Risk Factors for Clostridioides difficile Infection in Ulcerative Colitis: A Single-Center Case- Control Study

Risk Factors for Clostridioides difficile Infection in Ulcerative Colitis: A Single-Center Case- Control Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors for Clostridioides difficile Infection in Ulcerative Colitis: A Single-Center Case- Control Study Mei Bai¹, Chunchuan Li¹, Qin Liu¹, Xiaomei Song¹, Wei Tan¹, Yan Liu¹, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8776738/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 19 You are reading this latest preprint version Abstract Objective To identify independent risk factors for Clostridioides difficile infection (CDI) in patients with ulcerative colitis (UC). Methods A retrospective case-control study was conducted at a tertiary hospital. Hospitalized UC patients diagnosed between January 2022 and December 2023 were included. Patients were categorized into a CDI-positive group (n = 35) and a CDI-negative control group (n = 154). CDI diagnosis followed a two-step algorithm (glutamate dehydrogenase [GDH] / toxin enzyme immunoassay [EIA] plus confirmatory toxin gene PCR). Independent risk factors were analyzed using Firth penalized logistic regression. Results In multivariate analysis, active disease state (adjusted odds ratio [aOR] = 0.01, 95% confidence interval [CI]: 0.00–0.07; P < 0.001) and prior CDI history (aOR = 4.86, 95% CI: 1.43–20.08; P = 0.011) were independent risk factors for CDI. Body mass index (BMI) at admission, recent antibiotic use, and 5-aminosalicylic acid (5-ASA) therapy showed no significant independent association. Conclusion UC patients with active disease or a prior CDI history are at high risk for CDI and warrant enhanced surveillance and targeted preventive measures. Ulcerative Colitis Clostridioides difficile Infection Risk Factors Case-Control Study Disease Activity Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by continuous, diffuse inflammation and ulceration of the colorectal mucosa and submucosa. Its etiology involves a complex interplay of genetic, immune, microbial, and environmental factors. While UC incidence has stabilized in Western nations, it is rising in some developing countries adopting Westernized lifestyles [ 1 , 2 ], contributing to a substantial global disease burden [ 3 ]. Clostridioides difficile is an anaerobic, spore-forming, gram-positive bacterium and a leading cause of antibiotic-associated diarrhea and pseudomembranous colitis [ 4 ]. CDI presents a wide clinical spectrum, from asymptomatic carriage to severe, life-threatening complications such as toxic megacolon [ 5 ]. In UC patients, CDI is a significant pathogen implicated in disease exacerbation [ 6 , 7 ] and is associated with prolonged hospitalization, increased healthcare costs, and higher mortality [ 8 – 10 ]. Recent data indicate a concerning rise in CDI incidence among UC patients [ 11 ], exacerbating morbidity and healthcare burden. Identifying specific risk factors for CDI in this vulnerable population is therefore critical for optimizing clinical management and preventive strategies. This single-center, retrospective case-control study aimed to systematically investigate independent risk factors for CDI in hospitalized UC patients by integrating rigorous diagnostic criteria and advanced statistical methods. Materials and Methods Study Population and Design This retrospective case-control study was conducted at the Department of Gastroenterology, Chongqing General Hospital. We consecutively enrolled adult patients (≥ 18 years) hospitalized between January 2022 and December 2023 with a confirmed diagnosis of UC based on established clinical, endoscopic, and histological criteria [ 12 ]. Participants were stratified into a CDI-positive group and a CDI-negative control group based on their CDI status during the index hospitalization. Inclusion and Exclusion Criteria Inclusion criteria were: (1) age ≥ 18 years; (2) established UC diagnosis; (3) completion of standardized CDI testing during admission; and (4) availability of complete clinical documentation. Exclusion criteria were: (1) pre-existing CDI at admission; (2) concurrent other severe intestinal infections; (3) diagnosis of colorectal neoplasia; (4) UC disease duration < 3 months (to minimize inclusion of cases where the initial presentation might be precipitated by CDI); and (5) critically incomplete medical records. Assessment of Disease Activity Disease activity was assessed using the Partial Mayo Score, a validated clinical index ranging from 0 to 9 based on stool frequency, rectal bleeding, and the physician's global assessment [ 13 ]. Active disease was defined as a Partial Mayo Score ≥ 3. Patients not meeting this criterion were classified as being in remission. This classification was performed retrospectively based on documented clinical findings at admission. Diagnosis of Clostridioides difficile Infection CDI diagnosis adhered to international guidelines and required clinically significant diarrhea (≥ 3 unformed stools per 24 hours). A two-step diagnostic algorithm was employed: stool samples were initially tested simultaneously for C. difficile glutamate dehydrogenase (GDH) antigen and toxins A/B using enzyme immunoassays (EIA). Specimens that were GDH-positive but toxin-negative