One therapy, many targets: redefining ulcerative colitis treatment through fecal microbiota transplantation

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease driven by a multifactorial interplay between gut microbiota dysbiosis, immune dysregulation, and epithelial barrier dysfunction. Accurate diagnosis and a deeper understanding of UC pathogenesis are essential for developing durable and mechanism-based therapies. Despite major advances, conventional treatments such as immunosuppressants and biologics often fail to achieve sustained remission and carry significant adverse effects, underscoring the need for novel, multi-target interventions. This review synthesizes current insights into UC pathogenesis, diagnostic approaches, and therapeutic strategies, with a particular focus on fecal microbiota transplantation (FMT) as a single therapy acting on multiple disease axes. By restoring microbial equilibrium, FMT can modulate host immunity and reinforce epithelial integrity, collectively promoting mucosal healing. We summarize mechanistic evidence, findings from preclinical and clinical studies, and key variables influencing FMT efficacy, including donor selection, preparation, and delivery routes. While evidence supports the therapeutic promise of FMT, challenges remain regarding standardization, long-term engraftment, and sustained safety. Nonetheless, FMT represents a transformative therapeutic platform that redefines UC treatment by bridging microbial restoration, immune modulation, and barrier repair. Future research should aim to refine FMT protocols and develop next-generation microbiota-based therapeutics, such as defined microbial consortia and live biotherapeutic products, to enable safer, more consistent, and personalized modulation of the gut ecosystem in UC.

Plain language summary

Transferring healthy gut bacteria: how one treatment can target multiple causes of ulcerative colitis

Ulcerative colitis is a long-term disease that causes inflammation and ulcers in the large intestine. It can lead to symptoms such as stomach pain, diarrhea, and tiredness, which often return even after treatment. The exact cause is not fully understood, but scientists know that it involves three main problems: an imbalance in the gut bacteria (dysbiosis), a weakened gut barrier that normally protects the intestine, and an overactive immune system. Traditional treatments, like anti-inflammatory drugs and immune suppressants, help control symptoms but do not always prevent the disease from coming back and can have side effects. This has encouraged researchers to look for new, more natural ways to treat the condition. Fecal microbiota transplantation (FMT) is a new approach where beneficial gut bacteria from a healthy donor are transferred into the patient’s intestine. This helps restore the natural balance of bacteria, strengthens the intestinal barrier, and calms the immune system. In other words, one treatment can act on several levels of the disease at once - microbes, the gut wall, and the immune response. Our review article explains how FMT works, what current research shows about its safety and success, and what challenges remain. It also looks ahead to the future of microbiota-based therapies, including using specific bacterial mixes instead of whole stool, to make the treatment safer, more effective, and personalized for each patient.

Introduction

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease (IBD) that continues to challenge both clinicians and researchers. Despite major advances in diagnostics and therapeutics, its global incidence is steadily increasing, particularly in newly industrialized regions, reflecting the profound impact of environmental and lifestyle factors on intestinal health. Current pharmacological options—including immunosuppressants, corticosteroids, and biologics—can induce remission but often fail to sustain it, underscoring the need for therapeutic strategies that address the disease at its ecological and immunological roots.

The pathogenesis of UC remains incompletely understood, yet mounting evidence implicates a dynamic interplay between host genetics, immune dysregulation, and environmental triggers. Central to this interplay is the gut microbiota, which orchestrates immune maturation, epithelial integrity, and metabolic balance. Perturbations of this complex ecosystem, termed dysbiosis, are increasingly recognized not merely as bystanders but as potential drivers of chronic mucosal inflammation. However, whether dysbiosis is a cause, a consequence, or both remains a subject of intense investigation.

This evolving understanding has sparked growing interest in microbiome-targeted interventions that aim to restore ecological and immunological equilibrium rather than suppress inflammation alone. Among these, fecal microbiota transplantation (FMT) represents a pioneering approach that seeks to re-establish microbial diversity and function through the transfer of a healthy donor microbiota. Although FMT has achieved remarkable success in recurrent Clostridioides difficile infection (CDI), its therapeutic role in UC remains debated due to heterogeneity in study designs, donor characteristics, and delivery protocols.

This review provides an integrative perspective on the role of the gut microbiome in UC pathogenesis and therapy, emphasizing the mechanistic rationale, current evidence, and translational challenges of FMT. It also outlines emerging directions in next-generation microbiota-based therapeutics, aiming to shift UC management toward precision restoration of host–microbiome symbiosis.

