Microbiota Transplantation Effectively Treats Immune Checkpoint Inhibitor-Associated Colitis: A Multi-Center, Retrospective Case Series

Abstract

Background: Immune-mediated colitis is an adverse effect of therapy with immune checkpoint inhibitors (ICIs). This study aims to evaluate the efficacy and safety of washed microbiota transplantation (WMT) in patients with ICI-associated colitis.

Methods: This multi-center, retrospective case series included six patients with ICI-associated colitis who received WMT between September 2023 and December 2025. Cases were voluntarily contributed by each center where data were available and complete and thus do not represent a complete consecutive case series.

Results: In total, 6 patients with ICI-associated colitis were included for analysis. Among all patients, 5 were male and 1 was female, with an age range of 46–71 years (mean 59.5 years). ICI-associated colitis occurred between cycle 1 and cycle 6 of ICI treatments. According to Common Terminology Criteria for Adverse Events (CTCAE) grading, 3 patients had grade 2, 2 had grade 3, and 1 had grade 4 colitis. Endoscopic findings included mucosal hyperemia, edema, erosion, or shallow ulcers; pathology predominantly showed chronic active inflammation. All 6 patients (100%) achieved clinical remission, with time to remission ranging from 3 to 7 days (4 patients within 5 days). At the last follow-up, all patients had recovered to 1–2 bowel movements per day with formed stools, and no clinical recurrence of colitis was observed during follow-up. No tumor progression occurred during or after WMT. Five patients subsequently resumed or continued anti-tumor therapy. No WMT-related adverse events were observed.

Conclusion: WMT is associated with rapid clinical remission of ICI-associated colitis with a favorable safety profile, and may create conditions for the resumption of anti-tumor therapy. It also shows salvage therapy potential for severe, steroid-refractory cases, although further prospective studies are needed.

Graphical abstract

Keywords

case report / fecal microbiota transplantation / immune checkpoint inhibitor-related colitis / microbiome / transendoscopic enteral tube

1 Introduction

The application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with various malignancies, however, the frequent occurrence of immune-related adverse events (irAEs) remains a major clinical challenge. Among the numerous adverse events, ICI-associated colitis is one of the most common gastrointestinal irAEs, and it can lead to treatment discontinuation, compromise antitumor efficacy, and even become life-threatening [1, 2]. Currently, first-line treatment for moderate to severe ICI-associated colitis primarily relies on corticosteroids. For patients who do not respond adequately, second-line immunosuppressive agents such as infliximab or vedolizumab are often required. This approach may increase the risk of infections and other complications; moreover, after treatment failure, patients frequently face a lack of effective therapeutic options, forcing the premature cessation of antitumor therapy.

In recent years, the role of the gut microbiota in regulating immune homeostasis and influencing ICI efficacy has attracted considerable attention. Studies have indicated that the composition and alterations of the gut microbiome are associated with the risk of irAEs [3]. This provides a theoretical basis for using microbiota-modulating interventions in the treatment of ICI colitis. Fecal microbiota transplantation (FMT), particularly its new technology, washed microbiota transplantation (WMT), has demonstrated a superior safety profile in recurrent Clostridioides difficile infection and in some cases of inflammatory bowel disease (IBD) [4]. Nevertheless, the efficacy and safety of WMT in ICI-associated colitis require further validation through clinical practice. Therefore, this multi-center retrospective case series study was conducted to analyze ICI colitis patients receiving WMT, summarizing their clinical characteristics, treatment outcomes, and safety profile, with the aim of providing decision-making evidence based on a larger sample size for clinical management.

2 Materials and Methods

2.1 Study Design and Patients

This study is a multi-center, retrospective case series aiming to describe the clinical application of WMT in patients with ICIs. We assembled expert teams from the First Hospital of Lanzhou University, the First Affiliated Hospital of Xi'an Jiaotong University, the Second Affiliated Hospital of Nanjing Medical University, Western Center Hospital of Shijiazhuang City, the Affiliated Suzhou Hospital of Nanjing University Medical School, and Wuxi People's Hospital to retrospectively analyze patients who received WMT while on ICIs. Inclusion criteria were (1) patients aged ≥ 18 years with histopathologically confirmed malignancies; (2) receipt of at least one cycle of ICI therapy, either as first-line or second-line treatment; (3) development of new or worsening intestinal symptoms (e.g., diarrhea, abdominal pain, or hematochezia) during ICI therapy; and (4) completion of at least one full cycle of WMT. Exclusion criteria were (1) diarrhea attributable to other definite causes, including infectious colitis (ruled out by negative stool cultures, C. difficile detection, and cytomegalovirus [CMV] and Epstein-Barr virus [EBV]), chemotherapy-related diarrhea, tumor-related bowel involvement, or pre-existing active uncontrolled IBD; and (2) severely missing clinical data or loss to follow-up that precluded assessment of the primary outcome.