underwent confirmatory nucleic acid amplification testing (NAAT) targeting the toxin B gene (tcdB). A definitive CDI diagnosis required compatible clinical symptoms plus laboratory confirmation meeting either of the following criteria: (a) positive for both GDH and toxins A/B by EIA, or (b) positive for GDH by EIA and positive for tcdB by NAAT. Data Collection Collected data included: demographics (age, sex, smoking/alcohol status, BMI); clinical features (UC duration, Montreal classification extent, disease activity, prior CDI history); laboratory parameters (albumin, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], complete blood count); and medication exposures within the preceding 3 months (antibiotics, 5-aminosalicylic acid [5-ASA], proton pump inhibitors [PPIs], corticosteroids, immunomodulators, biologic agents, Janus kinase [JAK] inhibitors). Statistical Analysis Continuous variables are presented as mean ± standard deviation or median (interquartile range [IQR]); categorical variables are presented as frequencies (percentages). Group comparisons used the Student’s t-test or Mann-Whitney U test for continuous data, and the chi-square or Fisher’s exact test for categorical data. Variables with a univariate association with CDI (P < 0.05) were entered into a multivariable Firth’s penalized logistic regression model to identify independent risk factors while mitigating bias from limited events. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated. A two-sided P-value < 0.05 indicated statistical significance. All analyses were performed using R software (version 4.3.1). Results Baseline Characteristics The study enrolled 189 UC patients, comprising 35 (18.5%) in the CDI-positive group and 154 (81.5%) in the CDI-negative control group. No significant differences were observed between groups regarding sex, age, age at IBD diagnosis, alcohol use, smoking status, or Montreal classification (all P > 0.05). Significant differences were identified in the following areas: Clinical Features: Patients in the CDI group had a significantly lower BMI at admission than controls (median [IQR]: 20.30 [18.20–24.00] vs. 21.95 [19.70–24.00], P = 0.043). A history of prior CDI was more frequent in the CDI group (51.43% vs. 16.88%, P < 0.001). Furthermore, all patients (100%) in the CDI group were classified as having active disease (Partial Mayo Score ≥3), compared to only 29.87% in the control group (P < 0.001) (Table1). Laboratory parameters : all routine laboratory parameters, including white blood cell count (WBC), hemoglobin (Hb), platelet count (Plt), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 25-hydroxyvitamin D [25(OH)D], prealbumin (PA), and albumin (ALB), showed no statistically significant differences (all P > 0.05) (Table2). Medication Exposure: Antibiotic exposure within the preceding month was markedly more common in the CDI group (57.14% vs. 12.34%, P < 0.001). The use of 5-ASA was also significantly higher in the CDI group (60.00% vs. 40.52%, P = 0.036). No significant intergroup differences were found for PPIs, biologic agents, immunomodulators, JAK inhibitors, or corticosteroids (Table3). Multivariable Analysis Variables significant in univariate analysis (BMI, prior CDI history, active disease, recent antibiotic use, 5-ASA use) were included in the multivariable Firth model. The analysis identified two independent risk factors (Table4): Prior CDI Infection: A history of previous CDI was associated with a nearly fivefold increase in the odds of current CDI (aOR = 4.86, 95% CI: 1.43–20.08; P = 0.011). Active Disease: Active disease status was a strong independent predictor. Patients in remission had drastically lower odds of infection (aOR for remission = 0.01, 95% CI: 0.00–0.07; P 0.05), suggesting their associations may be confounded by or mediated through disease activity. Discussion Epidemiology of CDI in UC Clostridioides difficile infection (CDI) is increasingly recognized as a major contributor to disease exacerbation in inflammatory bowel disease (IBD). Enhanced clinical awareness and improved diagnostic methods have led to higher detection rates in ulcerative colitis (UC) patients. Nevertheless, epidemiological studies focusing specifically on UC populations remain scarce. One retrospective cohort study reported an annual CDI incidence of 4.6% in IBD patients, independent of disease activity or treatment [15; 16]. In our cohort, the prevalence of CDI was 18.52%, consistent with previously reported Chinese data (ranging from 19.3% to 24.7%) but notably higher than rates in Western populations [17; 18]. This discrepancy may reflect differences in lifestyle; healthcare practices; or regional risk factors. Prior CDI History and Disease Activity as Independent Risk Factors Recent advances in pathogenesis highlight intestinal dysbiosis, barrier dysfunction, and immune dysregulation as key contributors to CDI [ 19 – 21 ]. Our findings reinforce the view that active UC and a history of CDI are strong, independent risk factors. A prior CDI episode was a powerful predictor, consistent with evidence that initial infection leads to sustained microbial imbalance and reduced colonization resistance [ 22 – 25 ]. This supports the need for vigilant monitoring and consideration of secondary prophylaxis in UC patients with previous CDI. Disease activity also emerged as a critical determinant. During flares, increased intestinal inflammation, loss of barrier integrity, and elevated permeability create a microenvironment favorable for C. difficile colonization and toxin - mediated damage [ 26 ]. Furthermore, active disease is often associated with immunosuppression and antibiotic exposure, both of which may amplify CDI risk. Our observation that remission is strongly protective suggests that effective control of UC activity may mitigate CDI susceptibility. 