Diagnosis, pathogenesis, and treatment of UC

Accurate diagnosis of UC requires an integrated assessment of clinical symptoms, laboratory findings, and endoscopic, histological, and imaging evaluations, as no single test can confirm the disease.^1,2 An overview of key diagnostic tools is provided in Table 1. Diagnosis is primarily established by excluding infectious causes (notably C. difficile) and other pathologies such as Crohn’s disease, ischemic colitis, or malignancy, followed by the confirmation of continuous colonic inflammation via colonoscopy and chronic inflammatory changes on histology.^2–4 While noninvasive biomarkers such as fecal calprotectin aid in detecting inflammation, and advanced imaging techniques support assessment in selected cases, colonoscopy with biopsy remains the gold standard.^4–8 Emerging molecular approaches, including transcriptomic and microbiome profiling, together with artificial intelligence-assisted tools, are being explored primarily for disease stratification, prediction of therapeutic response, and personalized disease monitoring, but they are not currently used for routine diagnostic confirmation of UC. ⁹ UC is a chronic immune-mediated inflammatory disease characterized by a multifactorial pathogenesis involving genetic susceptibility, environmental triggers, epithelial barrier dysfunction, immune dysregulation, and alterations in the gut microbiota.^1,10–13 The pathophysiology of UC is multifactorial and remains incompletely understood. As a chronic immune-mediated inflammation of the colon, UC pathogenesis is centered on identifying the factors that lead to an aberrant immune response. ¹⁰ Although a clear triggering agent has not yet been identified, current evidence supports a working model that incorporates multiple contributors to disease development and progression.^1,11 The disease is thought to result from complex interactions between environmental (e.g., urban lifestyle, exposure to pollution, diet, and medication), microbial (gut microbiome), and immune-mediated factors in a genetically susceptible host.^12,13 Understanding of UC pathogenesis has historically advanced more slowly than that of Crohn’s disease. This discrepancy may have stemmed from the lack of strong associations with specific single-nucleotide polymorphisms, as well as the atypical immunologic features of UC. Although the pathogenesis of UC and Crohn’s disease (CD) is frequently discussed together, it is crucial to emphasize the distinct mechanisms involved. CD is typically characterized by a Th1/Th17-skewed immune response driven by interleukin (IL)-12 and IL-23 signaling, resulting in transmural inflammation. In contrast, UC exhibits a more atypical Th2-like immune pattern involving IL-5 and IL-13 production, frequently associated with NKT cell activation and inflammation confined to the mucosa.^14,15

Table 1.

Diagnostic tools for UC.

Tool/method	Role	Advantages/limitations
Clinical evaluation	Assessment of symptoms (bloody diarrhea, abdominal pain, urgency)	Noninvasive; subjective and symptom-based
Blood tests	Anemia, CRP, ESR	Easy to perform; nonspecific markers of inflammation
Stool tests	Fecal calprotectin and lactoferrin exclude infection (e.g., Clostridioides difficile)	Non-invasive; useful for distinguishing IBD from IBS; cannot localize disease
Endoscopy	Visual confirmation of continuous inflammation	Gold standard; invasive and requires bowel prep
Histology (biopsy)	Architectural distortion, crypt abscesses, mucin depletion	Confirms chronic inflammation; requires endoscopy
Serologic markers	p-ANCA (limited diagnostic utility)	Helpful for differential diagnosis; limited sensitivity/specificity
Imaging (e.g., ultrasound, CT, MRI)	Supportive role, especially in children	Noninvasive; useful when endoscopy is contraindicated
NBI	Enhanced mucosal detail to detect dysplasia	Improves dysplasia detection; requires advanced equipment
CLE	Real-time microscopic examination of tissue at the cellular level	High-resolution visualization; not widely available

CLE, confocal laser endomicroscopy; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; NBI, narrow-band imaging; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibodies.

