Comparative Efficacy of Fecal Microbiota Transplantation in Treating Refractory or Recurrent Clostridioides difficile Infection among Patients with and without Inflammatory Bowel Disease: A Retrospective Cohort Study

Clostridioides difficile infection (CDI) worsens inflammatory bowel disease (IBD) prognosis. While fecal microbiota transplantation (FMT) is effective for refractory or recurrent CDI (rrCDI), comparative success rates between IBD and non-IBD patients are scarce. This study addresses this gap. A retrospective cohort study was conducted at Chang Gung Memorial Hospital from April 2019 to October 2023. Patients receiving FMT for rrCDI were categorized into IBD and non-IBD groups. Baseline characteristics and outcomes were compared at one month and one year, with successful FMT defined as the resolution of diarrhea without CDI recurrence. The study included 88 patients: 30 with IBD and 58 without IBD. The IBD group was younger, with fewer comorbidities. Success rates at one month were similar between groups (IBD: 80.0% vs. non-IBD: 78.9%, p = 0.908), as were negative toxin tests (IBD: 83.3% vs. non-IBD: 63.8%, p = 0.174). One-year success rates (IBD: 70.0% vs. non-IBD: 67.6%, p = 0.857) and eradication rates (IBD: 94.4% vs. non-IBD: 73.9%, p = 0.112) were also similar. Poor bowel preparation predicted FMT failure at one month (OR = 0.23, p = 0.019). No safety issues were reported. FMT is a safe, effective treatment for rrCDI, demonstrating similar success rates in patients with and without IBD.


Introduction
Clostridioides difficile infection (CDI) is a prevalent healthcare-associated infection with a recurrence rate of 15-20% and a mortality rate of 5% [1][2][3].Its incidence is rising in both adults and children, posing a significant challenge in healthcare settings globally [4][5][6].Risk factors for CDI include advanced age, hospitalization, certain underlying illnesses like cancer and inflammatory bowel disease (IBD), recent antibiotic usage such as cephalosporins and quinolones [7,8], and the use of proton pump inhibitors (PPIs) [5,9].IBD is an independent risk factor for CDI, even in the absence of traditional risk factors [10].In individuals without IBD, the prevalence of CDI is around 0.45% [11].However, for those with IBD, the risk is significantly higher, with reported incidence rates two to eight times greater than for those without IBD [4,[12][13][14][15], particularly among those with ulcerative colitis (UC) [11,16].The increasing use of advanced therapies, such as biological therapies and small molecules like infliximab and adalimumab, in IBD treatment has led to a rapid increase in CDI prevalence among this population [10,17].CDI is responsible for about 19% of acute IBD flare-ups [18,19].Additionally, it leads to poorer clinical outcomes, including a higher risk of IBD therapeutic escalation, readmission, emergency department visits, colectomy, severe disease course, and even mortality [17,[20][21][22][23][24][25].Moreover, treatment failure and recurrence rates are much higher in patients with IBD compared to the general population [10,15].
Fecal microbiota transplantation (FMT) is an effective and safe treatment for refractory or recurrent Clostridioides difficile infection (rrCDI) [9,[26][27][28][29][30], endorsed by international guidelines [10,15,[31][32][33][34][35][36].In contrast to standard antibiotics, which can exacerbate gut dysbiosis and contribute to CDI, FMT works by reinstating the normal microbial community structure and function in the gut [37].Therefore, it leads to higher successful rates and lower recurrent rates in treating CDI [9,32].A network meta-analysis and systematic review of randomized controlled trials have also demonstrated that FMT is the most efficacious among various therapeutic interventions, particularly when compared to commonly used antibiotics such as vancomycin or fidaxomicin [38,39].Previous studies indicate success rates of 73% for vancomycin and 62.9% for fidaxomicin, with both treatments being associated with a high recurrence rate [40].
FMT is not only effective for the treatment of recurrent CDI in patients without IBD, but also for those with IBD [41,42].The Rome consensus recommends FMT as a treatment option for both mild and severe recurrent or refractory CDI in patients with IBD [15].However, previous studies have shown conflicting results regarding the success rate of FMT in treating CDI between patients with and without IBD.Some studies suggest that FMT is less effective in patients with IBD compared to those without IBD [37], while others indicate similar success rates between the two groups [3,41,42].Due to the lack of shortand long-term data on FMT efficacy (most studies focus on recurrence rates within 1 to 3 months post-transplant), this study aimed to compare the short-and long-term success rates of FMT between both groups and identify predictors of FMT failure to provide valuable insights into personalized treatment strategies for CDI.

