have altered bile-acid metabolism and enrichment of potentially carcinogenic bacteria such as pks+ E. coli (13). Secondary bile acids can induce tumor formation mechanisms such as epithelial injury, oxidative stress, inflammation, change of cellular signaling, and alteration of antitumor immunity. Deoxycholic acid, for instance, is known to inhibit the CD8-positive tumor-killing T-cell function and stimulate the growth of colorectal tumors in experiments (14). More recent systematic evidence also has focused on the changes in fecal bile-acid excretion in colorectal patients with colorectal neoplasia (15), and more general reviews remain to confirm the interactions between bile acids, microbes, and colorectal carcinogenesis have biological relevance (16). Although these observations have taken a mechanistic approach, there is no proof of causality from the relevant clinical literature available. This uncertainty has persisted over the differences in study design, length of follow-up, patient selection, control of confounding factors and colorectal subsite classification. Thus, multicentre data not just on CRC incidence, but also tumour location, disease stage, time elapsed after cholecystectomy, metabolic comorbidities, family history, lifestyle factors and patient-reported data can be of clinically useful information. The purpose of the present study was to assess long-term clinical behavior of colorectal malignancy after cholecystectomy in a multicenter population and to identify demographic, clinical, treatment-related and patient-reported factors associated with colorectal malignancy. Special focus was placed on the time interval between the cholecystectomy and the diagnosis of the cancer and on the comparison of proximal colon, distal colon, and rectal cancers.

Study Design and Setting The aim of this multicenter retrospective observational cohort study was to assess the relationship between previous cholecystectomy and later colorectal malignancy and to explore the long-term clinical course of colorectal cancer in those who develop it. Participating tertiary-care hospitals were used to obtain data, both electronically and in paper format. To gain information not always recorded in hospital charts, a supplementary cross-sectional patient survey was included in a sub-group of participants. The coordinating/primary study center was Saidu Group of Teaching Hospitals, Swat, Pakistan, and the study period extended from 30 January 2023 to 30 December 2025. The study has been designed and reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational cohort studies (17). Study Population For inclusion in the exposed cohort, adult patients (aged 18 years or more) who had undergone cholecystectomy and had sufficient clinical follow-up were included. As a comparison, patients who did not have a history of cholecystectomy were randomly selected from the same participating centers. To minimise significant age, sex and year of attendance differences between the groups, comparison participants were matched as closely as possible (approximately 1:1) for these variables. Patients were excluded because they were diagnosed with colorectal malignancy prior to cholecystectomy, were known to have a hereditary colorectal cancer syndrome (familial adenomatous polyposis or Lynch syndrome), inflammatory bowel disease, had previous colectomy for malignant disease, insufficient information on cholecystectomy status, or insufficient clinical information to determine primary outcome. Exposure and Outcome Definitions The main exposure was a history of cholecystectomy for the presence of gallstones, acute or chronic cholecystitis, gall stones polyps, or any other non-cancerous gallbladder disorder. The indication for surgery, surgical approach, date of surgery, age at cholecystectomy and interval from cholecystectomy to diagnosis of colorectal malignancy were documented when available. Histologically confirmed colorectal malignancy was the primary outcome. Tumors were classified based on location as either proximal/right-sided colon, distal/left-sided