Genetic factors clearly play a role in UC. First-degree relatives of UC patients have a 4-fold increased risk of developing the disease. Moreover, Ashkenazi Jewish populations have a 3- to 5-fold higher risk compared to the general population. ¹⁶ Genome-wide association studies have identified numerous susceptibility loci linked to UC, most of which involve immune regulation (e.g., IL23-R, IL-12, JAK2, CARD9, TNFSF18, and IL-10). Among these, the strongest associations are found within the human leukocyte antigen region. ¹³ Environmental influences may contribute to disease development through alterations in the gut microbiota and disruption of the intestinal epithelial barrier (IEB), triggering inappropriate immune activation. ⁴ Some authors even define UC as a barrier disease initiated by epithelial dysfunction. ¹ A growing body of evidence links intestinal dysbiosis to UC pathogenesis, suggesting that the cross-talk between the intestinal epithelium, the immune system, and the microbiota is a central driver of disease onset.^12,17

Regarding management, the updated Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) consensus (2020) emphasizes a “treat-to-target” strategy. Treatment goals now encompass both symptomatic relief and endoscopic healing to improve quality of life and prevent long-term complications such as colectomy or colorectal cancer. ¹⁸ Pharmacological management is tailored to disease severity, typically following a step-up approach. Options range from conventional therapies (5-aminosalicylic acid, corticosteroids) to advanced agents, including biologics (anti-tumor necrosis factor (TNF), anti-integrins, anti-interleukins) and targeted small molecules (Janus kinase inhibitors, S1P modulators; Table 2).^1,15 Despite these advances, mucosal healing is achieved in only ~40% of patients.^19,20 Given the crucial role of dysbiosis in UC, microbiota-directed therapies are increasingly emerging as a promising strategy to bridge this therapeutic gap.

Table 2.

Standard medical therapy for the treatment of UC.

Disease severity	Pharmacotherapy	Notes
Mild to moderate	Mesalamine (5-ASA)	First-choice treatment
	Rectal corticosteroid enemas or foam	Recommended for patients with prominent rectal bleeding
Moderate to severe	Systemic corticosteroids	First-line for induction of remission; not for maintenance
	IV corticosteroids	First-line therapy for patients hospitalized with severe UC
	Anti-TNF therapy (infliximab, adalimumab, golimumab)	Used alone or in combination with corticosteroids
	Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)	For steroid-refractory severe UC unresponsive to IV corticosteroids
	Anti-integrins (e.g., vedolizumab)	Used for maintenance of remission; gut-selective mechanism
	JAK inhibitors (e.g., tofacitinib, upadacitinib)	Oral small molecules, especially in anti-TNF–exposed patients
	S1P modulators (e.g., ozanimod, etrasimod)	New oral selective therapies for adults
	Anti-IL therapy (e.g., ustekinumab (anti-IL-12/23), mirikizumab, guselkumab, risankizumab (anti-IL-23))	Used in patients with inadequate response to other biologics

Source: Adapted from Kucharzik et al., ² Feuerstein et al., ⁴ Burri et al., ¹¹ Paik, ²¹ Afif et al., ²² Sands et al., ²³ Rubin et al., ²⁴ and Li. ²⁵

Both JAK inhibitors and S1P modulators are considered selective small-molecule therapies.

5-ASA, 5-aminosalicylic acid; IL, interleukin; JAK, Janus kinase; S1P, sphingosine-1-phosphate; TNF, tumor necrosis factor; UC, ulcerative colitis.

Gut microbiome in health and UC

The human gut microbiome is established early in life and undergoes dynamic maturation influenced by delivery mode, feeding practices, antibiotic exposure, and environmental factors (Figure 1). Early life microbial imprinting has long-term consequences for immune programming and susceptibility to inflammatory diseases, including UC. Critical developmental windows coincide with the induction of immune tolerance. Perturbation during this period can lead to pathological imprinting.^26,27 By the age of 3–5 years, the gut microbiota approximates the adult-like configuration.^28,29

Figure 1.

Development and early life modulation of the human gut microbiota. The figure illustrates the development of the human gut microbiota from fetal life through childhood, highlighting key modulatory factors. While the existence of an in utero microbiome remains debated, microbial colonization of the infant gut is widely accepted to begin at birth, influenced by maternal and environmental sources. The mode of delivery (vaginal birth vs Cesarean section) and gestational age (term vs preterm) strongly shape the initial microbial community composition. During lactation, the infant gut microbiota is further modulated by feeding mode. Introduction of solid foods shifts the microbiota toward an adult-like composition, characterized by expansion of dominant anaerobic phyla such as Bacillota (formerly Firmicutes) and Bacteroidota (formerly Bacteroidetes). Antibiotic exposure and Western diets may lead to dysbiosis and increase long-term susceptibility to inflammatory and metabolic diseases.

