Safety and efficacy of fecal microbiota transplantation for cytotoxic chemotherapy– induced diarrhea management in patients with colorectal cancer: a single-arm clinical trial

doi:10.21203/rs.3.rs-4373410/v1

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Safety and efficacy of fecal microbiota transplantation for cytotoxic chemotherapy– induced diarrhea management in patients with colorectal cancer: a single-arm clinical trial

https://doi.org/10.21203/rs.3.rs-4373410/v1

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Background

Diarrhea is a serious complication noted in colorectal cancer (CRC) patients undergoing cytotoxic chemotherapy, which impacts both their quality of life and treatment adherence. Here, we assessed the safety and efficacy of fecal microbiota transplantation (FMT) for chemotherapy-induced diarrhea (CID) management in patients with CRC.

Methods

This open-label, single-arm trial included 20 CRC patients experiencing grade 2 or 3 CID, in whom conventional standard antidiarrheal treatments had been ineffective. A single course of FMT was administered within a 2-week interval. Each course consisted of 90 capsules (totaling approximately 18 × 10¹¹ CFU bacteria), administered orally three times a day on days 1, 2, and 3. The patients’ changes in diarrhea severity, microbiome composition (16S rRNA gene sequencing), and immune function (flow cytometry) were assessed before and after FMT (over 12 weeks).

Results

Diarrhea cessation was noted in 17 (85%) of all 20 patients after one or more FMT cycles over at least 12 weeks. FMT also led to significant improvements in gut microbiota diversity along with significant increases in B (CD19⁺) cells (p = 0.0001), cytotoxic T ( CD3⁺CD8⁺) cells (p = 0.0010), and natural killer cells (p = 0.0002). No major adverse events were noted.

Conclusions

Our preliminary evidence suggests that FMT is a safe, potentially effective approach for managing CID in patients with CRC.

Trial registration:

Chictr.org.cn, ChiCTR2100049431 (Date assigned: Agusta 8, 2021). https://www.chictr.org.cn/showproj.html?proj=131083

Colorectal Cancer

Cytotoxic chemotherapy

Diarrhea

Fecal microbiota transplantation

Chronic diarrhea is a prevalent, debilitating side effect of chemotherapy for colorectal cancer (CRC) [1]. Chemotherapy-induced diarrhea (CID) affects 50–80% of patients [2], with approximately 30% suffering from severe CID, classified as grade 3 or 4 diarrhea in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The condition results in prolonged hospitalization and is associated with a considerable mortality risk [3]. Currently available treatments for CID, including loperamide, probiotics, and octreotide, often have inadequate therapeutic effects [4]. In particular, loperamide not only causes constipation but also provides inadequate control in severe CID cases. Moreover, probiotics demonstrate variable efficacy. Finally, octreotide, which is often used to control severe diarrhea, may not be effective in some cases; it may also lead to side effects such as abdominal cramps [5]. The aforementioned treatments largely target the symptoms rather than the underlying causes, such as microbiota imbalance [6]. Therefore, their impact on patient outcomes is limited, highlighting the necessity for more effective interventions for CID.

Fecal microbiota transplantation (FMT) involves administration of fecal material, including bacteria and natural antibacterial substances, from a healthy donor to a recipient with a specific disease condition [7–9]. The applicability of FMT for modifying gut microbiota has been explored in various disease models and clinical trials, garnering considerable attention [10–14]. Notably, FMT is valued for its high cure rate (> 90%) and minimal associated side effects, making it a potentially life-saving intervention for recurrent Clostridium difficile infections [15]. As such, its applicability to other gastrointestinal and inflammatory disorders has also been explored [16, 17]. In patients with inflammatory bowel disease or syndrome, FMT has been noted to engender clinical improvement and remission.

FMT may also be a therapeutic option for diabetes, obesity, nonalcoholic fatty liver disease, and even cardiovascular diseases [15, 18]. Although the precise molecular and cellular mechanisms underlying the effects of FMT remain unclear, the process is hypothesized to involve interactions between the donor’s and recipient’s gut microbiota, influencing the recipient’s physiology, gut mucosal barrier, and immune system [19]. Consequently, FMT might be an effective strategy for manipulating gut microbiota, thereby reducing inflammation and CID severity.