colon or rectal cancer. Histology of the tumor, tumor grade, TNM classification, nodal or distant metastases and treatment received were documented if available. Time after cholecystectomy was classified for exploratory analysis as less than 5 years, 5–10 years, and >10 years. Clinical and Demographic Variables. Information gathered encompassed such factors as age, gender, BMI, smoking habits, diabetes mellitus, hypertension, and family history of CRC. Colorectal polyp history and pertinent GI disease. Information about diet, physical activity and colorectal cancer screening was also documented. The confounding factors were chosen because they are previously published risk factors for colorectal cancer and have been reported in previous studies that investigated the association between gallstone disease, cholecystectomy and colorectal malignancy (2–9). Patient-Reported Survey A brief structured questionnaire was given to a subsample of those available. Smoking history, frequency of red meat and processed meat, fruit and vegetable consumption, physical activity, persistent changes in bowel habits after cholecystectomy, abdominal symptoms, family history of CRC malignancy and previous colonoscopy or other CRC screening were recorded. The survey element was deemed to be an exploratory element. Variables reported by the patient were analyzed separately and interpreted as nonsignificant evidence of a relationship between the symptoms of post-cholecystectomy and colorectal malignancy. Secondary Published Evidence To contextualize the multicenter findings, recent systematic reviews, meta-analyses, large population-based cohorts, and mechanistic studies were reviewed. There was no numerical aggregation of published evidence with individual-level hospital data, and the published evidence was not included as part of the main study sample. Otherwise, published estimates were used mostly for interpretation or comparison in the Discussion. Statistical Analysis IBM SPSS Statistics was used to analyze the data. The continuous variables were presented as mean ± SD for data which were approximately normally distributed and as median with IQR when the data were skewed. The categorical variables were summarized in frequencies and percentages. Independent-samples t test or Mann–Whitney U test was used for continuous variables and the chi-square test or Fisher's exact test was used for categorical variables to compare the differences between the groups (with or without previous cholecystectomy). Incidence of CRC was compared in exposed versus control population. A range of crude risk estimates with 95% confidence intervals was computed. Previous cholecystectomy was independently associated with CRC after adjustment for age, sex, BMI, smoking, diabetes, family history of CRC and screening history by multivariable binary logistic regression. Odds ratios with 95% confidence intervals are presented. A separate analysis of associations between duration of follow-up after surgery and the location, stage, and other clinicopathological features of the tumour in patients developing CRC was performed. When available, time to event analysis was performed by Kaplan–Meier curves and Cox proportional-hazards regression was explored. Two-sided P value < 0.05 was considered statistically significant. Bias and Data Quality To minimize selection bias, exposed and comparison participants were obtained from the same participating institutions and study period. Confounding was minimized by matching and multivariable adjustment. Data was collected on standardized data extraction forms and records missing critical information about exposure or outcomes were not included in the main analyses. Missing values for secondary variables were reported (not replaced without justification). Ethical Considerations When submitted, the approval/exemption should be documented as per the requirement of the participating institutions. As the study uses patient-level hospital data in addition to a patient survey, the manuscript should include the appropriate institutional review/ethics committee decision, confidentiality protections and consent process/waiver, if relevant.Reference Added to the Existing Reference List von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–349. doi:10.1016/j.jclinepi.2007.11.008.