Source: Adapted from Ma et al.,^26,30 Al Nabhani et al., ³¹ and Turunen et al. ³² Taxonomic terminology updated according to the Genome Taxonomy Database (GTDB, release R220). Created in Biorender.com. Demeckova, V. (2026) https://BioRender.com/xx23xgm

Defining a universal healthy gut microbiome remains challenging due to pronounced inter-individual variability. ³³ The dominant bacterial phyla in healthy adults include Bacillota (formerly Firmicutes), Bacteroidota (formerly Bacteroidetes), Actinomycetota (formerly Actinobacteria), Pseudomonadota (formerly Proteobacteria), and Verrucomicrobiota (formerly Verrucomicrobia). Longitudinal analysis and cross-sectional comparisons of fecal 16S rRNA gene sequencing defined the most abundant genera: Bacteroides, Faecalibacterium, Alistipes, Ruminococcus, Roseburia, Blautia, and species within the Eubacterium genus. Crucially, the major butyrate-producing groups belong to the families Ruminococcaceae (historically referred to as Clostridium cluster IV) and Lachnospiraceae (historically Clostridium cluster XIVa). Among these, Bacteroides often accounts for up to 30% of the microbial population, underscoring its central role in host–microbiome interactions. These genera are continuously present in people of different ages and ethnicities, and, therefore, they comprise the so-called “microbial core.” Notable species within this core include Faecalibacterium prausnitzii, Oscillibacter species (formerly Oscillospira), and Blautia obeum (formerly Ruminococcus obeum).^33,34 Functionally, the microbiome contributes to host homeostasis through short-chain fatty acid (SCFA) production, particularly butyrate, transformation of primary into secondary bile acids (SBAs), metabolism of tryptophan-derived compounds, maintenance of epithelial barrier integrity, and colonization resistance against opportunistic pathobionts. ³³ Loss of these core functions, rather than simple taxonomic shifts, appears central to disease development. To capture this functional complexity beyond individual taxa, recent ecological models have refined microbiome characterization through the concept of enterosignatures. These describe co-occurring bacterial guilds with shared functional properties rather than fixed community types.^35,36 Enterosignature composition evolves across the lifespan and responds dynamically to environmental perturbations, providing an interpretable framework for linking microbiome structure to health and disease states (Figure 2).

Figure 2.

Developmental trajectory and clinical relevance of ESs across life stages. The figure illustrates dynamic changes in gut microbial ESs from infancy through adulthood and into inflammatory conditions such as UC. Early infancy is dominated by ES-Bifidobacterium and ES-Escherichia signatures, the latter being associated with preterm birth, antibiotic exposure, and immune dysfunction. During childhood and adulthood, healthy microbiomes typically transition toward combinations of ES-Bacteroidota, ES-Bacillota, and ES-Prevotella. In UC, ES profiles become disrupted, often showing ES-Escherichia dominance or atypical configurations characterized by low microbial diversity and enrichment of pathobionts, marking a state of dysbiosis.

Source: Adapted from Frioux et al. ³⁶ and Akiyama et al. ³⁷ Created in Biorender.com. Demeckova, V. (2026) https://BioRender.com/npsvnbw

ES, enterosignature; UC, ulcerative colitis.

While the bacterial microbiome has been the primary focus of most studies, the adult gut ecosystem also includes fungi and viruses, collectively forming the mycobiome and virome. UC is associated with alterations in the fecal mycobiome characterized by expansion of Saccharomyces and Candida during endoscopic inflammation and relative enrichment of Penicillium during remission. ³⁸ This fungal dysbiosis appears immunologically relevant, as Candida species can induce Th17 responses via Dectin-1 signaling. ³⁹ Consequently, the expansion of such pro-inflammatory fungi may directly contribute to the persistence of Th17-mediated inflammation in UC, suggesting that restoration of the mycobiome is a crucial component of FMT efficacy. Similarly, mucosal virome dysbiosis has been reported in UC, characterized by expansion of Caudovirales-like bacteriophages, particularly those targeting Escherichia and other Enterobacteriaceae, accompanied by reduced viral diversity and disrupted virus–bacteria interaction networks. ⁴⁰ Mechanistically, this phage bloom may exacerbate inflammation directly via TLR9-mediated sensing of viral DNA or indirectly by inducing bacterial lysis and releasing pro-inflammatory endotoxins. ⁴¹ Restoration of balanced phage–bacteria dynamics may therefore represent an additional, yet still underexplored, mechanism contributing to FMT efficacy in UC.