2.2 Donor Selection and WMT Procedure

All microbiota suspensions used in this study were sourced from the China Microbiota Transplantation System, with consistent methodology and quality control [5]. Donor screening strictly adhered to the criteria of the Nanjing Consensus II on WMT [6], employing questionnaires, face-to-face interviews, and comprehensive blood and stool testing (including infectious disease pathogens and intestinal pathogenic bacteria) to exclude individuals with infectious disease risks or potential health problems. The preparation process for WMT followed the consensus standards: feces from qualified donors were subjected to gradient centrifugation, filtration, and purification using the automatic microfiltration machine to produce cryopreserved microbiota suspension, which was stored at −80°C. Each unit of enriched bacteria as one dose was delivered once. Prior to infusion, the suspension was thawed in a 37°C water bath. After colonic transendoscopic enteral tubing (TET) was placed using a single-use endoscopic drug delivery tube (FMT-DT-F-27/1350, Nanjing FMT Medical, China) under colonoscopic guidance, microbiota transplantation was performed via the TET tube. One unit was administered for 3 consecutive days, which constituted one standard course.

2.3 Data Collection

Data were collected by reviewing electronic medical record systems and reported according to the PRIM 2024 guidelines [7]. The following information was gathered: (1) demographics and tumor characteristics, including age, sex, primary tumor type, and stage; (2) immunotherapy-related information, including ICI type, regimen, treatment cycles, and whether ICI was withheld or discontinued due to colitis; (3) colitis characteristics and diagnosis, which comprised: (a) time of symptom onset, frequency of diarrhea, and presence of hematochezia, abdominal pain, and other clinical manifestations; (b) severity graded by the Common Terminology Criteria for Adverse Events (CTCAE); and (c) endoscopic and pathological findings; (4) prior treatments; (5) WMT treatment and outcomes, including transplantation route, number of transplant cycles, time to and degree of remission, resumption of anti-tumor therapy, and any WMT-related adverse events; and (6) follow-up, including clinical status at the last follow-up or at the time of death. Clinical remission was defined as improvement of diarrhea to grade ≤ 1 according to the CTCAE v5.0.

3 Results

3.1 Baseline Characteristics of Patients

3.1.1 Demographics and Tumor Characteristics

This study reported a total of 6 patients from six hospitals with ICI colitis between September 2023 and December 2025. Among them, there were 5 males (5/6) and 1 female (1/6), with an age range of 46–71 years and a mean age of 59.5 years. Primary tumor types included esophageal squamous cell carcinoma (1 case), gastric adenocarcinoma (2 cases), hepatocellular carcinoma (1 case), lung adenocarcinoma (1 case), and pulmonary mucinous adenocarcinoma (1 case). Cases 1–5 were all stage III or IV and Case 6 was stage IB.

3.1.2 ICI Treatment and Colitis Characteristics

All cases received ICI-containing combination regimens, and the ICI used was a programmed death 1 (PD-1) inhibitor in every case. The onset of colitis occurred between cycle 1 and cycle 6 of ICI treatment, with 4 cases developing within the first 3 cycles. According to CTCAE grading, there were 2 cases of grade 3 (2/6), 3 cases of grade 2 (3/6), and 1 case of grade 4 (1/6). The main clinical manifestations were diarrhea, mucopurulent bloody stools, or hematochezia; 83.3% (5/6) of patients had bloody stools, with peak daily bowel movements ranging from 6 times to 50 times. Patient 4 had the most severe symptoms, with watery bloody stools up to 50 times per day.

3.1.3 Endoscopic and Pathological Findings

Endoscopic examination revealed varying degrees of colonic mucosal hyperemia, edema, erosion, or shallow ulcers in all 6 patients; some showed purulent exudate, active bleeding, or white mucus adherence. Pathological findings were predominantly chronic active inflammation, with some cases showing inflammatory granulation tissue, inflammatory exudate, and crypt abscesses, consistent with the pathological features of immune-related colitis. All cases discontinued ICI therapy after the onset of colitis. Regarding prior treatment, 3 patients received systemic corticosteroids, and 1 patient received second-line therapy with infliximab; the remaining patients did not receive biologic agents. Conventional treatments were poorly effective in all cases.