Compliance with Ethical Standards
This retrospective study was approved by the Institutional Review Board (IRB) of Chang Gung Medical Foundation (approval No. 202400814B0) under the project titled "Microbiota Transplantation for the Treatment of Refractory or reccurent Clostridioides difficile Infection and Prognostic Study".Due to its retrospective design, the IRB waived the requirement for individual patient consent for the review of medical records.

Patients
In this retrospective cohort analysis, the patients enrolled underwent FMT via colonoscopy for rrCDI at Chang Gung Memorial Hospital in Linkou, Chiayi, and Kaohsiung between April 2019 and October 2023.Participants were divided into two groups based on their underlying conditions: the IBD group and the non-IBD group.The analysis thoroughly investigated risk factors, clinical presentations, and outcomes associated with each group.Donor specimens were obtained from the fecal bank at Chang Gung Microbiota Therapy Center.

Definitions
Successful FMT is defined as the resolution of diarrhea and no recurrence of CDI within one month and one year [3,26,37,43,44].Recurrence of CDI is characterized by recurrent diarrhea along with laboratory confirmation of positive CD toxin A/B tests [3,10,26,37,[44][45][46].CDI itself is defined by diarrhea (≥3 loose or watery stools per day for at least 2 consecutive days or ≥8 loose stools in 48 h) and a positive stool test for CD toxin [3,26,36,37,44,46].The Mayo score, a widely employed disease activity index in placebo-controlled trials for UC, consists of four components: rectal bleeding, stool frequency, physician assessment, and endoscopy appearance [9,47].Each component is assigned a rating from 0 to 3, resulting in a total score ranging from 0 to 12. Mildly active disease is indicated by a score of 3 to 5 points, moderately active disease by a score of 6 to 10 points, and severely active disease by a score of 11 to 12 points.Two shortened versions, namely the partial Mayo score (excluding the endoscopy subscore) and the non-invasive six-point score (comprising only rectal bleeding and stool frequency) [9,48] have been developed and validated.

Data Collection
Comprehensive data, including demographic information (age, gender, BMI), IBD type, Crohn's Disease Activity Index (CDAI), Mayo score, underlying diseases, antibiotics used for CDI treatment (e.g., Metronidazole, Vancomycin, Fidaxomicin), degree of bowel cleansing, location of FMT transplant, IBD medication (Steroid, Biologics), and associated clinical symptoms (fever, diarrhea, abdominal pain, bloody stools) were meticulously collected from the medical records of qualifying participants.Key laboratory values such as total white blood cell count, hemoglobin, C-reactive protein, and albumin levels were recorded, along with instances of mortality or the date of the last follow-up.

Statistical Analyses
Descriptive statistics were utilized to present continuous variables as mean and standard deviation, and categorical variables as counts or percentages.The Student's t-test was employed for the analysis of continuous variables, while categorical variables were analyzed using either the chi-squared test or Fisher's exact test, depending on the data distribution.A p-value of less than 0.05 was considered statistically significant.To investigate potential predictors for the success rate of FMT, a logistic regression model was applied.First, univariate logistic regression analysis was conducted with all predictors.Then, factors with a p-value less than 0.05 were selected for multivariate logistic regression analysis.If only one factor had a p-value less than 0.05, all factors with p-values less than 0.2 were included in the multivariate logistic regression analysis.All statistical analyses were conducted using SPSS version 26.0 (Armonk, NY, USA, IBM Corp).

Baseline Characteristics and Clinical Outcome
Our study enrolled 88 patients who underwent FMT via colonoscopy for rrCDI between April 2019 and October 2023.This cohort comprised 30 patients in the IBD group and 58 in the non-IBD group.The primary indications for FMT were refractory CDI in 54 patients, recurrent CDI in 31 patients, and both conditions in 3 patients.Within the IBD subgroup, 20 patients had UC and 10 had CD.

The Clinical Outcomes of rrCDI after FMT
At one-month follow-up, disease severity improved in the IBD group, with the mean partial Mayo score decreasing by 2.9 points, the endoscopic Mayo subscore decreasing by 0.7 points, and CDAI decreasing by 79.98 points.The IBD group exhibited similar negative CD toxin A/B test rates (83.3% vs. 63.8%,p = 0.174) and FMT success rates (80.0% vs. 78.9%,p = 0.908) compared to the non-IBD group at this time.One year after FMT, the disease activity of the IBD group further improved, with the mean partial Mayo score decreasing by 4.09 points, the endoscopic Mayo subscore decreasing by 0.82 points, and CDAI decreasing by 135.81 points.The eradication rate (94.4% vs. 73.9%,p = 0.112) and success rates of FMT (70.0% vs. 67.6%,p = 0.857) were comparable between both groups.No safety issues or adverse effects were reported.Success rates of FMT were defined as the absence of CDI recurrence within the follow-up period.Further laboratory findings and clinical outcomes are detailed in Table 2.