Dysbiosis in UC

The highest prevalence of UC is observed in industrialized countries, a trend frequently linked to Westernized dietary patterns, reduced fiber intake, increased consumption of processed foods, and widespread antibiotic exposure. ⁴² On the other hand, early life exposure to pets and farm animals, ⁴³ larger family size, ⁴⁴ and breastfeeding ⁴⁵ have been associated with a decreased risk of IBD, including UC. These observations support the concept that the gut microbiota acts as a critical interface between environmental exposures and mucosal immune regulation.^46–48 Accordingly, immune activation in UC may arise, at least in part, from microbial dysbiosis.^48,49 High-throughput sequencing technologies have consistently demonstrated reproducible alterations in the gut ecosystem of UC patients compared to healthy individuals. ⁵⁰ Meta-analytical frameworks confirm that UC-associated dysbiosis is characterized by reduced microbial diversity, depletion of obligate anaerobic SCFA-producing taxa, and expansion of facultative anaerobic bacteria.^51,52 At the phylum level, UC has most frequently been associated with reduced abundance of Bacillota, ⁵³ (particularly members of the Clostridia class) and Bacteroidota, ⁵⁴ alongside relative expansion of Pseudomonadota, ⁵⁵ although findings vary across populations and disease states.^50,56 Beyond broad taxonomic shifts, UC is characterized by depletion of commensal bacteria with anti-inflammatory properties, such as F. prausnitzii, and enrichment of potentially pro-inflammatory taxa, including Escherichia coli.^56,57 The abundance of F. prausnitzii, one of the dominant obligate anaerobes in the healthy colon, inversely correlates with disease activity and has been proposed as a biomarker of mucosal inflammation.^42,58,59

Importantly, UC-associated dysbiosis is not merely compositional but also functional. Reduced concentrations of SCFAs, particularly butyrate, are consistently observed and reflect depletion of SCFA-producing taxa.^57,60 SCFAs play a central role in epithelial barrier maintenance, immune tolerance, and regulatory T cell induction. Comprehensive metagenomic analyses have demonstrated that butyrate production in the human colon is primarily driven by a diverse and functionally redundant community, with key contributors belonging to Lachnospiraceae and Ruminococcaceae. Disruption of this functional guild, rather than loss of a single taxon, appears central to disease-associated dysbiosis. ⁶¹ Similarly, several SBAs, including lithocholic acid, deoxycholic acid, and their conjugated derivatives, are decreased in UC patients,^62–64 whereas primary bile acids are relatively increased, ⁶⁴ suggesting impaired microbial bile acid transformation. Microbial conversion of primary to SBAs is mediated by specialized anaerobic bacteria possessing bile salt hydrolase and 7α-dehydroxylation activities, many of which belong to the phylum Bacillota, particularly members of the class Clostridia. This metabolic disruption has significant immunological consequences, as SBAs function as signaling molecules activating the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). Through these receptors, bile acids modulate epithelial integrity, innate immune gene expression, and metabolic homeostasis. Reduced availability of SBAs may therefore impair receptor-mediated immunoregulation and contribute to sustained mucosal inflammation. ⁶⁵ Disruption of microbial tryptophan metabolism and reduced circulating tryptophan levels have also been reported.^53,66,67 Mechanistically, specific commensals within Bacillota, particularly members of the class Clostridia, together with selected taxa formerly classified within the genus Lactobacillus (e.g., Limosilactobacillus and Lactiplantibacillus) and certain Bacteroides species, metabolize dietary tryptophan into indole derivatives, which serve as endogenous ligands for the aryl hydrocarbon receptor (AhR). AhR signaling is pivotal for intestinal homeostasis, as it enhances epithelial barrier integrity and exerts anti-inflammatory effects. Given the immunomodulatory roles of these tryptophan-derived metabolites, their depletion may directly compromise AhR-mediated immune regulation and contribute to chronic mucosal inflammation in UC. ⁶⁸ These metabolic disturbances provide a mechanistic bridge between microbial imbalance and epithelial barrier dysfunction.