3.1.4 Overview of the WMT Intervention Protocol

Accordingly, these patients underwent WMT. Regarding the route of WMT intervention, all 6 cases initially received colonic TET transplantation. In one patient, due to severe malnutrition, a nasojejunal tube was used for WMT combined with enteral nutrition during the second transplant cycle. The number of transplant cycles ranged from 1 to 3. During WMT, Patient 1 received concomitant dexamethasone enema, mesalazine suppository, and albumin infusion; Patient 2 had no specified concomitant medication; Patient 3 received concomitant mesalazine enema; Patient 4, due to concurrent Pneumocystis jirovecii pneumonia, received concomitant trimethoprim-sulfamethoxazole tablets and corticosteroids; Patient 5 received concomitant probiotics (live combined Clostridium butyricum triple and live combined Bacillus subtilis double); Patient 6 received concomitant mesalazine enteric-coated tablets and probiotics. Finally, patients were followed up after treatment completion, with follow-up durations ranging from 6 to 18 months (Table 1).

3.2 Treatment Response and Prognosis

The results showed that all 6 patients (100%) achieved clinical remission, with the time to remission ranging from 3 to 7 days, of which 4 patients achieved remission within 5 days. At the last follow-up, all 6 patients had recovered to 1–2 bowel movements per day with formed stools and achieved a clinical response. In terms of long-term outcomes, none of the patients experienced clinical recurrence of colitis. Regarding oncologic treatment outcomes, 5 patients resumed or continued anti-tumor therapy after WMT, while the remaining 1 patient did not restart anti-tumor therapy because expert evaluation deemed further treatment unnecessary. In terms of safety, no WMT-related serious adverse events were observed in any patient, nor were any WMT-related adverse events reported. These findings suggest that WMT may be associated with rapid symptom alleviation of immune-related colitis within a short period, has a favorable safety profile, and may create conditions for the subsequent resumption of anti-tumor therapy (Table 2).

3.3 Typical Case Presentation

3.3.1 Case Background and Diagnosis

Case 4 was a patient with severe, steroid-refractory, refractory immune-related colitis complicated by a serious infection. The patient was diagnosed with advanced lung cancer with liver and bone metastases. After receiving three cycles of serplulimab combined with chemotherapy, the patient developed severe diarrhea, with a maximum of 50 bowel movements per day, characterized by watery stools and hematochezia. Colonoscopy showed multiple linear bleeding erosions (Figure 1A). Histopathology revealed abundant infiltration of lymphocytes, plasma cells, and a few neutrophils in the interstitium, without obvious cryptitis or crypt abscesses, consistent with chronic active inflammatory changes. Comprehensive testing showed negative results for stool culture, C. difficile, CMV, and EBV, initially ruling out infectious diarrhea. It was also necessary to differentiate from colitis caused by other drugs, particularly chemotherapy-induced colitis. During chemotherapy, the patient did not experience common adverse reactions such as nausea, vomiting, or neutropenia. Given the onset of severe diarrhea after the third cycle of tumor therapy and the lack of response to conventional therapies, chemotherapy-induced toxicity was not supported. Pathological findings suggested immune-related enteritis. Therefore, the final diagnosis was ICI-associated colitis.

3.3.2 Treatment Course

The patient received sequential treatment with methylprednisolone, cefozoxime, levofloxacin, vancomycin, and total parenteral nutrition, but the colitis remained uncontrolled. During this period, the patient developed secondary Pneumocystis jirovecii pneumonia, along with severe malnutrition and cachexia. Body weight decreased by more than 12 kg from baseline, with a body mass index (BMI) of 20.3 kg/m². Laboratory evaluation showed hypoalbuminemia (albumin, 28.9 g/L), elevated C-reactive protein (CRP, 179.5 mg/L), and anemia (hemoglobin [Hb], 82 g/L). Under these circumstances, continued use of biologics such as infliximab would significantly increase the risk of infection spread and death. Therefore, after thorough discussion with the patient and family, WMT was chosen as the primary treatment regimen. The patient received WMT via a colonic TET tube for 3 consecutive days, using cryopreserved microbiota suspension from China Microbiota Transplantation System, with each dose comprising 1 unit of microbiota. Five days after the first WMT, the patient's symptoms improved rapidly: abdominal distension and pain almost disappeared, bowel movement frequency decreased from 6–10 times per day to 1–2 times per day, and stool consistency changed from watery to pasty. Follow-up tests showed CRP of 9.48 mg/L and Hb of 96 g/L. Three days after WMT, the patient was able to receive enteral nutrition and gradually transitioned to a liquid diet, with marked improvement in nutritional status. Chest computed tomography (CT) showed partial absorption of bilateral lung infection. The patient was discharged after stabilization. One month after discharge, the patient remained stable clinically, with diet transitioning from liquid to normal food. The colonoscopy conducted 1 month after first WMT showed mucosal hyperemia and erosion throughout the colon (Figure 1B). Therefore, a second WMT was performed.