5 - ASA Use: Association or Confounder? 5 - ASA remains a cornerstone of UC maintenance therapy. In our univariate analysis, 5 - ASA use was more common in CDI patients—a finding echoed in studies linking 5 - ASA to recurrent CDI [27; 28]. However, this association likely reflects confounding by disease activity, as patients with active UC are more frequently prescribed 5 - ASA. Notably, gut microbial metabolism of 5 - ASA may alter its efficacy and potentially affect microbiota homeostasis [ 29 ]. Although a direct causal role remains unproven, clinicians should be aware of the potential interaction. Future studies should examine 5 - ASA within multifactor models and explore its effects on gut microecology. Antibiotic Exposure: A Context-Dependent Risk Although antibiotics are a well-established risk factor for CDI, their effect was not significant in our multivariate model. However, this may be due to confounding by severity—patients with severe flares are more often prescribed antibiotics for suspected complications, making antibiotic use a marker of severe disease rather than an independent driver in this cohort. Guidelines emphasize the higher CDI risk with broad-spectrum agents [ 30 ]. Biologics, Immunomodulators, and JAK Inhibitors: No Apparent CDI Signal In our study, use of biologics, immunomodulators, or JAK inhibitors was not associated with increased CDI risk—a reassuring finding consistent with several prior reports [ 13 , 34 ]. Although some studies have linked immunomodulators to CDI [ 32 ], others, including a meta-analysis, found no significant risk with vedolizumab [ 33 ]. JAK inhibitors such as tofacitinib also appear relatively safe, with lower CDI incidence possibly related to better disease control [ 34 , 35 ]. These observations suggest that modern UC therapies may not intrinsically elevate CDI risk and might even protect indirectly through improved inflammatory control. Conclusion This study identifies active disease status and a prior history of CDI as key independent risk factors for CDI in patients with UC. These findings highlight the importance of achieving disease remission and conducting targeted surveillance in high-risk individuals. Future research should focus on prospective, multicenter cohorts to validate these risk factors, clarify the temporal relationship between medication exposure and CDI, and investigate microbiome-mediated mechanisms. Such efforts could ultimately inform risk-stratified prevention strategies and improve outcomes in UC patients at risk for CDI. Limitations Our findings should be interpreted considering several limitations. First, the single-center, retrospective design with a modest sample size (n = 35 CDI cases) may limit generalizability and statistical power for subgroup analyses. Second, inclusion of only hospitalized patients likely selected for a more severely ill population, potentially overestimating the association between disease activity and CDI risk. Third, while we employed a standardized clinical score (Partial Mayo), the lack of uniform endoscopic assessment at admission could introduce classification bias. Fourth, detailed data on antibiotic subtypes and the precise timing of medication exposure relative to flare onset were unavailable, limiting mechanistic insights. Finally, we could not stratify prior CDI history by recency or recurrence frequency due to sample size constraints. Declarations Ethics approval and consent to participate The study protocol was approved by the Medaical Ethics Committee of Chongqing General Hospital, and a waiver of informed consent was granted (Approval No.: IIT S2025-010-01,Date: 05/30/2025). Due to the retrospective design of the study, the requirement for informed consent was waived by the Ethics Committee. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for publication Not applicable. Funding This study was supported by the National Key R&D Program of China (2023YFC2507300) and the Science and Health Joint Medical Research Program of Chongqing Municipality (2024QNXM036, 2024ZDXM009). The funding bodies had no role in the design of the study, data collection, analysis, interpretation of data, or in writing the manuscript. Author Contribution Mei Bai and Chunchuan Li contributed to data collection and manuscript drafting. Qin Liu and Xiaomei Song performed the data analysis. Wei Tan, Yan Liu, and Lingya Xiang were responsible for patient management and case collection. Hong Guo critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request. References Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies[J]. Lancet. 2017;390(10114):2769–78. Beaugerie L, Langholz E, Nyboe-Andersen N, et al. 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Nguyen GC, Kaplan GG, Harris ML, et al. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients[J]. Am J Gastroenterol. 2008;103(6):1443–50. Barber GE, Hendler S, Okafor P, et al. Rising Incidence of Intestinal Infections in Inflammatory Bowel Disease: A Nationwide Analysis[J]. Inflamm Bowel Dis. 2018;24(8):1849–56. Saffouri G, Gupta A, Loftus EJ, et al. The incidence and outcomes from Clostridium difficile infection in hospitalized adults with inflammatory bowel disease[J]. Scand J Gastroenterol. 2017;52(11):1240–7. Spartz EJ, DeDecker LC, Fansiwala KM, et al. Recent trends and risk factors associated with Clostridioides difficile infections in hospitalized patients with inflammatory bowel disease[J]. Aliment Pharmacol Ther. 2024;59(1):89–99. Feakins R, Torres J, Borralho-Nunes P, et al. ECCO Topical Review on Clinicopathological Spectrum and Differential Diagnosis of Inflammatory Bowel Disease[J]. 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Clostridium Difficile Infection Worsen Outcome of Hospitalized Patients with Inflammatory Bowel Disease[J]. Sci Rep. 2016;6:29791. Yang H, Wu X, Li X, et al. A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response[J]. Nat Commun. 2024;15(1):2842. Pan Z, Wu N, Jin C. Intestinal Microbiota Dysbiosis Promotes Mucosal Barrier Damage and Immune Injury in HIV-Infected Patients[J]. Can J Infect Dis Med Microbiol, 2023,2023:3080969. Stolfi C, Maresca C, Monteleone G et al. Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases[J]. Biomedicines, 2022,10(2). Zhou Y, Guo L, Xiao T, et al. Characterization and dynamics of intestinal microbiota in patients with Clostridioides difficile colonization and infection[J]. Microbes Infect. 2024;26(8):105373. Sehgal K, Yadav D, Khanna S. The interplay of Clostridioides difficile infection and inflammatory bowel disease[J]. Th Adv Gastroenterol. 2021;14:1088203261. Rodriguez C, Romero E, Garrido-Sanchez L, et al. MICROBIOTA INSIGHTS IN CLOSTRIDIUM DIFFICILE INFECTION AND INFLAMMATORY BOWEL DISEASE[J]. Gut Microbes. 2020;12(1):1725220. Buffie CG, Bucci V, Stein RR, et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile[J]. Nature. 2015;517(7533):205–8. Sartor RB, Wu GD. Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches[J]. Gastroenterology. 2017;152(2):327–39. Vitikainen K, Haapamaki J, Farkkila M, et al. Clostridium difficile infection in patients with inflammatory bowel disease: a case control study[J]. Scand J Gastroenterol. 2018;53(8):947–51. Razik R, Rumman A, Bahreini Z, et al. Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study[J]. Am J Gastroenterol. 2016;111(8):1141–6. Mehta RS, Mayers JR, Zhang Y, et al. Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease[J]. Nat Med. 2023;29(3):700–9. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)[J]. Clin Infect Dis. 2018;66(7):e1–48. Navaneethan U, Mukewar S, Venkatesh PG, et al. Clostridium difficile infection is associated with worse long-term outcome in patients with ulcerative colitis[J]. J Crohns Colitis. 2012;6(3):330–6. Saad Alshahrani A, Mohammad D, Attieh Alzahrani M, et al. Vedolizumab does not increase risk of clostridium difficile infection in patients with inflammatory bowel disease using vedolizumab: A retrospective cohort study[J]. Saudi Pharm J. 2023;31(9):101736. Alghamdi M, Alyousfi D, Mukhtar MS, et al. Association between vedolizumab and risk of clostridium difficile infection in patients with ulcerative colitis: A systematic review and meta-analysis[J]. Saudi J Gastroenterol. 2024;30(6):346–52. Loftus EV, Baumgart DC, Gecse K, et al. Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program[J]. Inflamm Bowel Dis. 2023;29(5):744–51. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis[J]. N Engl J Med. 2017;376(18):1723–36. Additional Declarations No competing interests reported. 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Its etiology involves a complex interplay of genetic, immune, microbial, and environmental factors. While UC incidence has stabilized in Western nations, it is rising in some developing countries adopting Westernized lifestyles [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], contributing to a substantial global disease burden [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClostridioides difficile is an anaerobic, spore-forming, gram-positive bacterium and a leading cause of antibiotic-associated diarrhea and pseudomembranous colitis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. CDI presents a wide clinical spectrum, from asymptomatic carriage to severe, life-threatening complications such as toxic megacolon [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In UC patients, CDI is a significant pathogen implicated in disease exacerbation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and is associated with prolonged hospitalization, increased healthcare costs, and higher mortality [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent data indicate a concerning rise in CDI incidence among UC patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], exacerbating morbidity and healthcare burden. Identifying specific risk factors for CDI in this vulnerable population is therefore critical for optimizing clinical management and preventive strategies.\u003c/p\u003e \u003cp\u003eThis single-center, retrospective case-control study aimed to systematically investigate independent risk factors for CDI in hospitalized UC patients by integrating rigorous diagnostic criteria and advanced statistical methods.