Effect of dysbiosis on IEB

The IEB is a complex, multilayered system in which each component fulfills a distinct functional role. From the luminal to the basolateral side, the gastrointestinal mucosa comprises a mucus layer and a monolayer of epithelial cells that together form a physical barrier. Beneath the epithelium, the lamina propria and submucosa serve as immunologically active compartments that coordinate immune responses through resident immune cells.^69,70 Together, these structural components form a semi-permeable barrier that enables nutrient absorption and immune surveillance while restricting the translocation of potentially harmful antigens, thereby maintaining intestinal homeostasis. As the IEB represents a critical defense interface between the host and luminal microbes, its disruption is closely linked to the initiation and perpetuation of intestinal inflammation. ⁷¹

During active UC, endoscopic and histological findings consistently demonstrate profound barrier alterations, including goblet cell depletion, altered mucin composition, impaired defensin production, thinning of the mucus layer, and tight junction disruption. ⁷² Similar to the ongoing debate surrounding dysbiosis, it remains unclear whether epithelial barrier dysfunction represents a primary driver of UC or a secondary consequence of chronic inflammation. However, accumulating evidence supports a bidirectional interaction in which dysbiosis and epithelial injury reinforce each other, perpetuating mucosal inflammation.

Mechanistic insights into this interplay suggest that commensal microbiota and their metabolites are essential for barrier maintenance. In humans, diversion colitis, which develops in the defunctioned colon after fecal stream diversion, illustrates the consequences of reduced microbial stimulation and markedly decreased levels of SCFAs. ⁷³ The lack of luminal microbial-derived metabolites has been associated with mucosal atrophy, impaired epithelial proliferation, and altered mucin production, mirroring findings observed in germ-free models.^74,75 Furthermore, microbial sensing through innate immune pathways is crucial for epithelial regeneration, underscoring the physiological role of microbiota-derived signals in tissue repair. ⁷⁶ The mucus layer represents a particularly dynamic interface. Its thickness, stratification, and penetrability are strongly influenced by microbial composition. ⁷⁷ In UC patients, the mucus layer is often penetrable by bacteria, ⁷⁸ a defect that allows direct bacterial–epithelial contact. This pathological state is mechanistically supported by animal models, such as MUC2-deficient mice, where the lack of a protective inner mucus layer leads to spontaneous inflammation. ⁷⁹ Importantly, microbiota transfer experiments have demonstrated that mucus properties are transmissible, suggesting that the altered mucus phenotype in UC may be partly driven by the dysbiotic community structure. ⁷⁷ Dietary factors further modulate this axis; chronic fiber deficiency promotes the expansion of mucin-degrading bacteria, accelerating mucus erosion and increasing epithelial exposure to luminal microbes. ⁸⁰

Beyond structural defects and direct bacterial contact, altered microbial metabolic output (as discussed above) further compromises epithelial resilience. In UC, depletion of protective metabolites and enrichment of toxic microbial products collectively weaken tight junction stability, impair epithelial energy metabolism, and promote pro-inflammatory signaling. In parallel, expansion of sulfate-reducing bacteria such as Desulfovibrio increases hydrogen sulfide production, which disrupts epithelial mitochondrial function and induces apoptosis.^56,81

Regardless of its position in the pathogenic cascade, barrier dysfunction appears to actively amplify mucosal inflammation once established. Elevated permeability has been observed not only during active disease flares but also in patients with quiescent or clinically remitted UC,^82,83 where paracellular leakage may persist despite the absence of overt endoscopic activity. ⁸⁴ Barrier impairment in UC involves both structural and functional alterations, including mucus layer thinning, tight junction disruption, reduced antimicrobial peptide production, and compromised epithelial cohesion. Collectively, these defects weaken mucosal defense and facilitate closer microbial–epithelial contact. As a consequence, bacteria more readily adhere to and interact with the epithelial surface, enhancing antigen sampling by dendritic cells (DCs) and promoting epithelial injury. Loss of barrier integrity further enables the diffusion of microbial metabolites and the translocation of luminal bacteria into the lamina propria, thereby sustaining and amplifying immune activation.^85–87

These processes initiate coordinated innate and adaptive immune activation within the colonic mucosa. Antigen-presenting cells respond to microbial translocation and epithelial injury, driving effector T-cell responses that sustain inflammation. In UC, this immune activation predominantly exhibits a Th2-skewed profile, consistent with the pathogenic framework described above. A schematic overview of this inflammatory cascade is provided in Figure 3.