After transplantation, the patient had normal bowel movements (once daily, yellow formed soft stools). During the 3-month follow-up after the first WMT, the patient's gastrointestinal symptoms had completely resolved. A colonoscopy showed a smooth colonic mucosa with clear vascular markings (Figure 1C). Considering the potential benefits of WMT in enhancing the efficacy of immunotherapy, the patient underwent a third WMT via TET into the colon. Albumin increased to 37.8 g/L and hemoglobin to 108 g/L, both showing a sustained upward trend. Body weight recovered from a nadir of 60 to 64 kg, indicating significantly improved nutritional status. Notably, the patient experienced no adverse events during any of the three WMT procedures and successfully resumed anti-tumor therapy after multidisciplinary evaluation.

3.3.3 Outcomes and Follow-Up

Although the patient eventually died due to tumor progression, severe respiratory failure, and multisystem complications, no recurrence of immune-related colitis was observed from the first WMT until death during follow-up, suggesting that WMT has good salvage therapy potential even for severe, complicated immune-related colitis.

4 Discussion

The advent of ICIs has significantly improved the prognosis of various advanced malignancies, but the accompanying irAEs have become a key focus and challenge in clinical management. This multi-center retrospective case series reports the application of WMT in ICI-associated colitis, providing new clinical evidence for microbiota-based interventions in this condition.

FMT was first reported for treating ICI-associated colitis in a case report published in 2018 [1], achieving favorable outcomes in a steroid-refractory patient. Since then, it has been mentioned as a potential emerging option for severe and refractory cases in some guidelines and expert consensus [8]. In the present study, all 6 patients achieved symptomatic relief after WMT, which is highly consistent with the findings of several key studies in recent years. Halsey et al. treated 12 patients with ICI colitis who were refractory to corticosteroids and biologics using FMT, reporting an 83% symptomatic improvement rate, a 92% clinical remission rate after repeated FMT, and a 42% rate of combined endoscopic and histologic remission. Responders showed a significant increase in gut microbiota α-diversity, elevated abundances of Collinsella and Bifidobacterium, and decreased infiltration of CD8+ T cells in the colonic mucosa of histologic responders [9]. Elkrief et al. treated five refractory patients with FMT, four of whom achieved clinical improvement, further confirming the reproducible efficacy of FMT in this population [10]. This study further extends the evidence from conventional FMT to WMT, a method that removes food residues, pro-inflammatory metabolites, and potential pathogens from feces through an automated process of separation, filtration, and purification, thereby further improving treatment safety and patient acceptance compared with FMT [11].

According to current guidelines, systemic corticosteroids remain the first-line treatment for moderate to severe ICI-associated colitis, while biologic agents such as infliximab or vedolizumab are recommended as second-line options for steroid-refractory patients [12]. However, studies have indicated that although corticosteroids play a key role in managing irAEs related to ICIs, they also induce co-inhibitory molecules such as PD-1, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3), thereby affecting ICI efficacy [13]. Regarding second-line treatment after corticosteroid failure, the study by Ruf et al. also pointed out that only about 74.3% of patients with steroid-refractory irAEs achieve remission after receiving second-line biologic therapy, while 4.3% still have persistent symptoms, 3.9% are left with permanent sequelae, and 4.3% die due to uncontrolled symptoms [14]. Therefore, exploring novel therapeutic approaches that can effectively control intestinal inflammation while preserving the anti-tumor efficacy of ICIs has become an urgent need in this field. WMT provides a new treatment option for refractory ICI-associated colitis. In the present study, all 6 patients achieved symptomatic relief after WMT. It is worth noting that all patients in this cohort had colitis associated with PD-1 monotherapy. Compared with colitis induced by CTLA-4 inhibitors or combination regimens, the immunopathological mechanism may be relatively more homogeneous, which might also be related to the favorable response rate to WMT [15]. Current guidelines still recommend a step-up treatment strategy. A recent study for the first time evaluated the safety and efficacy of FMT in seven patients with de novo immune-related colitis. It rapidly alleviated symptoms in most patients, avoided the use of corticosteroids and their associated complications, and allowed safe resumption of immunotherapy, providing preliminary evidence for FMT as an effective first-line treatment for ICI-associated colitis [16]. In our cohort, 3 patients achieved remission with WMT without receiving corticosteroids, and 2 patients without receiving biologics, suggesting that early application of WMT may be an effective and safe option for patients with newly diagnosed moderate to severe ICI colitis, particularly those on PD-1/programmed death-ligand 1 (PD-L1) inhibitor monotherapy without definite infectious contraindications. However, whether early use of WMT confers greater benefit to patients warrants further investigation through larger-scale studies. Furthermore, FMT/WMT is showing potential in both controlling irAEs and sensitizing immunotherapy. In 2021, Davar et al. and Baruch et al. used FMT from anti-PD-1 responders combined with PD-1 inhibitors in PD-1-refractory melanoma patients, achieving clinical benefit in 6 out of 15 patients and 3 out of 10 patients, respectively; these effects were accompanied by enhanced CD8+T-cell activation in the gut and tumor microenvironment, as well as favorable remodeling of immune cell populations [17, 18]. These studies collectively demonstrate that FMT from immunotherapy responders can help overcome resistance to anti-PD-1 therapy in melanoma patients. This suggests that microbiota remodeling may serve as a full-course intervention strategy for ICI therapy, with potential both in controlling established colitis and in restoring and enhancing anti-tumor immune responses.