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Population and Design\u003c/h2\u003e\n \u003cp\u003eThis retrospective case-control study was conducted at the Department of Gastroenterology, Chongqing General Hospital. We consecutively enrolled adult patients (\u0026ge;\u0026thinsp;18 years) hospitalized between January 2022 and December 2023 with a confirmed diagnosis of UC based on established clinical, endoscopic, and histological criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Participants were stratified into a CDI-positive group and a CDI-negative control group based on their CDI status during the index hospitalization.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria were: (1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (2) established UC diagnosis; (3) completion of standardized CDI testing during admission; and (4) availability of complete clinical documentation. Exclusion criteria were: (1) pre-existing CDI at admission; (2) concurrent other severe intestinal infections; (3) diagnosis of colorectal neoplasia; (4) UC disease duration\u0026thinsp;\u0026lt;\u0026thinsp;3 months (to minimize inclusion of cases where the initial presentation might be precipitated by CDI); and (5) critically incomplete medical records.\u003c/p\u003e\n\u003ch3\u003eAssessment of Disease Activity\u003c/h3\u003e\n\u003cp\u003eDisease activity was assessed using the Partial Mayo Score, a validated clinical index ranging from 0 to 9 based on stool frequency, rectal bleeding, and the physician\u0026apos;s global assessment [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Active disease was defined as a Partial Mayo Score\u0026thinsp;\u0026ge;\u0026thinsp;3. Patients not meeting this criterion were classified as being in remission. This classification was performed retrospectively based on documented clinical findings at admission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis of\u003c/strong\u003e \u003cstrong\u003eClostridioides difficile\u003c/strong\u003e \u003cstrong\u003eInfection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCDI diagnosis adhered to international guidelines and required clinically significant diarrhea (\u0026ge;\u0026thinsp;3 unformed stools per 24 hours). A two-step diagnostic algorithm was employed: stool samples were initially tested simultaneously for \u003cem\u003eC. difficile\u003c/em\u003e glutamate dehydrogenase (GDH) antigen and toxins A/B using enzyme immunoassays (EIA). Specimens that were GDH-positive but toxin-negative underwent confirmatory nucleic acid amplification testing (NAAT) targeting the toxin B gene (tcdB). A definitive CDI diagnosis required compatible clinical symptoms plus laboratory confirmation meeting either of the following criteria: (a) positive for both GDH and toxins A/B by EIA, or (b) positive for GDH by EIA and positive for tcdB by NAAT.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eCollected data included: demographics (age, sex, smoking/alcohol status, BMI); clinical features (UC duration, Montreal classification extent, disease activity, prior CDI history); laboratory parameters (albumin, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], complete blood count); and medication exposures within the preceding 3 months (antibiotics, 5-aminosalicylic acid [5-ASA], proton pump inhibitors [PPIs], corticosteroids, immunomodulators, biologic agents, Janus kinase [JAK] inhibitors).\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eContinuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range [IQR]); categorical variables are presented as frequencies (percentages). Group comparisons used the Student\u0026rsquo;s t-test or Mann-Whitney U test for continuous data, and the chi-square or Fisher\u0026rsquo;s exact test for categorical data. Variables with a univariate association with CDI (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were entered into a multivariable Firth\u0026rsquo;s penalized logistic regression model to identify independent risk factors while mitigating bias from limited events. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated. A two-sided P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance. All analyses were performed using R software (version 4.3.1).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study enrolled 189 UC patients, comprising 35 (18.5%) in the CDI-positive group and 154 (81.5%) in the CDI-negative control group. No significant differences were observed between groups regarding sex, age, age at IBD diagnosis, alcohol use, smoking status, or Montreal classification (all P \u0026gt; 0.05). Significant differences were identified in the following areas:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eClinical Features:\u003c/strong\u003e Patients in the CDI group had a significantly lower BMI at admission than controls (median [IQR]: 20.30 [18.20\u0026ndash;24.00] vs. 21.95 [19.70\u0026ndash;24.00], P = 0.043). A history of prior CDI was more frequent in the CDI group (51.43% vs. 16.88%, P \u0026lt; 0.001). Furthermore, all patients (100%) in the CDI group were classified as having active disease (Partial Mayo Score \u0026ge;3), compared to only 29.87% in the control group (P \u0026lt; 0.001)\u0026nbsp;(Table1).