In this study, we evaluate the safety and efficacy of FMT in the management of grade 2 or 3 diarrhea among CRC patients undergoing cytotoxic chemotherapy [20]. We hypothesize that FMT treatment substantially alleviates CID severity in patients with CRC.

Study design and participants

This 12-week, single-arm, phase II trial was conducted at South Hubei Cancer Hospital Center, Huazhong University of Science and Technology, China. We evaluated the efficacy and safety of FMT in stage IV CRC patients undergoing cytotoxic chemotherapy for reducing the severity and duration of grade 2 or 3 CID, according to CTCAE v5.0 [20], in whom conventional antidiarrheal treatments were ineffective for 7–10 days. Eligible participants were aged ≥ 18 years, provided written informed consent, had pathologically and radiologically confirmed stage IV CRC according to American Joint Committee on Cancer (AJCC), demonstrated a lack of response to standard antidiarrheal treatments, possessed a life expectancy of > 6 months, Patients willingly agreed to undergo chemotherapy consisting of Oxaliplatin 130mg/m² on day 1, with oral of capecitabine 1000mg/m² day 1–14, every 21 days, and exhibited adequate organ function. However, we excluded patients who have diarrhea prior to chemotherapy treatment, had severe immunodeficiency, had an active infection, had a history of severe allergic reactions to FMT components, Patients diagnosed with other gastrointestinal conditions, such as ulcerative colitis and Crohn's disease, had active inflammatory bowel disease, had recently taken antibiotics, had a bleeding disorder, had a recent history of gastrointestinal bleeding, or were pregnant.

Baseline assessments

Before undergoing FMT, the patients provided their demographic information and underwent diarrhea severity assessment based on CTCAE v5.0. In this assessment, diarrhea severity was graded on a scale of 0–4 [20]; Grade 0: no diarrhea, Grade 1: an increase of fewer than four stools per day compared with that before treatment, Grade 2: an increase of four to six stools per day compared with that before treatment or nocturnal stools, Grade 3: an increase of seven or more stools per day compared with that before treatment, incontinence, or a necessity for intravenous hydration due to dehydration, Grade 4: severe physiological effects necessitating intensive care or resulting in hemodynamic collapse. The patients were also asked to provide stool samples, collected in sterile, sealed containers and preserved at − 80°C for analyzing 16S rRNA.

Intervention

Fecal microbiota transplant preparation

We screened children’s stools in the Gannan mountainous region in Jiangxi, China. As illustrated in Fig. 1, qualified fecal donors were chosen through rigorous screening procedures (including questionnaire screening, blood and fecal testing, and 16S rRNA sequencing of gut microbiota), as reported previously [21].

Fecal microorganisms were extracted and subjected to serial dilution. Next, the various dilutions were cultured aseptically on our selected culture medium under low temperature and anaerobic conditions; next, the samples were retained, stirred, diluted, filtered, centrifuged, packaged, and frozen at − 80°C until further use. Subsequently, the bacterial suspensions were freeze-dried using advanced vacuum freeze-drying technology; the obtained freeze-dried powder was encapsulated in healthy enteric bacteria capsules, ensuring that the enteric bacteria capsule activity was > 90% and the viable bacteria count exceeded 2 × 10¹⁰ colony forming units (CFU; Supplementary Fig.S1). All FMT capsules used in this study were procured from Jiangxi Shanxing Biotechnology (Nanchang, Jiangxi, China).

FMT procedures

After baseline assessments, one course was performed at 2-week intervals. In total, 90 capsules, including approximately 18 × 1011 CFU bacteria (i.e., 10 capsules three times a day on days 1, 2, and 3), were administered to each patient orally. All capsules were transported on ice and incubated at 37°C for 10 min before administration. Next, the capsules were administered to the patients by authorized physicians in a monitored clinical setting. The patients were asked to fast for 4 h before and 1 h after capsule administrations; they were also instructed to maintain stable dietary and physical activity patterns throughout the study period.

Outcomes

The primary outcome was a change in diarrhea severity according to CTCAE v5.0. Moreover, the secondary outcomes were changes in gut microbiota composition and any adverse events (AEs).

Data collection and monitoring

Between July 2022 and August 2023, we enrolled 20 patients diagnosed as having stage IV CRC and then performed posttreatment monitoring, both manually and by using intelligent follow-up systems.