Figure 3.

Dysbiosis, disrupted IEB, and chronic inflammation in UC. In a healthy gut, microbiome is in a balanced state. Normobiosis contributes to optimal function of the IEB and the mucosal immune system. In UC-associated dysbiosis, beneficial bacterial strains are depleted, and pathogens are over-represented. Dysbiotic microbiota promotes disruption of the IEB, including mucin depletion, destruction of TJs, and damaging of IECs. DCs and macrophages recognize DAMPs of injured IECs and PAMPs from bacteria that have translocated across the disrupted IEB. After phagocytosis, these antigens are presented to naïve T cells, which differentiate into effector T cells. In case the immunoregulatory mechanisms are compromised, the effector T cells continue to recruit more and more immune cells into the tissue. As part of the inflammatory response, immune cells release inflammatory cytokines, which further damage the IECs and inhibit the healing of IEB. Therefore, the inflammatory response is not attenuated, and a cycle of chronic inflammation develops.

Source: Created with Biorender.com. Demeckova, V. (2026) https://BioRender.com/9jkpgsu

DAMP, damage-associated molecular pattern; DC, dendritic cell; IEB, intestinal epithelial barrier; IEC, intestinal epithelial cell; PAMP, pathogen-associated molecular pattern; Th, Helper T cells; TJ, tight junction; UC, ulcerative colitis.

Pro-inflammatory cytokines released by immune cells in the lamina propria further contribute to epithelial injury. Macrophage-derived IL-1, IL-6, and TNF-α, markedly increase during active UC and contribute to barrier disruption. In addition, IL-13, a characteristic Th2 cytokine produced by NKT cells, exerts direct cytotoxic effects on epithelial cells and is consistently upregulated in UC patients.^10,87 Together, these mechanisms establish a self-reinforcing inflammatory loop: barrier disruption permits microbial translocation, immune activation amplifies cytokine release, and sustained cytokine exposure further impairs epithelial integrity. ¹⁷ Importantly, the directionality of this loop remains debated. Recent perspectives have challenged the concept of a UC-specific “dysbiotic signature,” suggesting that many reported microbial alterations are not unique to UC and may normalize during remission. According to this “egg rather than chicken” framework, dysbiosis may arise secondary to primary epithelial defects, such as impaired antimicrobial peptide secretion or altered mucin production. Nevertheless, once established, dysbiosis can further destabilize barrier function and perpetuate mucosal inflammation. This evolving view underscores the need for therapeutic strategies that simultaneously target microbial composition and reinforce epithelial resilience to interrupt the chronic inflammatory cycle. ⁸⁸

FMT: Modulation of the gut microbiome as a novel approach to treat UC

Given the central role of dysbiosis and impaired barrier function in UC pathogenesis, therapeutic strategies that modulate the gut microbiota have gained increasing attention. Several approaches can be used to influence intestinal microbial composition in patients with UC. The most physiological strategy involves dietary modulation, particularly increased intake of dietary fiber, which serves as a prebiotic substrate for commensal bacteria. Prebiotics can also be administered as supplements in capsule or tablet form.^89,90 Another approach is the use of probiotics, live microorganisms that confer health benefits to the host, or their combination with prebiotics (synbiotics).^19,90 However, in contrast to these interventions, FMT represents a more comprehensive strategy for microbiota modulation, as it transfers an entire microbial community rather than selected strains or substrates. ⁹¹