\u003c/li\u003e\n\u003c/ul\u003e\u003cimg width=\"553\" height=\"743\" src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1775584825.png\" v:shapes=\"图片_x0020_4\" alt=\"image\"\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eLaboratory parameters\u003c/strong\u003e: all routine laboratory parameters, including white blood cell count (WBC), hemoglobin (Hb), platelet count (Plt), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 25-hydroxyvitamin D [25(OH)D], prealbumin (PA), and albumin (ALB), showed no statistically significant differences (all P \u0026gt; 0.05)\u0026nbsp;(Table2).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMedication Exposure:\u003c/strong\u003e Antibiotic exposure within the preceding month was markedly more common in the CDI group (57.14% vs. 12.34%, P \u0026lt; 0.001). The use of 5-ASA was also significantly higher in the CDI group (60.00% vs. 40.52%, P = 0.036). No significant intergroup differences were found for PPIs, biologic agents, immunomodulators, JAK inhibitors, or corticosteroids\u0026nbsp;(Table3).\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\u003cimg width=\"554\" height=\"439\" src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1775584824.png\" v:shapes=\"图片_x0020_3\" alt=\"image\"\u003e\u003cimg width=\"553\" height=\"766\" src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img177558482561.png\" v:shapes=\"图片_x0020_5\" alt=\"image\"\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariable Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVariables significant in univariate analysis (BMI, prior CDI history, active disease, recent antibiotic use, 5-ASA use) were included in the multivariable Firth model. The analysis identified two independent risk factors\u0026nbsp;(Table4):\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"554\" height=\"386\" src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img177558482528.png\" v:shapes=\"图片_x0020_6\" alt=\"image\"\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003ePrior CDI Infection:\u003c/strong\u003e A history of previous CDI was associated with a nearly fivefold increase in the odds of current CDI (aOR = 4.86, 95% CI: 1.43\u0026ndash;20.08; P = 0.011).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eActive Disease:\u003c/strong\u003e Active disease status was a strong independent predictor. Patients in remission had drastically lower odds of infection (aOR for remission = 0.01, 95% CI: 0.00\u0026ndash;0.07; P \u0026lt; 0.001).\u003cbr\u003e\u0026nbsp;Variables not retained as independent predictors included admission BMI, recent antibiotic exposure, and 5-ASA use (all P \u0026gt; 0.05), suggesting their associations may be confounded by or mediated through disease activity.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEpidemiology of CDI in UC\u003c/h2\u003e \u003cp\u003eClostridioides difficile infection (CDI) is increasingly recognized as a major contributor to disease exacerbation in inflammatory bowel disease (IBD). Enhanced clinical awareness and improved diagnostic methods have led to higher detection rates in ulcerative colitis (UC) patients. Nevertheless, epidemiological studies focusing specifically on UC populations remain scarce. One retrospective cohort study reported an annual CDI incidence of 4.6% in IBD patients, independent of disease activity or treatment [15; 16]. In our cohort, the prevalence of CDI was 18.52%, consistent with previously reported Chinese data (ranging from 19.3% to 24.7%) but notably higher than rates in Western populations [17; 18]. This discrepancy may reflect differences in lifestyle; healthcare practices; or regional risk factors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrior CDI History and Disease Activity as Independent Risk Factors\u003c/h2\u003e \u003cp\u003eRecent advances in pathogenesis highlight intestinal dysbiosis, barrier dysfunction, and immune dysregulation as key contributors to CDI [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our findings reinforce the view that active UC and a history of CDI are strong, independent risk factors.\u003c/p\u003e \u003cp\u003eA prior CDI episode was a powerful predictor, consistent with evidence that initial infection leads to sustained microbial imbalance and reduced colonization resistance [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This supports the need for vigilant monitoring and consideration of secondary prophylaxis in UC patients with previous CDI.\u003c/p\u003e \u003cp\u003eDisease activity also emerged as a critical determinant. During flares, increased intestinal inflammation, loss of barrier integrity, and elevated permeability create a microenvironment favorable for C. difficile colonization and toxin - mediated damage [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, active disease is often associated with immunosuppression and antibiotic exposure, both of which may amplify CDI risk. Our observation that remission is strongly protective suggests that effective control of UC activity may mitigate CDI susceptibility.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e5 - ASA Use: Association or Confounder?