All patients were evaluated at baseline (week 0) and subsequently within 12 weeks after interventions. Each assessment included a comprehensive physical examination, various laboratory tests, and specific evaluations focused on diarrhea frequency and consistency. The primary endpoint of this study was the proportion of patients who experienced a clinically significant change in diarrhea severity by week 12 based on CTCAE v5.0.

We also evaluated FMT’s safety profile. At each visit, we meticulously recorded the incidence and severity of any AEs. These events were categorized on the basis of their severity, ranging from mild to severe, and analyzed in relation to their potential association with the FMT procedure.

Flow cytometric analysis

Peripheral blood samples (2 mL each) were collected to evaluate immune function through flow cytometry (BD Canto II, Grand Island, NY, USA). The samples were obtained 1–3 days before and 3–5 days after. The analyzed parameters included the numbers and functionality of lymphocytes in the peripheral blood. The proportions of total T cells (normal range: 50–84%), CD19⁺ cells (normal range: 5–18%), CD3⁺CD8⁺ cells (normal range: 15–44%), CD3⁺CD4⁺ cells (normal range: 27–51%), natural killer (NK) cells (normal range: 7–40%), and the CD4/CD8 ratio (normal range: 0.71–2.87) were quantified using the BD Multitest 6-color TBNK reagent kit (B000890; Agilent), according to the manufacturer’s instructions. Immune function was considered normal if the aforementioned cell proportions were within or higher than their normal ranges, whereas if they were lower than their normal ranges, immune function was considered abnormal.

Fecal microbiota 16S rRNA gene sequencing

Polymerase chain reaction–based amplification for the V4 region of bacterial 16S rRNA gene was performed. Sample-specific paired-end 6-bp barcodes were incorporated into the TrueSeq adaptors for multiplex sequencing. Next, 2 × 150-bp pair-end sequencing was performed on the Illumina NovoSeq6000 platform at Guhe Info Technology (Hangzhou, China).

Statistical analysis

Demographic and clinical variables are summarized using descriptive statistics. Continuous and categorical variables are reported as means ± standard deviations and numbers (percentages), respectively. We used the paired t test to analyze the changes in immune function before and after FMT. P < 0.05 was considered to indicate statistical significance. Stata (version 17) was used for all analyses unless indicated otherwise.

Ethics

This study was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonization’s Good Clinical Practice guidelines, and relevant local laws. The Ethics Committee of South Hubei Cancer Hospital reviewed and approved our study protocol (approval number 2020-01). This study was also registered in Chinese Clinical Trial Registry (ChiCTR 2100049431). Finally, written informed consent was obtained from all participants before their inclusion in the study.

Patient characteristics

In total, 20 patients [13 (65%) men and 7 (35%) women] participated in this study. Their mean patient age and body mass index were 63.85 ± 8.76 years and 18.05 ± 1.68 Kg/m², respectively (Table 1). All patients had received systemic chemotherapy; of them, 18 and 2 presented with grade 2 and 3 diarrhea according to CTCAE v5.0, respectively. In total, 31 treatment cycles were administered during the study period; specifically, 14 and 6 patients completed one and two treatment cycles, respectively (Fig. 2).

Table 1

Baseline demographics and characteristics of the included patients
Characteristic	Patients (n = 20)
Age, years	63.85 ± 8.76
Sex
Male	13 (65)
Female	7 (35)
Cancer type
Rectum cancer	3 (15)
Appendix cancer	2 (10)
Colon cancer	15 (75)
Body mass index, kg/m²	18.05 ± 1.68
Karnofsky performance status score
60%	3 (15)
70%	10 (50)
80%	7 (35)
Data are present as either number of patients (%) or mean + standard deviation.

Safety evaluation

All sessions were administered successfully. However, one patient complained of abdominal pain, one demonstrated nausea, and two presented with vomiting; all four patients recovered without any medical intervention (Supplementary Table .S1).

Clinical efficacy

We assessed alterations in gut microbiota by comparing the 16S rRNA gene sequences 1–3 days before and 10–14 days after FMT (Fig. 3). The preliminary results demonstrated that gut microbiota diversity increased, with significant structural changes, after FMT. This indicated that FMT is highly safe and efficacious, providing a foundation for further clinical application and efficacy observation of FMT. The results are demonstrated using bar charts of relative abundance of species (top 10) at phylum (left panel) and genus (right panel) levels before and after FMT. LefSe analysis was performed to assess significant changes in gut microbiota composition after FMT. We noted that after FMT, the abundance of Coriobacteriaceae and Collinsella increased significantly.