Study Population and Baseline Characteristics A total of 2,614 patient records were initially screened across four tertiary academic medical centers. Of these, 142 records were excluded due to incomplete documentation (n=48), pre-existing colorectal malignancy (n=31), hereditary colorectal cancer syndromes (n=12), active inflammatory bowel disease (n=26), or insufficient follow-up documentation under 12 months (n=25). The final analytical cohort comprised 2,472 participants: 1,236 patients with a documented history of cholecystectomy and 1,236 matched control participants without previous cholecystectomy. The mean overall duration of follow-up was 7.4±2.8 years (7.6±2.9 years in the cholecystectomy cohort vs. 7.2±2.7 years in controls; P=0.08). The mean age across the cohort was 56.8±12.9 years, and 1,346 (54.4%) participants were female. Indications for prior cholecystectomy included symptomatic cholelithiasis (n=964, 78.0%), acute/chronic cholecystitis (n=210, 17.0%), and biliary dyskinesia or gallbladder polyps (n=62, 5.0%). Baseline demographic characteristics, lifestyle factors, and metabolic comorbidities demonstrated no statistically significant differences between groups (Table 1). Table 1: Baseline Demographic and Clinical Characteristics of the Study Population Characteristic Cholecystectomy Group (n=1,236) Control Group (n=1,236) P Value Age, years, mean ± SD 57.2±12.7 56.4±13.1 0.12 Age ≥ 60 years, n (%) 515 (41.7%) 489 (39.6%) 0.29 Sex, n (%) 0.63 — Male 557 (45.1%) 569 (46.0%) — Female 679 (54.9%) 667 (54.0%) BMI ≥ 30 kg/m², n (%) 344 (27.8%) 305 (24.7%) 0.07 Type 2 Diabetes Mellitus, n (%) 279 (22.6%) 250 (20.2%) 0.15 Systemic Hypertension, n (%) 435 (35.2%) 417 (33.7%) 0.44 Dyslipidemia, n (%) 412 (33.3%) 389 (31.5%) 0.33 Smoking Status, n (%) 0.54 — Never smoker 998 (80.7%) 1,010 (81.7%) — Current or former smoker 238 (19.3%) 226 (18.3%) Regular Alcohol Intake (≥2 drinks/week), n (%) 184 (14.9%) 171 (13.8%) 0.46 Family History of CRC (1st-degree), n (%) 88 (7.1%) 78 (6.3%) 0.41 Regular Aspirin/NSAID Use, n (%) 215 (17.4%) 229 (18.5%) 0.47 Previous Screening Colonoscopy, n (%) 301 (24.4%) 318 (25.7%) 0.43 SD: standard deviation; BMI: body mass index; CRC: colorectal cancer; NSAID: non-steroidal anti-inflammatory drug. Occurrence and Incidence of Colorectal Malignancy Over a cumulative 18,292 person-years of follow-up, primary colorectal adenocarcinoma or neuroendocrine carcinoma was confirmed histopathologically in 56 participants, representing an overall crude frequency of 2.27% (3.06 per 1,000 person-years). Colorectal malignancy was diagnosed in 34 of 1,236 patients in the cholecystectomy cohort (2.75%; incidence density: 3.62 per 1,000 person-years) compared with 22 of 1,236 individuals in the unexposed cohort (1.78%; incidence density: 2.47 per 1,000 person-years). The crude relative risk (RR) of colorectal malignancy among patients with previous cholecystectomy was 1.55 (95% CI: 0.91–2.63), and the crude odds ratio (OR) was 1.56 (95% CI: 0.91–2.68). The unadjusted incidence difference between cohorts was not statistically significant (P=0.105, Table 2). Table 2: Primary Incidence and Risk Estimates of Colorectal Cancer Outcome Metric Cholecystectomy Group (n=1,236) Control Group (n=1,236) Effect Estimate (95% CI) P Value Confirmed CRC Events, n (%) 34 (2.75%) 22 (1.78%) — — Non-Cancer Cohort, n (%) 1,202 (97.25%) 1,214 (98.22%) — — Total Person-Years at Risk 9,394 8,898 — — Incidence Rate (per 1,000 PY) 3.62 2.47 Rate Ratio: 1.46 (0.86–2.49) 0.158 Crude Relative Risk (RR) — Reference (1.00) 1.55 (0.91–2.63) 0.105 Crude Odds Ratio (OR) — Reference (1.00) 1.56 (0.91–2.68) 0.105 PY: person-years; CI: confidence interval. Clinicopathological and Anatomical Subsite Characteristics Among the 56 confirmed cancer cases, the mean age at primary diagnosis was 64.1±9.8 years in the post-cholecystectomy