Predictors for Successful FMT
One month after FMT, poor bowel preparation was the only negative independent predictor for successful FMT in the multivariate logistic regression analysis (OR = 0.230, 95% CI = 0.067-0.785).During the one-year follow-up, liver cirrhosis and the use of Fidaxomicin were negative independent predictors for successful FMT in the multivariate logistic regression analysis.Liver cirrhosis was associated with a decreased success rate (OR = 0.056, 95% CI = 0.005-0.586),and the use of Fidaxomicin for treating CDI also showed reduced success rates (OR = 0.151, 95% CI = 0.033-0.680).More detailed insights can be found in Tables 3 and 4.

Discussion
CDI significantly worsens the prognosis of IBD.However, the treatment of CDI with antibiotics often results in low success rates and high recurrence rates.Our study highlights several critical findings regarding the use of fecal microbiota transplantation (FMT) for treating rrCDI in patients with and without IBD.Despite previous conflicting reports, our data suggest that FMT is equally effective in both patient groups.
In our cohort, the non-IBD group consisted of older patients with a higher prevalence of diabetes mellitus, cancer, and hypertension, which aligns with existing literature indicating a higher risk of CDI in older individuals with comorbidities [3,49].Previous studies have shown that fidaxomicin has similar efficacy and safety to vancomycin [50].The higher use of fidaxomicin in the non-IBD group suggests that patients without IBD are more likely to be treated with this second-line antibiotic, whereas IBD patients might prefer FMT due to its potential to improve inflammation concurrently with treating CDI.Although statin use has been associated with severe or complicated CDI in IBD patients [51], the higher rate of HMG-CoA reductase inhibitor use in the non-IBD group in our study can be explained by the older age and higher prevalence of hyperlipidemia and other comorbidities in these patients.
Our results showed no significant difference in the CDI clearance rate and overall success rate of FMT between patients with and without IBD, corroborating findings from the other study [3].These findings suggest that FMT's efficacy in treating rrCDI does not significantly differ based on the presence of IBD, despite initial concerns about IBD potentially complicating FMT outcomes.In comparison, another retrospective study found that the effectiveness of FMT in treating recurrent CDI was lower in patients with IBD (CDI clearance rates of 74.4% and 92.1%, respectively; p = 0.001) [37].This discrepancy may be due to differences in study design, patient demographics, and definitions of success.
We observed that poor bowel preparation was a significant predictor of FMT failure at one month ([OR] 0.230, 95% [CI] 0.067-0.785),emphasizing the importance of adequate bowel cleansing before FMT.This finding underscores the need for rigorous pre-FMT preparation protocols to enhance treatment success.Additionally, liver cirrhosis and prior fidaxomicin use emerged as negative predictors for FMT success at one year ([OR] 0.056, 95% [CI] 0.005-0.586and [OR] 0.151, 95% [CI] 0.033-0.680,respectively).These factors suggest that patients with severe underlying conditions or those who have undergone extensive antibiotic treatment may require additional monitoring and tailored therapeutic approaches.
Our study's strengths include comprehensive follow-up, providing robust data on the long-term efficacy of FMT in both IBD and non-IBD patients.However, the retrospective design and single-center setting, along with a relatively small sample size, may limit generalizability.Future prospective, multicenter studies are warranted to validate these findings and explore additional factors influencing FMT outcomes.

Conclusions
FMT via colonoscopy is an effective treatment for rrCDI, demonstrating similar success rates in patients with and without IBD.However, specific patient populations, particularly those with poor bowel preparation, liver cirrhosis, or prior fidaxomicin use, may experience lower success rates.These findings highlight the importance of tailored patient management to optimize FMT outcomes.Further research should focus on refining pre-FMT protocols and identifying additional predictors of success to enhance the efficacy and safety of FMT in diverse patient populations.

Table 1 .
Baseline characteristics of inflammatory bowel disease patients and non-inflammatory bowel disease patients.

Table 2 .
Clinical outcomes of Clostridioides difficile infection in inflammatory bowel disease patients and non-inflammatory bowel disease patients one month and one year after FMT.
Abbreviations: BMI, body mass index; CDAI, Crohn's disease activity index; IBD, inflammatory bowel disease.Definition of successful rate is defined as a resolution of diarrhea and no recurrence of CDI within one month and one year following FMT.

Table 3 .
Predictor for successful FMT at one month: univariate and multivariate logistic regression analysis.

Table 4 .
Predictor for successful FMT at one year: univariate and multivariate logistic regression analysis.