C. difficile is widely distributed in nature and has been isolated from diverse environments, including water, soil, food products, and both domestic and farm animals, as well as household settings (4). Within healthcare facilities, C. difficile has been recovered from the hands of patients and healthcare personnel, hospital surfaces, medical equipment (5), and even hospital pet therapy dogs (6). The organism's ability to form robust spores contributes significantly to its persistence in both community and healthcare settings. These dormant spores exhibit remarkable resistance to environmental stressors such as heat, acid, antibiotics, and disinfectants, thereby facilitating environmental survival and transmission. Upon reaching the intestinal tract, the spores germinate into vegetative cells capable of producing toxins that drive the pathogenesis of C. difficile infection (CDI).

Clinical manifestations are related to intestinal damage by toxins. C. difficile produces two major toxins, TcdA and TcdB, encoded by the tcdA and tcdB genes within the pathogenicity locus (PaLoc). TcdA primarily functions as an enterotoxin, promoting intestinal inflammation and fluid secretion, whereas TcdB is a potent cytotoxin that induces epithelial cell death and mucosal damage (7, 8). Both toxins glucosylate Rho family GTPases (Rho, Rac, and Cdc42), disrupting the actin cytoskeleton, impairing tight junctions, and triggering apoptosis. Importantly, some strains express only TcdB yet still cause severe disease, highlighting TcdB as the principal virulence determinant. A subset of epidemic strains also produces a binary toxin (CDT), encoded by cdtA and cdtB, which ADP-ribosylates actin, leading to cytoskeletal disruption and the formation of microtubule-based protrusions that may enhance bacterial adherence. Although its precise role remains under investigation, CDT is associated with increased disease severity and recurrence. Toxin expression is tightly regulated within the PaLoc by tcdR (positive regulator), tcdC (negative regulator), and tcdE (involved in secretion), and is further influenced by environmental factors such as nutrient availability, antibiotic exposure, and pH (7–9).

Non-toxigenic C. difficile (NTCD) strains lack the genes encoding toxins A (tcdA) and B (tcdB) and are therefore generally considered non-pathogenic. Despite their inability to produce toxins, NTCD can colonize the gastrointestinal tract, particularly in children, without causing clinical disease. These strains retain the ability to form spores, allowing them to persist in both the environment and the host gut. NTCD can establish asymptomatic colonization, which may be transient or, in some cases, long-term. Although they lack toxin genes, NTCD strains are genetically diverse and may carry other virulence-associated genes. Asymptomatic colonization with NTCD is frequently observed in healthy individuals, especially in pediatric populations, without associated clinical symptoms. Understanding these mechanisms is particularly relevant in pediatric populations, where C. difficile infection can range from asymptomatic colonization to life-threatening colitis, and where recurrence remains a significant clinical challenge (10).

While CDI is often associated with disease relapses, a substantial number of pediatric cases are identified at the time of IBD diagnosis. CDI and IBD are interrelated conditions, where CDI can worsen IBD symptoms, and having IBD increases the risk of developing CDI.

C. difficile may contribute to the development of IBD in susceptible individuals, although its role is not fully established. Several studies have reported a higher prevalence of toxigenic C. difficile in newly diagnosed pediatric and adult patients with IBD, even in the absence of prior antibiotic exposure, suggesting that colonization might precede or promote disease onset (18–20). Clostridium species contribute to the pathogenesis and progression of IBD through both protective and pathogenic mechanisms. Commensal species, such as Clostridium butyricum, produce short-chain fatty acids (SCFAs) like butyrate that strengthen the intestinal barrier, enhance mucus production, and modulate immune responses by promoting regulatory T cell differentiation, thereby maintaining gut homeostasis and protecting against inflammation, or inversely their disbalance can promote the gut inflammation (21–23). The major toxins produced by C. difficile, TcdA and TcdB, disrupt the intestinal epithelial barrier, increase gut permeability, and trigger pro-inflammatory cytokine release, which may favor chronic intestinal inflammation (24, 25). Overall, while C. difficile appears to play a role in promoting intestinal inflammation and may act as a risk factor for IBD in predisposed individuals, it is not considered a primary cause of the disease. In contrast, pathogenic species, particularly C. difficile, disrupt epithelial integrity through toxin production, trigger pro-inflammatory Th1/Th17 immune responses, and can precipitate disease flares in susceptible individuals (26–29). Dysbiosis favoring pathogenic clostridia amplifies mucosal inflammation and exacerbates disease severity, highlighting the dual and critical influence of these bacteria in both the onset and progression of IBD (30–32).

The potential role of Clostridioides/Clostridium species in gut homeostasis and in inflammatory bowel disease development appears in Figure 1.