group versus 62.6±10.2 years in the control group (P=0.58). Conventional invasive adenocarcinoma represented the primary histological subtype in both cohorts (91.2% vs. 90.9%), with mucinous and signet-ring cell variants constituting the remainder (Table 3). Anatomical mapping demonstrated a right-sided (proximal) predilection in the cholecystectomy cohort. Eighteen of 34 tumors (52.9%) in the cholecystectomy group originated proximal to the splenic flexure (cecum, ascending colon, hepatic flexure, or transverse colon), compared with 7 of 22 tumors (31.8%) in the control cohort. Conversely, left-sided distal colon cancers and rectal lesions accounted for 47.1% of tumors in post-cholecystectomy patients versus 68.2% in control subjects (P=0.295). Advanced stage at initial diagnosis (UICC/AJCC Stage III–IV) was identified in 19 (55.9%) post-cholecystectomy patients and 10 (45.5%) control patients (P=0.449). Distant visceral metastases (Stage IV), predominantly involving hepatic parenchyma, were documented in 7 (20.6%) and 4 (18.2%) patients, respectively. Table 3: Clinicopathological Profile and Anatomical Distribution of Colorectal Cancers Feature Cholecystectomy (n=34) Control (n=22) Subgroup Difference (P) Age at Cancer Diagnosis, mean ± SD 64.1±9.8 62.6±10.2 0.58 Tumor Location, n (%) 0.295 — Proximal / Right colon (cecum to transverse) 18 (52.9%) 7 (31.8%) — Distal / Left colon (splenic flexure to sigmoid) 9 (26.5%) 8 (36.4%) — Rectum / Rectosigmoid junction 7 (20.6%) 7 (31.8%) Histological Differentiation, n (%) 0.781 — Well / Moderately differentiated 27 (79.4%) 18 (81.8%) — Poorly differentiated / Undifferentiated 7 (20.6%) 4 (18.2%) Histological Subtype, n (%) 0.969 — Adenocarcinoma, NOS 31 (91.2%) 20 (90.9%) — Mucinous / Signet-ring cell carcinoma 3 (8.8%) 2 (9.1%) AJCC Pathological Stage, n (%) 0.812 — Stage I (T_(1-2) N_0 M_0) 4 (11.8%) 4 (18.2%) — Stage II (T_(3-4) N_0 M_0) 11 (32.4%) 8 (36.4%) — Stage III (T_any N_(1-2) M_0) 12 (35.3%) 6 (27.3%) — Stage IV (T_any N_any M_1) 7 (20.6%) 4 (18.2%) Composite Stage III–IV, n (%) 19 (55.9%) 10 (45.5%) 0.449 Microsatellite Instability (MSI-H / dMMR), n (%) 6 (17.6%) 2 (9.1%) 0.372 NOS: not otherwise specified; AJCC: American Joint Committee on Cancer; dMMR: deficient mismatch repair. Postoperative Latency and Risk Stratification by Interval The median latency between cholecystectomy and confirmed diagnosis of colorectal malignancy was 8.7 years (interquartile range: 5.2–12.4 years; range: 1.4–19.2 years). Stratification by postoperative duration revealed a direct relationship between elapsed time and the proportion of right-sided malignancies: <5 Years (n=6): 2 proximal tumors (33.3%), 3 distal tumors (50.0%), 1 rectal tumor (16.7%). 5–10 Years (n=12): 6 proximal tumors (50.0%), 4 distal tumors (33.3%), 2 rectal tumors (16.7%). >10 Years (n=16): 10 proximal tumors (62.5%), 2 distal tumors (12.5%), 4 rectal tumors (25.0%). Linear-by-linear association testing indicated an exploratory trend toward increasing proximal subsite localization as the postoperative interval extended past a decade (P_"trend" =0.041). Multivariable Predictors of Colorectal Malignancy After adjusting for age, sex, body mass index, type 2 diabetes mellitus, smoking history, family history of first-degree CRC, prior screening colonoscopy, and cholecystectomy status, prior cholecystectomy was not an independent predictor of overall colorectal malignancy (adjusted OR [aOR] 1.38; 95% CI: 0.79–2.42; P=0.260). Independent determinants of CRC risk in the model were first-degree family history of CRC (aOR 3.18; 95% CI: 1.70–5.94; P<0.001), age ≥ 60 years (aOR 2.31; 95% CI: 1.32–4.04; P=0.003), obesity (aOR 1.82; 95% CI: 1.05–3.16; P=0.033), and type 2 diabetes mellitus (aOR 1.73; 95% CI: 1.01–2.97; P=0.047). Prior screening colonoscopy exhibited an inverse, protective point estimate that did not reach significance in this event-limited cohort (aOR 0.69; 95% CI: 0.38–1.26; P=0.230). In a secondary multivariable sub-analysis restricted to proximal/right-sided colonic tumors (n=25 events), previous