The efficacy of WMT in ICI-associated colitis is not an isolated phenomenon but rather reflects a shared microbiota-based pathophysiological basis for cancer treatment-related intestinal injury. The incidence of tyrosine kinase inhibitor (TKI)-induced diarrhea/enteritis can reach 30%–50%. In a randomized controlled trial (RCT) involving patients with metastatic renal cell carcinoma, Ianiro et al. reported that donor FMT achieves a 100% complete remission rate at 1 week for TKI-induced diarrhea, significantly superior to the placebo group [19]. Regarding radiation enteritis, Ding et al. reported that FMT improves the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) toxicity grade by ≥ 1 grade in patients with chronic radiation enteritis [20]. Wang et al. showed that WMT is superior to conventional therapy for radiation enteritis, and Holdemanella biformis was identified as a key functional bacterium [21]. Tu et al. revealed that FMT could repair radiation-induced injury by modulating microbiota-mediated tryptophan metabolism [22]. Collectively, this evidence across different cancer types and treatment modalities suggests that regardless of whether the initial trigger of intestinal injury is immune activation, epithelial toxicity, or radiation damage, microbiota remodeling may represent a common intervention target. Future head-to-head comparative studies with larger sample sizes are warranted to determine the optimal donor selection, timing of transplantation, and dosing regimen of FMT in different cancer treatment contexts.

Although this study did not perform longitudinal microbiome or immune profiling, the rapid clinical improvement observed is consistent with prior reports that microbiota reconstitution may alleviate ICI-associated colitis through immune modulation [9, 10]. The underlying mechanism may be associated with increased gut microbial α-diversity, elevated abundance of beneficial taxa, and reduced infiltration of inflammatory immune cells such as CD8+T cells and CD68+macrophages in the colonic mucosa following FMT [10, 23]. However, the specific mechanisms await direct validation through integrated multi-omics analyses in future prospective studies. Regarding safety, no patients in this study experienced WMT-related serious adverse events, and Case 4 showed favorable tolerability despite severe immunocompromise. A meta-analysis by Berry [24] et al. in immunocompromised patients further indicated that the safety profile of FMT in mildly to moderately immunocompromised populations is comparable to that in immunocompetent cohorts. In conclusion, WMT has a favorable safety profile in patients with ICI-associated colitis, supporting its use as a salvage therapy option in this population, while its potential role as first-line treatment requires further investigation.

This study has several limitations. First, as a retrospective case series, the small sample size and lack of a control group limit the generalizability of our findings and preclude any conclusions regarding the comparative efficacy of WMT versus standard care. Second, the cases were enrolled in a non-consecutive manner, which may introduce selection bias. Third, several patients received concomitant medications including corticosteroids, mesalazine, and probiotics, which constitute confounding factors that prevent us from attributing the observed clinical remission solely to WMT. Although the temporal association of symptom improvement occurring within 3–7 days after WMT suggests a role for WMT, the uncontrolled design precludes us from establishing causality. Nevertheless, this case series fully documents the application process and favorable outcomes of WMT, providing preliminary evidence for future prospective studies.

5 Conclusions

This multi-center case series suggests that for ICI-associated colitis, WMT may be a safe and potentially effective salvage strategy capable of rapidly inducing clinical remission and potentially enabling patients to resume anti-tumor therapy. Prospective, multi-center, randomized controlled trials are necessary to confirm its efficacy and to determine the optimal timing and regimen. At the same time, multi-omics analyses should be integrated to elucidate the underlying mechanisms and to explore predictive biomarkers of response, ultimately advancing this therapy toward precision and individualized application.

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