Exposure to antibiotics is the primary risk factor for both healthcare-associated and community-associated CDI in children (54). Many recognized risk factors for CDI in the general population—such as hospitalization and antibiotic use—are also more common in patients with IBD, which may contribute to their increased susceptibility. Antibiotics can disrupt the normal gastrointestinal microbiome, creating conditions that favor the overgrowth of C. difficile and enhanced toxin production (55). Although any antibiotic can elevate the risk of CDI, the degree of risk varies by antibiotic class (56). In children, the risk of CDI varies by antibiotic class. Clindamycin and third-generation cephalosporins carry the highest risk, while broad-spectrum penicillins, fluoroquinolones, and carbapenems pose a moderate risk. Tetracyclines and aminoglycosides are rarely associated with CDI in pediatric patients. These differences reflect both the spectrum of activity and the frequency of use in children, with high-risk agents often disrupting gut microbiota more profoundly (55, 56).

In children, the use of PPIs, and to a lesser extent histamine-2 receptor antagonists (H2RAs), has been linked to an elevated risk of CDI (57). However, studies examining CDI in children with IBD has found no significant link between the use of acid-suppressing medications and the risk of developing CDI (37, 46, 50).

A diverse intestinal microbiota provides protection against the establishment of potential pathogens, including C. difficile—a mechanism known as colonization resistance (58). Individuals with IBD exhibit a dysbiotic gut microbiome, characterized by reduced microbial diversity and altered microbial composition (59, 60). This disruption creates an intestinal environment that favors the colonization and spore germination of C. difficile. Comparative studies examining the gut microbiota of patients with IBD, with and without CDI have revealed distinct microbial differences between these groups.

Gut dysbiosis—marked by reduced microbial diversity and altered composition—creates conditions that favor C. difficile colonization and spore germination. Comparative studies show that IBD patients with CDI often exhibit depletion of butyrate-producing Firmicutes, which are important for epithelial integrity, along with expansion of opportunistic Proteobacteria. These microbial alterations not only weaken colonization resistance but may also intensify mucosal inflammation, increasing susceptibility to CDI (59, 60).

Although, medications such as antibiotics and PPIs are recognized risk factors for CDI in the general population, can also increase CDI risk in patients with IBD, however, many patients with IBD develop CDI even in the absence of these exposures (61).

CDI can exacerbate IBD symptoms, and patients with more extensive disease may have a higher risk of CDI, often necessitating greater use of immunosuppressive agents and corticosteroids. Importantly, this does not imply that these therapies themselves directly increase CDI risk.

There is conflicting evidence regarding whether anti-inflammatory and immunomodulatory therapies used for IBD contribute to an increased risk of CDI. In both the general population and adults with IBD, the use of immunosuppressive agents and corticosteroids has been associated with a higher risk of CDI (62). However, a recent meta-analysis of 14 studies examining CDI in children with IBD found no significant association between CDI risk and the use of steroids, immunomodulators, or biologic agents, suggesting that pediatric CDI may have distinct clinical characteristics (50). Interestingly, only 5-aminosalicylic acid (5-ASA) therapy was linked to an increased risk of CDI in children with IBD (odds ratio = 1.95, 95% CI 1.26–3.0) (50), though the underlying mechanism for this association remains unclear.

In adult populations, both C. difficile–associated disease (CDAD) and colonization with toxigenic C. difficile are more frequently observed in UC compared with CD (33, 63). In pediatric populations, however, studies generally report no significant difference in CDI or toxigenic C. difficile colonization between UC and CD (18, 35, 37, 47). Nevertheless, colonic involvement in pediatric IBD is consistently associated with an increased risk of CDI (18, 35, 47).

Beyond IBD subtype, disease severity is a major factor influencing CDI risk. CDI is more frequently observed and often more severe in patients with active or severe IBD (18, 35, 47). Pediatric studies suggest that worsening microbial dysbiosis associated with severe IBD may reduce colonization resistance, facilitating overgrowth of C. difficile (33). As a result, some investigators have proposed that detection of toxigenic C. difficile in IBD may serve primarily as a marker of underlying disease activity rather than indicating a distinct infectious process.

The imbalance in bile acid metabolism (11) and other metabolomes (13) may contribute to the increased susceptibility of patients with IBD to CDI. Consistent with this, children with IBD and active CDI have been observed to have elevated fecal primary bile acids and diminished secondary bile acids (13, 64). These metabolic alterations may also hold potential for the development of novel diagnostic approaches for CDI.

Diarrhea is the most common symptom, ranging from mild to profuse watery stools. Abdominal pain, cramping, and bloody diarrhea are frequently reported, particularly in patients with ulcerative colitis. Additional symptoms such as urgency, tenesmus, and rectal discomfort reflect lower gastrointestinal tract involvement.

Systemic manifestations, including fever, malaise, and dehydration, may occur in moderate to severe cases. Laboratory abnormalities such as leukocytosis, anemia, elevated C-reactive protein (CRP), and hypoalbuminemia are common but non-specific and may also reflect active IBD.

Recurrent CDI (rCDI) represents a significant clinical challenge in children with IBD, largely due to persistent intestinal dysbiosis, prior antibiotic exposure, and ongoing immunosuppressive therapy. rCDI is defined as a new episode of CDI occurring within eight weeks of the initial infection. Reported recurrence rates among pediatric IBD populations range from 25% to 34% (39, 46, 48).

