Ahmad Lambert

Background:  Clostridioides difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is associated with significant morbidity and mortality, particularly in patients with underlying inflammatory bowel disease (IBD).¹ IBD, including Crohn’s disease and ulcerative colitis, is characterized by chronic inflammation due to an aberrant immune response to gut microbiota.¹ A key challenge in managing CDI among IBD patients is recurrent infection, driven in part by microbiota dysbiosis and immune dysregulation. Emerging evidence suggests that microRNAs (miRNAs), which are small, non-coding RNA molecules that regulate gene expression post-transcriptionally, may play a role in modulating host immune responses in both IBD and CDI.² Notably, miR-27a-5p and miR-135a have been identified as key regulators of intestinal inflammation, offering novel therapeutic insights.^3,4 Fecal microbiota transplantation (FMT), which restores microbial diversity, has also been shown to influence host miRNA expression and could serve as a dual therapeutic tool.^5,6

Objective:  This narrative review explores how miRNA-mediated immune modulation following FMT impacts inflammation and susceptibility to CDI in patients with IBD.

Search Methods:  A literature review was conducted using the Discovery Service for Texas A&M University Libraries and PubMed for studies published between 2018 and 2025. Keywords included: “Clostridioides difficile,” “C. difficile,” “microRNA,” “fecal microbiota transplantation,” “FMT,” “IBD,” “recurrent CDI,” “inflammation,” “gut dysbiosis,” and “immune modulation.” Both in vitro and in vivo studies examining miRNA regulation, NF-κB signaling, and FMT outcomes were included.

Results:  Studies demonstrate that miR-27a-5p suppresses C. difficile-induced inflammation by downregulating the NF-κB pathway, which is responsible for the expression of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α.³ Infection with C. difficile flagellin reduced miR-27a-5p expression in intestinal epithelial cells. Introduction of a miR-27a-5p mimic reduced cytokine production and intestinal damage in murine models, suggesting its therapeutic potential.³ In parallel, miR-135a was shown to reduce inflammation and epithelial apoptosis in a DSS-induced colitis model, further supporting its role in maintaining mucosal integrity.⁴ Additionally, FMT has been shown to upregulate anti-inflammatory miRNAs in patients with recurrent CDI.⁶ These changes were observed in serum and tissue samples, as well as in ex vivo colonoid models. FMT-derived shifts in microbiota composition were associated with enhanced cytoskeletal stability, reduced epithelial apoptosis, and altered immune signaling.^6,7 Biomarker analysis further revealed that lower Ct values for the tcdB gene, combined with specific cytokine profiles (e.g., IL-6, IL-8, IL-10), can predict CDI recurrence.⁸

Conclusions:  The reviewed studies highlight the therapeutic potential of miRNA-targeted approaches in conjunction with or via FMT can manage CDI and chronic inflammation in IBD patients. MiRNAs such as miR-27a-5p and miR-135a are key regulators of host immune responses and may serve as adjunctive targets to reduce inflammation and prevent recurrence. FMT not only restores microbiota balance but also modulates host miRNA expression, offering a novel mechanism of immune regulation. Future research should focus on delivery strategies for miRNA-based therapies and personalized approaches incorporating microbial and immunologic biomarkers.

Works Cited:

1. Smith NRMC, Schub TB. Clostridium Difficile-Associated Disease. CINAHL Nursing Guide. August 2018. Accessed February 17, 2025. https://search.ebscohost.com/login.aspx?direct=true&db=nup&AN=T704549&site=eds-live&scope=site
2. Ramadan YN, Kamel AM, Medhat MA, Hetta HF. MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clin Exp Med. 2024;24(1). doi:10.1007/s10238-024-01476-z
3. Kobeissy PH, Denève-Larrazet C, Marvaud J-C, Kansau I. MicroRNA miR-27a-5p Reduces Intestinal Inflammation Induced by Clostridioides difficile Flagella by Regulating the Nuclear Factor-κB Signaling Pathway. J Infect Dis. 2025;231(1):e38-e46. doi:10.1093/infdis/jiae396
4. Chunyan Lou, Yanyang Li. Functional role of microRNA-135a in colitis. Journal of Inflammation. 2018;15(1):1-8. doi:10.1186/s12950-018-0181-z
5. Yadegar A, Bar-Yoseph H, Monaghan TM, et al. Fecal microbiota transplantation: current challenges and future landscapes. Clin Microbiol Rev. 2024;37:e00060-22. doi:10.1128/cmr.00060-22
6. Monaghan TM, Seekatz AM, Markham NO, et al. Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection Associates With Functional Alterations in Circulating microRNAs. Gastroenterology. 2021;161(1):255-270.e4. doi:10.1053/j.gastro.2021.03.050
7. Wortelboer K, Bakker GJ, Winkelmeijer M, et al. Fecal microbiota transplantation as a tool to study the interrelation between microbiota composition and miRNA expression. Microbiol Res. 2022;257:126972. doi:10.1016/j.micres.2022.12697
8. Madden GR, Rigo I, Boone R, et al. Novel Biomarkers, Including tcdB PCR Cycle Threshold, for Predicting Recurrent Clostridioides difficile Infection. Bäumler AJ, ed. Infection and Immunity. 2023;91(4). doi:https://doi.org/10.1128/iai.00092-23
9. Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology. 2014;146(6):1547-1553. doi:10.1053/j.gastro.2014.01.059