\u003c/h2\u003e \u003cp\u003e5 - ASA remains a cornerstone of UC maintenance therapy. In our univariate analysis, 5 - ASA use was more common in CDI patients\u0026mdash;a finding echoed in studies linking 5 - ASA to recurrent CDI [27; 28]. However, this association likely reflects confounding by disease activity, as patients with active UC are more frequently prescribed 5 - ASA. Notably, gut microbial metabolism of 5 - ASA may alter its efficacy and potentially affect microbiota homeostasis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Although a direct causal role remains unproven, clinicians should be aware of the potential interaction. Future studies should examine 5 - ASA within multifactor models and explore its effects on gut microecology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eAntibiotic Exposure: A Context-Dependent Risk\u003c/h2\u003e \u003cp\u003eAlthough antibiotics are a well-established risk factor for CDI, their effect was not significant in our multivariate model. However, this may be due to confounding by severity\u0026mdash;patients with severe flares are more often prescribed antibiotics for suspected complications, making antibiotic use a marker of severe disease rather than an independent driver in this cohort. Guidelines emphasize the higher CDI risk with broad-spectrum agents [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eBiologics, Immunomodulators, and JAK Inhibitors: No Apparent CDI Signal\u003c/h2\u003e \u003cp\u003eIn our study, use of biologics, immunomodulators, or JAK inhibitors was not associated with increased CDI risk\u0026mdash;a reassuring finding consistent with several prior reports [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Although some studies have linked immunomodulators to CDI [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], others, including a meta-analysis, found no significant risk with vedolizumab [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. JAK inhibitors such as tofacitinib also appear relatively safe, with lower CDI incidence possibly related to better disease control [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. These observations suggest that modern UC therapies may not intrinsically elevate CDI risk and might even protect indirectly through improved inflammatory control.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study identifies active disease status and a prior history of CDI as key independent risk factors for CDI in patients with UC. These findings highlight the importance of achieving disease remission and conducting targeted surveillance in high-risk individuals. Future research should focus on prospective, multicenter cohorts to validate these risk factors, clarify the temporal relationship between medication exposure and CDI, and investigate microbiome-mediated mechanisms. Such efforts could ultimately inform risk-stratified prevention strategies and improve outcomes in UC patients at risk for CDI.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur findings should be interpreted considering several limitations. First, the single-center, retrospective design with a modest sample size (n\u0026thinsp;=\u0026thinsp;35 CDI cases) may limit generalizability and statistical power for subgroup analyses. Second, inclusion of only hospitalized patients likely selected for a more severely ill population, potentially overestimating the association between disease activity and CDI risk. Third, while we employed a standardized clinical score (Partial Mayo), the lack of uniform endoscopic assessment at admission could introduce classification bias. Fourth, detailed data on antibiotic subtypes and the precise timing of medication exposure relative to flare onset were unavailable, limiting mechanistic insights. Finally, we could not stratify prior CDI history by recency or recurrence frequency due to sample size constraints.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe study protocol was approved by the Medaical Ethics Committee of Chongqing General Hospital, and a waiver of informed consent was granted (Approval No.: IIT S2025-010-01,Date: 05/30/2025). Due to the retrospective design of the study, the requirement for informed consent was waived by the Ethics Committee. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by the National Key R\u0026amp;D Program of China (2023YFC2507300) and the Science and Health Joint Medical Research Program of Chongqing Municipality (2024QNXM036, 2024ZDXM009). The funding bodies had no role in the design of the study, data collection, analysis, interpretation of data, or in writing the manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMei Bai and Chunchuan Li contributed to data collection and manuscript drafting. Qin Liu and Xiaomei Song performed the data analysis. Wei Tan, Yan Liu, and Lingya Xiang were responsible for patient management and case collection. Hong Guo critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNg SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies[J]. Lancet. 2017;390(10114):2769\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaugerie L, Langholz E, Nyboe-Andersen N, et al. 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Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study[J]. Am J Gastroenterol. 2016;111(8):1141\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta RS, Mayers JR, Zhang Y, et al. Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease[J]. Nat Med. 2023;29(3):700\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)[J]. Clin Infect Dis. 2018;66(7):e1\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNavaneethan U, Mukewar S, Venkatesh PG, et al. Clostridium difficile infection is associated with worse long-term outcome in patients with ulcerative colitis[J]. J Crohns Colitis. 2012;6(3):330\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaad Alshahrani A, Mohammad D, Attieh Alzahrani M, et al. Vedolizumab does not increase risk of clostridium difficile infection in patients with inflammatory bowel disease using vedolizumab: A retrospective cohort study[J]. Saudi Pharm J. 2023;31(9):101736.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlghamdi M, Alyousfi D, Mukhtar MS, et al. Association between vedolizumab and risk of clostridium difficile infection in patients with ulcerative colitis: A systematic review and meta-analysis[J]. Saudi J Gastroenterol. 2024;30(6):346\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoftus EV, Baumgart DC, Gecse K, et al. Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program[J]. Inflamm Bowel Dis. 2023;29(5):744\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis[J]. N Engl J Med. 2017;376(18):1723\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ulcerative Colitis, Clostridioides difficile, Infection, Risk Factors, Case-Control Study, Disease Activity","lastPublishedDoi":"10.21203/rs.3.rs-8776738/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8776738/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo identify independent risk factors for \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI) in patients with ulcerative colitis (UC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective case-control study was conducted at a tertiary hospital. Hospitalized UC patients diagnosed between January 2022 and December 2023 were included. Patients were categorized into a CDI-positive group (n\u0026thinsp;=\u0026thinsp;35) and a CDI-negative control group (n\u0026thinsp;=\u0026thinsp;154). CDI diagnosis followed a two-step algorithm (glutamate dehydrogenase [GDH] / toxin enzyme immunoassay [EIA] plus confirmatory toxin gene PCR). Independent risk factors were analyzed using Firth penalized logistic regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn multivariate analysis, active disease state (adjusted odds ratio [aOR]\u0026thinsp;=\u0026thinsp;0.01, 95% confidence interval [CI]: 0.00\u0026ndash;0.07; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and prior CDI history (aOR\u0026thinsp;=\u0026thinsp;4.86, 95% CI: 1.43\u0026ndash;20.08; P\u0026thinsp;=\u0026thinsp;0.011) were independent risk factors for CDI. Body mass index (BMI) at admission, recent antibiotic use, and 5-aminosalicylic acid (5-ASA) therapy showed no significant independent association.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eUC patients with active disease or a prior CDI history are at high risk for CDI and warrant enhanced surveillance and targeted preventive measures.\u003c/p\u003e","manuscriptTitle":"Risk Factors for Clostridioides difficile Infection in Ulcerative Colitis: A Single-Center Case- Control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 18:09:14","doi":"10.21203/rs.3.rs-8776738/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-23T06:46:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T04:25:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-14T18:52:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158712439552739447907519685584981399288","date":"2026-04-13T00:31:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-12T12:07:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-11T19:04:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"16629302501744513619718033520361539329","date":"2026-04-11T16:52:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-11T14:18:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"278497282429527465215048395255407289304","date":"2026-04-11T13:55:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306700634386656306832192268569292847792","date":"2026-04-11T08:09:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25611272336936748235914500654464925537","date":"2026-04-10T15:48:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320383525765334888887554838747084384013","date":"2026-04-10T00:28:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194273584405789179521338247778939744083","date":"2026-04-09T10:46:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14853542525190521325887448733749419662","date":"2026-04-09T05:29:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-02T04:54:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-31T05:22:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-06T19:04:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-04T20:35:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-03-04T13:20:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eedafb66-bb59-467e-9aac-b2c5f225e62e","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T16:23:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 18:09:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8776738","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8776738","identity":"rs-8776738","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}