Given the considerable clinical overlap between CDI and IBD relapse, stool testing for C. difficile toxins or genes should be performed in all pediatric patients with IBD presenting with new or worsening diarrhea, particularly following recent antibiotic exposure or hospitalization. Prompt identification and targeted treatment are essential to prevent severe outcomes and reduce the risk of recurrence (67).

Distinguishing a true CDI from an IBD flare in children can be challenging due to the relatively high rate of C. difficile colonization in this population. Colonization refers to the presence of toxigenic C. difficile in the gut without causing symptoms (66). Studies have reported that between 10% and 25% of children with IBD may carry C. difficile asymptomatically, complicating the interpretation of positive test results and the identification of active infection (36, 49, 68).

Although guidelines exist for the management of CDI in children (71, 77, 78), there are currently no recommendations specifically addressing CDI in pediatric patients with IBD therefore, existing recommendations are primarily extrapolated from adult studies and treatment data (14, 63). Following diagnosis, prompt initiation of antibiotic therapy is critical to prevent progression and complications of CDI. Evidence from a retrospective observational study in adults patients with IBD demonstrated that those with UC and CDI who were treated with oral vancomycin experienced fewer readmissions and shorter hospital stays compared with those receiving metronidazole (33, 63). Based on these findings, it has been suggested that oral vancomycin may be considered first-line therapy for CDI in adults with IBD, although direct pediatric data are lacking. Fidaxomicin may be considered as an alternative option for the management. In cases of severe or fulminant disease, rectal vancomycin can be administered when oral delivery is not feasible, and intravenous metronidazole may be used as adjunctive therapy. For recurrent CDI, current guidelines support treatment with pulse-tapered oral vancomycin or oral vancomycin followed by rifaximin or fidaxomicin. Bezlotoxumab, a monoclonal antibody against C. difficile toxin B, can be given as a single IV dose (10 mg/kg) alongside antibiotics to reduce recurrence in adults at high risk; it does not treat active infection. It is generally safe, though caution is advised in patients with heart failure. Guidelines recommend considering bezlotoxumab for patients with prior CDI, older age, immunocompromise, or severe infection (74). The pediatric doses for CDI infection appear in Table 3.

Importantly, immunosuppressive therapy should not be discontinued during CDI management. Because CDI and IBD flares share overlapping clinical features, careful and ongoing assessment for active colitis is essential. If diarrhea persists without improvement by day 3–4 of CDI-targeted antibiotic therapy, escalation of immunosuppressive treatment should be considered to address potential IBD activity (63). Pediatric CDI treatment Guidelines and Management: First-line, Alternatives, and Recurrence appear in Table 4.

The clinical response to therapy for CDI is primarily assessed based on symptomatic improvement. In cases of mild to moderate disease, most patients demonstrate clinical improvement within 48–72 h following the initiation of appropriate antibiotic treatment. However, complete resolution of diarrhea may take four to five days, especially in patients treated with metronidazole or carriers of NAP1/BI/027 strain even with effective therapy (65). Following completion of therapy, routine testing for C. difficile eradication (“test of cure”) is not recommended, as clinical improvement should guide treatment success (65, 71).

Surgical intervention, such as subtotal colectomy or diversion ileostomy, may be necessary as a life-saving measure in children with fulminant CDI who develop toxic megacolon, colonic perforation, acute abdomen, or septic shock. However, the indications for surgery in pediatric patients with severe or fulminant CDI are not well defined, and current practice is largely guided by adult experience and case-based clinical judgment (65).

Fecal microbiota transplantation (FMT) is increasingly utilized in pediatric gastroenterology, primarily for the treatment of recurrent C. difficile infection (rCDI). Beyond rCDI, growing evidence underscores the pivotal role of the gut microbiome in health and disease, prompting investigation of fecal microbiota transplantation (FMT) as a therapeutic approach for other conditions, including inflammatory bowel disease (IBD), graft-vs.-host disease, neuropsychiatric disorders, and metabolic syndrome. Recent ESPGHAN and NASPGHAN guidelines provide recommendations on FMT use in children with CDI especially with IBD, offering guidance on patient selection, procedural protocols, and safety considerations (75).

FMT is generally well tolerated, but children with IBD or compromised immune systems may experience more pronounced side effects. There is a potential for triggering IBD flares, and the long-term effects on the immune system remain unclear, highlighting the need for careful monitoring. These factors emphasize the importance of studying FMT specifically in pediatric populations. Recent systematic reviews call for well-designed studies to evaluate its effectiveness, monitor adverse events, and establish safe practices for use in children (76).

A multicenter retrospective cohort study demonstrated comparable efficacy of FMT for rCDI in children with and without IBD (76% vs. 81%, p = 0.17). Within the IBD cohort, treatment success was more likely when fresh donor stool was used, in patients without active diarrhea at the time of the procedure, and when the interval between CDI diagnosis and FMT was shorter. Post-procedure, 13% of children with IBD required hospitalization within three months; however, it remains unclear whether these events were attributable to FMT, the underlying disease, or both. These findings suggest that FMT is a viable therapeutic option for rCDI in pediatric IBD, though careful patient selection and monitoring are warranted (79).