Open research questions in Clostridium difficile and Clostridium perfringens research

What the literature leaves open

• The risk of infection complications in pediatric patients with hematological malignancies after allogeneic hematopoietic stem cell transplantation. The challenge of restoring and maintaining the diversity and stability of the gut microbiota. The need for careful evaluation of the use of probiotics and prebiotics in immunocompromised patients.

  Microbiota modulation for infectious complications following allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies · 2025 · DOI

• The assessment of safety and efficacy of microbiota modulation remains a significant challenge - Pediatric patients are at heightened risk of infections due to their immature immune systems - Rigorous donor screening and stringent sterile procedures are essential

  Microbiota modulation for infectious complications following allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies · 2025 · DOI

• Safety concerns regarding the long-term effects of FMT. Need for rigorous randomized controlled trials to advance FMT as an AD therapy. Challenges in translating FMT into a cutting-edge AD therapy, including standardization of protocols and personalized microbiota-based interventions.

  Fecal Microbiota Transplantation in Alzheimer’s Disease: Mechanistic Insights Through the Microbiota–Gut–Brain Axis and Therapeutic Prospects · 2025 · DOI

• rigorous randomized controlled trials are needed to advance FMT from bench to bedside, - personalized microbiota-based interventions should be explored, - further investigation into the safety and efficacy of FMT is necessary, - the mechanisms of Aβ clearance or renewal in the amygdala, hippocampus, and other brain structures should be studied

  Fecal Microbiota Transplantation in Alzheimer’s Disease: Mechanistic Insights Through the Microbiota–Gut–Brain Axis and Therapeutic Prospects · 2025 · DOI

• Elucidate the mechanism of ETBF pathogenesis in ETBF murine infection models using the identified BFT-responsive murine cell line, - Investigate the role of E-cadherin cleavage in the promotion of colitis in ETBF-infected mice

  Bacteroides fragilis Toxin Induces Sequential Proteolysis of E-Cadherin and Inflammatory Response in Mouse Intestinal Epithelial Cell Line · 2025 · DOI

• Lack of a BFT-responsive murine cell line. Limited understanding of the mechanism of ETBF pathogenesis in ETBF murine infection models. Unclear how BFT induces E-cadherin cleavage and inflammatory response in intestinal epithelial cells.

  Bacteroides fragilis Toxin Induces Sequential Proteolysis of E-Cadherin and Inflammatory Response in Mouse Intestinal Epithelial Cell Line · 2025 · DOI

• Investigate the effect of probiotics on diarrhea in calves with nutritional stress, - Examine the impact of probiotics on bacterial diversity in larger sample sizes

  Effect of Multi-Species Probiotic Supplementation on Fecal Microbiota in Pre-Weaned Holstein Dairy Calves in California · 2025 · DOI

• Lack of long-term durability and safety data for FMT in IBD, - Variability in donor selection criteria for FMT, - Limited standardization of FMT protocols, - Limited data on the use of FMT in pediatric IBD patients, - Insufficient evidence to support FMT application as a treatment for CD

  The Role of Fecal Microbiota Transplantation in IBD · 2024 · DOI

• Investigation of long-term durability and safety of FMT in IBD, - Standardization of FMT protocols, - Further study of FMT in pediatric IBD patients, - Examination of the role of diet in enhancing FMT effectiveness

  The Role of Fecal Microbiota Transplantation in IBD · 2024 · DOI

• One of the challenges identified is the high recurrence rate of CDI, which worsens the prognosis of IBD. Another challenge is the limited data on the comparative efficacy of FMT between IBD and non-IBD patients. The study also notes that poor bowel preparation is a predictor of FMT failure.

  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 · 2024 · DOI

• Further studies are needed to confirm the efficacy of FMT in larger patient populations, - Research is needed to investigate the potential benefits of FMT in improving inflammation in IBD patients, - Studies should explore the use of FMT in combination with other treatments for CDI

  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 · 2024 · DOI

• Limited sample size, - The study was not designed to specifically identify the difference in the prevalence of diarrhea

  Effect of Multi-Species Probiotic Supplementation on Fecal Microbiota in Pre-Weaned Holstein Dairy Calves in California · 2025 · DOI

• However, a major limitation of previous studies is that the majority of included patients had active IBD at baseline.

  Association between Clostridioides difficile colonization and inflammatory bowel disease activity in outpatients with remission · 2026 · DOI

• The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated.

  Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial · 2026 · DOI

• ABSTRACT Owing to its compositional and chemical complexity, much of the gut microbiota metabolome remains poorly characterized.

  Profiling the aromatic amino acid metabolome in the human gut microbiota reveals Clostridioides difficile -specific N -acyl amino acids · 2026 · DOI

• Although antibiotic exposure may increase susceptibility to disease, its contribution to the progression of sepsis has not been fully elucidated.

  Fecal microbiota transplantation reduces susceptibility to post–antibiotic CLP–induced sepsis by modulating the gut microbiota and its metabolites · 2026 · DOI

• perfringens populations circulating in clinically healthy broilers with subclinical intestinal and hepatic lesions remains poorly characterized.