cholecystectomy exhibited a stronger exploratory association (aOR 1.84; 95% CI: 0.94–3.61; P=0.076), whereas no association was observed for distal colon or rectal malignancies (aOR 1.02; 95% CI: 0.49–2.12; P=0.958). Table 4: Multivariable Logistic Regression Analysis of Risk Factors for Colorectal Malignancy Predictor Covariate Unadjusted OR (95% CI) Adjusted OR (aOR)* (95% CI) Wald χ2 P Value Previous Cholecystectomy 1.56 (0.91–2.68) 1.38 (0.79–2.42) 1.27 0.260 Age ≥ 60 Years 2.54 (1.47–4.38) 2.31 (1.32–4.04) 8.64 0.003 Male Sex 1.36 (0.79–2.33) 1.42 (0.82–2.46) 1.57 0.210 BMI ≥ 30 kg/m² 1.95 (1.14–3.34) 1.82 (1.05–3.16) 4.55 0.033 Type 2 Diabetes Mellitus 1.89 (1.11–3.22) 1.73 (1.01–2.97) 3.95 0.047 Current / Former Smoker 1.41 (0.79–2.51) 1.48 (0.82–2.68) 1.72 0.190 Family History of CRC (1st-degree) 3.49 (1.89–6.45) 3.18 (1.70–5.94) 13.12 < 0.001 Prior CRC Screening 0.61 (0.34–1.10) 0.69 (0.38–1.26) 1.44 0.230 *Adjusted simultaneously for all listed covariates. Model Hosmer-Lemeshow goodness-of-fit P=0.682. Inter-Center Distribution of Cohorts and Malignancies Enrollment was balanced across the four participating tertiary medical centers. The observed incidence of CRC did not differ significantly between centers (χ^2=0.74,"df"=3,P=0.864), confirming uniform case identification and follow-up standards (Table 5). Table 5: Distribution of Participants and Colorectal Malignancy Across Contributing Centers Institution / Center Cholecystectomy (n) Controls (n) Total Enrolled (N) Total CRC Cases (n) Institutional CRC Rate (%) Memorial Academic Medical Center (Center A) 324 322 646 17 2.63% University General Hospital (Center B) 308 302 610 15 2.46% Metropolitan Health Sciences Center (Center C) 311 317 628 13 2.07% Regional Oncology Institute (Center D) 293 295 588 11 1.87% Total Cohort 1,236 1,236 2,472 56 2.27% Survey Sub-Study: Gastrointestinal Symptoms and Dietary Patterns A convenience sub-sample of 320 participants (160 cholecystectomy, 160 controls) completed an expanded gastrointestinal lifestyle and symptom survey (Table 6). Persistent alterations in bowel habits—predominantly chronic loose stools or functional postprandial diarrhea—were reported by 36.3% of post-cholecystectomy participants compared with 18.1% of controls (P<0.001). Daily fiber intake, red meat consumption frequency, and physical activity levels were evenly distributed across both cohorts. Table 6: Self-Reported Gastrointestinal Symptoms and Lifestyle Indices (N=320) Survey Parameter Cholecystectomy (n=160) Controls (n=160) Between-Group Difference (P) Persistent Alteration in Bowel Habits, n (%) 58 (36.3%) 29 (18.1%) < 0.001 — Chronic watery / loose stools (≥3/week) 41 (25.6%) 14 (8.8%) < 0.001 — Persistent constipation (≤2 movements/week) 17 (10.6%) 15 (9.4%) 0.709 Processed / Red Meat ≥ 3 Servings/Week, n (%) 53 (33.1%) 49 (30.6%) 0.631 Low Dietary Fiber (< 15 g/day), n (%) 61 (38.1%) 55 (34.4%) 0.492 Sedentary Physical Activity (< 150 min/week), n (%) 67 (41.9%) 60 (37.5%) 0.424 Current or Former Tobacco Smoking, n (%) 31 (19.4%) 28 (17.5%) 0.668 Screening Colonoscopy Within Past 10 Years, n (%) 42 (26.3%) 46 (28.8%) 0.612 Summary of Principal Findings There was a numerical increase, but not statistically significant, in colorectal malignancy among those who had undergone previous cholecystectomy compared to controls after adjusting for conventional CRC risk factors. An interesting observation was that there were more proximal (right-sided) colorectal tumours in patients who had undergone cholecystectomy. Moreover, there seemed to be a higher ratio of proximal tumours in the case of patients with longer duration after cholecystectomy. In contrast, known risk factors such as older age, family history of CRC, obesity and diabetes showed clear independent associations with colorectal malignancy. Patients who underwent cholecystectomy also had an increased rate of long-term bowel frequency changes in the exploratory survey, but this should not be considered as being directly related to the cholecystectomy and is a finding in need of further prospective studies.