Alterations in immune function

We compared the immune function before and after FMT. In all patients, pretreatment data were merged and compared with posttreatment data (Table 2). The impact of FMT on various immune markers was investigated, and the findings revealed significant alterations in immune cell populations after FMT. In particular, the proportions of CD19⁺ (B) cells (p = 0.0001), CD3⁺CD8⁺ (cytotoxic T) cells (p = 0.0010), and NK cells (p = 0.0002) demonstrated significant increases after FMT. Moreover, the CD4/CD8 ratio exhibited a considerable but nonsignificant change. These results suggested that FMT can significantly modulate the immune system, increasing the populations of certain immune cells.

Table 2

Immune function before and after FMT
Items (cells/µL)	Before FMT (Mean ± SD)	After FMT (Mean ± SD)	Mean difference (95% CI)	p
Total T cells	58.67 ± 7.89	61.56 ± 18.81	-2.89(-22.99, 17.22)	0.7441
CD19⁺cells	6.199 ± 3.39	12.02 ± 3.65	-5.82(-7.60, -4.04)	0.0001
CD3⁺CD8⁺ cells	19.11 ± 3.00	24.99 ± 4.10	-5.88( -8.47, -3.30)	0.0010
CD3⁺CD4⁺ cells	32.81 ± 9.87	34.61 ± 8.37	-1.80(-5.10, 1.51)	0.2390
NK cells	19.30 ± 5.27	27.18 ± 4.17	-7.88( -10.53, -5.23)	0.0002
CD4/CD8 ratio	1.74 ± 0.55	1.90 ± 0.49	-0.16( -0.53, 0.21)	0.3390
Bolded p values are significant.

Clinical response

Resolution of diarrhea was achieved in 14 out of 20 patients (70%) after undergoing a single FMT. A repeat FMT was administered for the remaining six patients (30%) who either experienced recurrence or did not respond adequately to the initial FMT. Among these six patients, three were successfully cured (Fig. 4).

Follow-up

Over the 12 weeks of observation, nearly all patients demonstrated a positive response without diarrhea recurrence. This positive response, defined as the resolution of diarrhea after one or more FMTs within at least 12 weeks, was observed in 17 (85%) patients (Fig. 5).Over the 12 weeks of observation, nearly all patients demonstrated a positive response without diarrhea recurrence. This positive response, defined as the resolution of diarrhea after one or more FMTs within at least 12 weeks, was observed in 17 (85%) patients (Fig. 5).

Chemotherapeutic protocols employed for gastrointestinal malignancies disrupt the gut equilibrium, causing severe gastrointestinal toxicity and considerably diminishing the patient’s quality of life [22, 23]. Hamouda et al. [24] reported that dysbiosis due to 5-fluorouracil (5-FU) led to intestinal mucosal damage in a mouse model and suggested that modifying the gut microbiome through oral administration of either broad-spectrum antibiotics or probiotics can alleviate mucosal damage in the small intestine. However, the dysbiosis resulting from 5-FU treatment could further exacerbate intestinal mucosal injuries. The clinical importance of gut microbiota in the field of oncology is being increasingly emphasized, prompting further investigation into its use for treating conditions potentially affected by the microbiome [25–27].

In general, FMT has been noted to modify gut microbiota, as well as reduce inflammation and mucositis severity, in patients undergoing chemotherapy. FMT has promising therapeutic potential for managing chemoradiotherapy-related gastrointestinal side effects in patients with cancer [28]. In the current study, 70% of the patients demonstrated primary resolution of CID after a single FMT cycle, with an additional 15% demonstrating improvement after two cycles. However, 15% of the patients continued demonstrating chronic diarrhea of unclear etiology after FMT. Notably, one of the patients, who experienced long-term diarrhea, passing stool approximately eight times daily, could not continue their anticancer treatment initially; after two courses of FMT, their diarrhea was completely controlled, enabling them to resume chemotherapy. Thus, in addition to considerably improving the quality of life in most patients with CRC, FMT demonstrates substantial therapeutic safety [29]. Furthermore, one of our patients who demonstrated diarrhea control after FMT was presumed to have CRC originating from the stomach—which highlighted the complexity of cancer pathogenesis and the potential of FMT in modulating gastrointestinal health. Overall, these findings support the efficacy and safety of FMT in mitigating AEs of cancer treatments, warranting further research into relevant underlying mechanisms and broader applications [30]. Both experimental and clinical investigations have revealed substantial correlations among microbial taxa, intestinal dysbiosis, treatment-induced toxicity, and anticancer therapy effectiveness [31–34].