  Molecular epidemiology and PFGE-based genetic diversity of Clostridium perfringens in broiler chickens from Eastern Türkiye · 2026 · DOI

• Future research should focus on optimizing the FMT process to ensure long-term safety and explore the potential application of FMT in a broader range of medical conditions.

  Advances in Fecal Microbiota Transplantation for Gut Dysbiosis‐Related Diseases · 2025 · DOI

• Core functional genera, Agathobacter, Akkermansia, Roseburia, Blautia, Subdoligranulum, and Faecalibacterium, were lacking pre-treatment.

  Fecal microbiota transplantation restores gut microbiota diversity in children with active Crohn’s disease: a prospective trial · 2025 · DOI

• However, both phenomena need to be further investigated in the future to develop a complete array of antibacterial agents that will allow to permanently eradicate all types of bacterial infections.

  Recent advances in the understanding, detection and therapeutic targeting of bacterial recalcitrance · 2025 · DOI

• To the best of our knowledge, one of the identified RFX resistance-associated rpoB alleles (H502N, R505K, I750M) has not been previously described, whereupon, the amino acid substitutions I750M as well as I750V, E1037Q, A1205V, N1207A, A1208T, and D1232E were identified as neutral mutations that do not confer resistance to RFX.

  Rifaximin resistance in Clostridioides difficile is associated with specific rpoB alleles and multilocus sequence typing (MLST) clades · 2025 · DOI

• However, changes in the respiratory microbiota of patients with rifampicin-resistant TB (RR-TB) during the intensive-phase treatment have not been assessed.

  Sputum microbiota profiles of patients with rifampicin-resistant tuberculosis during the intensive-phase treatment · 2025 · DOI

• difficile virulence and transmission routes, little is known about the potential of Nanopore long-read sequencing in this field.

  Comparison of Illumina and Oxford Nanopore sequencing data quality for Clostridioides difficile genome analysis and their application for epidemiological surveillance · 2025 · DOI

• Fecal microbiota transplantation (FMT) has been reported to be effective for refractory acute GVHD; however, whether FMT is effective for refractory chronic GVHD (cGVHD) remains unknown.

  Fecal microbiota transplantation for refractory chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation: a pilot open-label, non-placebo-controlled study · 2025 · DOI

• The impact of IL-22BP on gut microbiota composition and functioning is poorly understood.

  Deficiency of IL-22–binding protein enhances the ability of the gut microbiota to protect against enteric pathogens · 2024 · DOI

Most-cited papers in Clostridium difficile and Clostridium perfringens research

• Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species · Science · 2010 · 3,407 citations
• Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile · New England Journal of Medicine · 2013 · 3,283 citations
• Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota · Nature · 2013 · 2,620 citations
• Burden of Clostridium difficile Infection in the United States · New England Journal of Medicine · 2015 · 2,321 citations
• An Epidemic, Toxin Gene–Variant Strain of Clostridium difficile · New England Journal of Medicine · 2005 · 1,743 citations
• A Predominantly Clonal Multi-Institutional Outbreak ofClostridium difficile–Associated Diarrhea with High Morbidity and Mortality · New England Journal of Medicine · 2005 · 1,664 citations
• Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe · The Lancet · 2005 · 1,207 citations
• Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity · Canadian Medical Association Journal · 2004 · 887 citations
• SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection · New England Journal of Medicine · 2022 · 534 citations
• Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism · Journal of Child Neurology · 2000 · 507 citations

Most recent work

• Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial · Nature Medicine · 2026
• The impact of an oral purified microbiome therapeutic on the gastrointestinal microbiome · Nature Medicine · 2026
• An oral protein cocktail therapeutic for C. difficile infection · bioRxiv · 2026
• Safety and efficacy of a novel fecal microbiota transplantation method using hydrogen nanobubble water without antibiotics or bowel cleansing in children with autism spectrum disorder: an open-label, single-arm study demonstrating improvements in core and comorbidity symptoms · Frontiers in Pediatrics · 2026
• Fecal Microbiota-Based Therapies Compared to Fecal Microbiota Transplantation for Preventing Recurrent C difficile Infection · Clinical Gastroenterology and Hepatology · 2026
• Clinical failure of an extended-pulsed fidaxomicin regimen associated with emergence of a Clostridioides difficile isolate with reduced fidaxomicin susceptibility in an elderly man · Antimicrobial Agents and Chemotherapy · 2026
• The Safety, Efficacy, and Feasibility of Fecal Microbiota Transplantation in a Population With Bipolar Disorder During Depressive Episodes: A Pilot Parallel Arm Randomized Controlled Trial: Sécurité, efficacité et faisabilité de la transplantation de microbiote fécal chez une population atteinte de troubles bipolaires, au cours d’épisodes dépressifs : essai pilote contrôlé à répartition aléatoire et à groupes parallèles · The Canadian Journal of Psychiatry · 2026
• A targeted cell lysis mechanism facilitates toxin release in Clostridioides difficile · bioRxiv · 2026
• Clostridioides difficile infection following COVID-19: a nationwide analysis using routine surveillance data in Wales · Journal of Hospital Infection · 2026
• 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial · Nature Medicine · 2026

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