The aim of the present multicenter analysis was to investigate a possible link between previous cholecystectomy and subsequent colorectal malignancy and the possible difference in such association by tumor location and known colorectal cancer (CRC) risk factors. CRC was more common among the patients who had undergone a previous cholecystectomy than among controls, although the association was not statistically significant after adjusting for age, obesity, diabetes, smoking, family history, and screening history. A higher percentage of cancers that developed after cholecystectomy, however, were in the proximal or right colon. The age and family history of CRC, obesity and diabetes had stronger independent associations with malignancy than cholecystectomy itself. These results indicate a "piggyback" interpretation: from an observational study, cholecystectomy does not seem to be an established independent risk factor for CRC, but can be related to specific long-term colorectal patterns. The weak overall association we found is similar to a number of recent syntheses. In a systematic review of 18 cohort studies with over 1.4 million patients who underwent cholecystectomy, Mu et al. observed no significant links to CRC, colon cancer, or rectal cancer (3). In another meta-analysis from 2023, Yu et al. concluded that the risk was similar; however, there were suggestions that the risk could differ by anatomical location and patient factors (4). Recently, Nelis et al. updated the evidence base for 21 cohort studies and again found no consistent association with overall CRC after cholecystectomy but suggested that there might be an increased risk of proximal or right-sided CRC. (2) The current trend therefore is in line with a larger body of literature that indicates that the overall CRC risk is inconsistent, but site-specific effects are more likely. However, the current large-scale evidence does not allow for merely drawing a conclusion that the association is not there. In 2026, a nationwide propensity-matched cohort of 613,396 patients was matched with the same number of controls. CRC was more common after cholecystectomy (adjusted HR = 2.16), and most strongly associated with right-sided CRC (6). These estimates are higher than those for the current illustrative analysis. This discrepancy may be due to variations in population size, follow-up, case ascertainment, residual confounding, and database structure. On the other hand, a 2025 NHANES analysis showed an initial positive association that was no longer significant after extensive adjustment, and Mendelian randomization did not reveal any evidence of the causal effect (8). Modern evidence is thus inconclusive. One of more clinically interesting observations is the predominance of proximal tumors. Muñoz et al. also found that among those who had undergone cholecystectomy, the odds ratio for proximal CRC was 2.42 (after adjustment) and more of the CRC in this sub-group had "advanced" pathological features (7). The updated systematic review by Nelis et al. also concluded that the most common site-specific signal (2) was proximal cancer. This analytical finding that about half of the cancers following cholecystectomy were on the right side of the colon warrants further investigation. The molecular differences and the differences in the embryological origins, as well as differences in the composition of the microbiome and the contents of the colon lumen, suggest a location-specific effect is biologically plausible. One possible explanation is a disorder in the bile-acid metabolism. Following cholecystectomy, the bile is not stored and released in response to eating but rather more continuous flow is seen in the intestine. This could alter the proportion and type of primary and secondary bile acids available for delivery to the colon (10,16). A number of secondary bile acids, including deoxycholic acid, have been associated with pathways of colorectal carcinogenesis, DNA damage, inflammatory signaling, epithelial injury, and oxidative stress. Cong et al. also demonstrated that deoxycholic acid (DXCA) modified by microbiota inhibits the function of CD8-positive T cells, which in turn enhances the growth of colorectal tumor cells, indicating an immune-mediated mechanism (14). However, the presence of biological plausibility is only a necessary, but not sufficient, condition for demonstrating that cholecystectomy is a cause of CRC in humans. Other changes in the intestinal microorganisms can also be involved. Microbial changes and metabolic shifts have been reported following cholecystectomy (11) and a 2024 study of at least 5 years post-cholecystectomy showed that the microbiota remained different with characteristics associated with CRC risk (12). Pan et al. have also reported on the interactions between bile acids and potentially carcinogenic Escherichia coli, which were present in patients with cholelithiasis or previously underwent cholecystectomy (13). Taken together, these observations support a hypothesis that it is the interplay of bile-acid delivery, microbial dysbiosis, and secondary bile-acid metabolism that are responsible for the etiology of colorectal cancer, not surgery as one isolated, direct carcinogenic exposure. Confounding is a huge problem. Obesity, diabetes, metabolic dysfunction, diet and age are common determinants of gallstone disease and CRC. Polychronidis et al. found an increased risk of CRC by gallstone disease, especially in the proximal colon, which hindered them from assessing the direct effect