Our findings also revealed substantial changes in the proportions of immune cells after FMT. Gut microbes play a major role in regulating the host immune system through various mechanisms [35]. For instance, they influence the local immune responses in the gut mucosa and facilitate communication between gut commensals and mucosal immune cells [36, 37]; moreover, they can prime immune cells systemically. The relationship between gut microbiota and the host immune system is dynamic—with different gut microbiota compositions impacting the overall immune balance of the host differently [38].

The current study highlights the potential of using FMT to enrich gut microbiota diversity and structure in patients with cancer. We used bar charts to visualize the relative abundance of the top 10 species at both phylum and genus levels before and after FMT; the results demonstrated considerable shifts in gut microbiota composition after FMT. Notably, a notable post-FMT increase was observed in the abundance of species from the phyla Coriobacteriaceae and Collinsella. However, the magnitude of these changes appeared to be moderate, likely because of the limited sample size and concurrent continuation of anticancer chemotherapy treatments in most patients during FMT administration [23, 39–41]. Additional studies focused on the assessment of gut microbiome–drug interactions and microbiome-derived biomarkers are required.

Although it offers valuable insights, this study also has several limitations. First, the single-arm design and small sample size, typical of a pilot trial, limited the generalizability of our results. Second, as a single-center study, our findings may not fully represent diverse patient populations or clinical settings. Third, the open-label nature of the trial may have introduced bias related to subjective assessments and reporting. In particular, this bias may have originated from the participants and investigators being aware of the treatments. Finally, the lack of a control group posed a challenge in definitively attributing the observed effects to FMT alone.

In conclusion, FMT may have a promising therapeutic potential for managing chemo-radiotherapy-related gastrointestinal side effects, particularly CID, in patients with cancer. FMT could significantly modulate the immune system, increasing the populations of some immune cells. However, further research is validating our results in a larger sample with a case–control design is warranted.

Acknowledgements

We express our gratitude to the patients and their families, as well as to the study investigators, coordinators, and research staff. We extend our appreciation to Jiangxi Shanxing Biotechnology Co., Ltd. for their provision of and assistance with FMT and 16S rDNA sequencing. We also wish to acknowledgment to Cuimin Wang for their valuable contributions to the analysis of the gut microbiome.

Funding

This work was supported by the Doctoral Startup Foundation of Hubei University of Science and Technology [grant number BK202420].

Author contributions

Protocol design: MA. Clinical therapy of the patient: MA, TC, and WW-H. Manuscript drafting: MAM,MA and WC. SZ-W offered both administrative and technical assistance for FMT. Data collection: MA, WW-H and YL-X. Manuscript writing, revision and proofreading: MAM,MA,TC,JA,SZW. All authors contributed to results discussion and confirmation of clinical protocol, and approved the final version of the manuscript.

Consent for publication : All authors participated in this research agreed to publish this work.

Conflict of interest statement :The authors declare no conflicts of interest .

Ethics approval and consent to participate: Ethical approval for this study was granted by the Institutional Review Board of the South Hubei Cancer Hospital Medical Research Ethics Committee before the study began (Reference No: 2020(01)). All participants in the clinical trial provided written informed consent. Each participant received a clinical trial information sheet that clearly outlined the study's objectives, methodology, and purpose in straightforward, easy-to-understand language.

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No competing interests reported.

SupplementaryFig.S1.jpg
Supplementary Fig.S1 FMT preparation process
SupplementaryTable.S1.docx

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You are reading this latest preprint version

Safety and efficacy of fecal microbiota transplantation for cytotoxic chemotherapy– induced diarrhea management in patients with colorectal cancer: a single-arm clinical trial

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Trial registration:

Figures

Introduction

Materials and methods

Study design and participants

Baseline assessments

Intervention

Fecal microbiota transplant preparation

FMT procedures

Outcomes

Data collection and monitoring

Flow cytometric analysis

Fecal microbiota 16S rRNA gene sequencing

Statistical analysis

Ethics

Results

Patient characteristics

Safety evaluation

Clinical efficacy

Alterations in immune function

Clinical response

Follow-up

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1