of gallstone disease vs. the effect of cholecystectomy (5). In the context of our model, there were more associations between obesity, diabetes, older age, and family history with CRC than with cholecystectomy. The crude association was reduced by the attenuation of the cholecystectomy estimate after adjustment; this indicates that some of the crude association may be due to shared risks. The time between surgery and malignancy should also be considered. The illustrative results showed that almost half of the cancers occurred more than 10 years after cholecystectomy, and that increasingly longer time periods were associated with a higher proportion of proximal cancers. This latency might be acceptable for a slow-acting carcinogenic process, but it may also be a sign of aging and/or exposure to other CRC risk factors. Appropriate lag periods should thus be used in future studies to minimize reverse causation and detection bias, and careful modeling of time since cholecystectomy should be done. Persistent or recurrent bowel-habit changes that were reported were more common in those with prior cholecystectomy during the exploratory survey. This should be taken as a minimum. Altered bile-acid handling can cause post-cholecystectomy bowel changes which do not necessarily mean neoplasia. Recall bias also is a possibility, since the survey is cross-sectional and not meant for predicting cancer. The main use of the survey is hypothesis generation, not prediction of cancer. Currently, there is no strong clinical evidence to support the view that cholecystectomy, by itself, is a proven carcinogenic procedure, or that colonoscopic surveillance should be more intense in patients with previous gallbladder removal. The current guidelines for CRC screening should remain in place, which are based on age and risk. However, clinicians should be aware of patients who have had previous cholecystectomy along with traditional high-risk factors including advanced age, obesity, diabetes mellitus, smoking and family history of gallstones, especially if gastrointestinal symptoms persist. The multicenter design, comparison group, evaluation of tumor subsite, consideration of time since surgery, and adjustment for major CRC risk factors are strengths of the proposed study. There are also some restrictions that must be noted. Information may be subject to selection bias and not properly documented for a retrospective study. There may be residual confounding due to diet, socioeconomic status, medications, gallstone severity, physical activity and screening behaviour. Relatively small number of CRC events precludes site-specific and time-stratified analyses. There is the possibility of recall bias in the survey and observational associations are not able to prove cause and effect. To conclude, the results support the hypothesis of a potential link between cholecystectomy and colorectal malignancy that is more likely to be seen in proximal colon cancer than in CRC in general. The overall association is unclear, and is heavily influenced by traditional risk factors and confounding. However, larger prospective multicenter cohorts with longer follow-up periods and detailed information on gallstone disease parameters as well as lifestyle and metabolic factors and tumor subsite-specific analyses will be needed before cholecystectomy can be regarded as an independent risk factor for colorectal cancer.

he aim of this multicentre study was to investigate the long-term association between cholecystectomy and colorectal malignant tumors with a special focus on the localization of the tumour and clinical risk factors. A history of cholecystectomy was also associated with colorectal cancer in the illustrative analysis, but this association was diminished after adjusting for traditional risk factors for colorectal cancer, and the association was not statistically significant or meaningful. The results of this study indicate that cholecystectomy is not an accepted independent risk factor for colorectal malignancy. An interesting finding was that more patients with colorectal tumours had had previous cholecystectomy, which occurred more frequently on the proximal, or right side of the colon than at the distal side. This is in line with the results of several recent epidemiological studies and could be biologically attributed to a chronic modification of bile-acid metabolism, ongoing intestinal exposure to bile acid, and gut microbiome changes. The mechanisms, however, are still only hypotheses and do not prove a causal relationship. These factors were seen to have stronger associations with malignancy and should continue to play a crucial role in the risk assessment process as older age, positive family history of colorectal cancer, obesity and diabetes. The association between cholecystectomy and colorectal cancer may also be partly attributable to shared metabolic risk factors for the two conditions. Currently, there is no indication to routinely conduct CRC screening based on a prior cholecystectomy. However, those who have other known risk factors and/or ongoing gastrointestinal symptoms should be clinically evaluated and screened for colorectal cancer at the appropriate age and risk level. To confirm these results, larger prospective multicenter studies with extended follow-up time should be conducted with careful adjustment for gallstone disease, lifestyle factors, metabolic characteristics and anatomic tumor subsite data to determine if cholecystectomy is a risk factor for long-term colorectal cancer.

1. Nelis PH, Grotto S, Ibis KA, et al. Colorectal Cancer Risk Following Cholecystectomy: An Updated Systematic Review. Cancers (Basel). 2025;17(19):3114. doi:10.3390/cancers17193114. This should be one of our principal references because it is the most recent comprehensive systematic review. 2. Aburumman R, Alsakarneh S, Asad O, Dahiya DS, Bilal M, Coelho-Prabhu N, et al. Long-term risk of colorectal cancer following cholecystectomy: a nationwide cohort study. Surg Endosc. 2026. doi:10.1007/s00464-026-13382-4. This is particularly valuable because 613,396 cholecystectomy patients were propensity-matched to controls; the study reported an adjusted HR of 2.16 for CRC and a particularly strong association with right-sided disease. 3. Zhou S, Zhao B, Qu J, Gao X, Wang X, Yang C, et al. Association between cholecystectomy and colorectal cancer: results from the National Health and Nutrition Examination Survey (NHANES) 2017–2023 and Mendelian randomization analyses. Transl Cancer Res. 2025;14(11):7954–7966. doi:10.21037/tcr-2025-1493. Importantly, the fully adjusted association was not statistically significant, making this an excellent contrasting study. 4. Narayana AS, Pai SA, Rao AN, Dhavaleshwar A. Association Between Cholecystectomy and Colorectal Cancer. Indian J Surg Oncol. 2025;16(6):1504–1507. doi:10.1007/s13193-025-02255-2. This recent case-control study also found no statistically significant association. 5. Muñoz RA, Ramos AA, Miranda FJ, De La Rosa JE, Muñoz AE, Ramírez AA, et al. Cholecystectomy Is a Risk Factor for Proximal Colon Cancer That May Also Relate to its Aggressiveness. J Surg Res. 2024;304:152–161. doi:10.1016/j.jss.2024.10.018. This is especially relevant to our multicenter design: it reported an adjusted OR of 2.42 for proximal CRC among patients with previous cholecystectomy. 6. Mu L, Li W, Ren W, Hu D, Song Y. The association between cholecystectomy and the risk of colorectal cancer: an updated systematic review and meta-analysis of cohort studies. Transl Cancer Res. 2023;12(6):1452–1465. doi:10.21037/tcr-22-2049. Eighteen studies were included; overall CRC, colon cancer and rectal cancer were not significantly associated with cholecystectomy. 7. Yu L, Liu W, Yan Y, Jiang Y, Gao X, Ruan S. No association between cholecystectomy and risk of colorectal cancer: a meta-analysis of cohort studies. Int J Colorectal Dis. 2023;38(1):179. doi:10.1007/s00384-023-04463-0. The pooled overall CRC estimate was nonsignificant, but several subsite and sex-specific signals were observed. 8. Polychronidis G, Siddiqi H, Ahmed FA, Papatheodorou S, Giovannucci EL, Song M. Association of gallstone disease with risk of colorectal cancer: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2023;52(5):1424–1434. doi:10.1093/ije/dyad042. Particularly important because it helps separate the effect of underlying gallstone disease from the effect of cholecystectomy itself. 9. Zhou X, Xu L, Zhang Q, Chen W, Xie H. The impact of long-term (≥5 years) cholecystectomy on gut microbiota changes and its influence on colorectal cancer risk: based on 16S rDNA sequencing analysis. Eur J Gastroenterol Hepatol. 2024;36(11):1288–1297. doi:10.1097/MEG.0000000000002827. This gives us contemporary mechanistic support for the “long-term” component of your title. 10. Pan SY, Zhou CB, Deng JW, Zhou YL, Liu ZH, Fang JY. The effects of pks+ Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy. J Gastroenterol Hepatol. 2024;39(5):868–879. doi:10.1111/jgh.16462. The study included 514 participants and provides an important microbiome–bile-acid mechanism linking cholecystectomy with colorectal neoplasia. 11. Cong J, Liu P, Han Z, et al. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions. Immunity. 2024;57(4):876–889.e11. doi:10.1016/j.immuni.2024.02.014. Excellent mechanistic evidence involving deoxycholic acid, microbiota and antitumor immunity. 12. Yang S, Wang Y, Sheng L, Cui W, Ma C. The effect of fecal bile acids on the incidence and risk-stratification of colorectal cancer: an updated systematic review and meta-analysis. Sci Rep. 2025;15:740. doi:10.1038/s41598-024-84801-6. This supports our proposed discussion of secondary bile-acid exposure and colorectal carcinogenesis. 13. Jiang X, Jiang Z, Cheng Q, Sun W, Jiang M, Sun Y. Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota. Front Med (Lausanne). 2022;9:1000563. doi:10.3389/fmed.2022.1000563. This will be one of the main references for the biological-mechanism subsection. 14. Xu F, Chen R, Zhang C, Wang H, Ding Z, Yu L, et al. Cholecystectomy Significantly Alters Gut Microbiota Homeostasis and Metabolic Profiles: A Cross-Sectional Study. Nutrients. 2023;15(20):4399. doi:10.3390/nu15204399. 15. Kuhls S, Osswald A, Ocvirk S. Bile acids, bile pigments and colorectal cancer risk. Curr Opin Gastroenterol. 2022;38(2):173–178. doi:10.1097/MOG.0000000000000820. This provides a solid background reference for bile-acid metabolism and colorectal carcinogenesis.