Glassner et al. ¹² summarized microbiome-based therapeutic strategies and categorized them according to the desired outcome of microbial manipulation (Table 3). These approaches aim to (1) replace beneficial microbes, (2) remove harmful taxa, (3) reset the microbial ecosystem, or (4) redesign the microbial structure and function. In the context of UC, replacement strategies may involve supplementation with anti-inflammatory taxa, such as F. prausnitzii, ⁹² or administration of their bioactive metabolites, including butyrate. Removal strategies may target expansion of pro-inflammatory bacteria through selective antibiotics or bacteriophage therapy. Reset approaches include short-term antibiotic use followed by microbial restoration. Among these strategies, FMT uniquely enables large-scale reconstitution of microbial diversity and ecological balance, which is particularly relevant in severe UC-associated dysbiosis. Looking forward, microbiome redesign through genetically engineered microorganisms has been proposed as a conceptual framework within microbiome-based interventions. Such approaches, currently limited to preclinical and experimental settings, aim to enable targeted delivery of bioactive molecules directly at sites of colonic inflammation or to selectively modulate microbial metabolic pathways. Beyond genetic engineering, emerging strategies increasingly incorporate systems biology and computational modeling. Integration of metagenomic, metabolomic, and strain-level datasets using machine learning approaches may allow prediction of donor–recipient compatibility, identification of responder-specific microbial signatures, and rational design of defined microbial consortia. Although these approaches remain investigational, they illustrate a shift from empirical microbiota transfer toward precision-guided ecosystem engineering. At present, however, these strategies remain far from routine clinical application in UC. ¹²

Table 3.

Microbiome-based treatment approaches. ¹² .

Desired outcome	Treatment approach	Notes
Replace	Specific anti-inflammatory bacterium (probiotics)	e.g., Faecalibacterium prausnitzii 92
	Multiple-bacteria probiotics
	Specific anti-inflammatory molecule	e.g., Butyrate
Remove	Specific inflammatory bacteria; remove with a phage	e.g., Escherichia coli
Reset	Antibiotics
Redesign	FMT	Single-donor, multi-donor, super-donor
	Genetically modified organisms to deliver medications and/or inflammatory molecules

FMT, fecal microbiota transplantation.

Concept and history of FMT

FMT procedure involves the transfer of processed fecal material from a carefully screened healthy donor—either individual or pooled—into the gastrointestinal tract of a recipient, aiming to restore microbial balance and functional homeostasis. Unlike probiotics, which provide a limited number of defined bacterial strains, FMT introduces a highly complex and metabolically diverse microbial consortium comprising bacteria, fungi, viruses, and archaea, thereby recapitulating the ecological architecture of a healthy gut microbiome. ⁹¹

The concept of fecal therapy dates back to traditional Chinese medicine in the 4th century, where fecal suspensions were used to treat severe diarrhea. Similar practices were documented during the Ming dynasty, and anecdotal historical reports describe the use of animal feces for dysentery treatment during World War II. ⁹³ The first documented use of FMT in Western medicine occurred in 1958, when Eiseman et al. ⁹⁴ successfully treated pseudomembranous colitis (now recognized as CDI) using fecal enemas. In the following decades, FMT became established as a highly effective therapy for recurrent and refractory CDI, achieving cure rates exceeding 80%, substantially outperforming antibiotic therapy alone. This success led to endorsement by major gastroenterological societies as standard care for recurrent CD.^17,20,91 Encouraged by these results, clinical research expanded to other dysbiosis-associated disorders, including UC. Early reports of FMT in UC include a self-administered case described by Bennet and Brinkman ⁹⁵ in 1989 and subsequent cases reported by Borody et al., ⁹⁶ demonstrating clinical and endoscopic remission. In the following decades, the growing recognition of FMT’s therapeutic potential led to efforts to standardize its preparation, delivery, and safety monitoring.

A major milestone in FMT standardization was the establishment of centralized stool banks, such as OpenBiome (founded in 2012), which introduced standardized donor screening, preparation, and distribution procedures to ensure safety and reproducibility across clinical centers. Further regulatory development introduced the category of Live Biotherapeutic Products (LBPs), defined as pharmaceutical-grade microbial preparations designed to restore microbiome function. Two LBPs, Rebyota (rectal suspension of donor stool-derived microbes) and Vowst (oral Firmicutes (Bacillota) spores), have received FDA approval for prevention of recurrent CD. ⁹⁷

Collectively, these developments illustrate the evolution of FMT from an empirical practice to a scientifically regulated microbiota-based therapy. While its clinical efficacy is firmly established in CDI, its role in UC remains an area of active investigation. Ongoing efforts to optimize donor selection, microbial profiling, delivery routes, and defined microbial consortia may ultimately transform FMT into a precision-based therapeutic strategy tailored to disease-specific dysbiosis, including UC.

Mechanisms of action

The therapeutic potential of FMT in UC is thought to rely on multiple, interconnected mechanisms involving both compositional and functional remodeling of the gut ecosystem. While dysbiosis has historically been described in taxonomic terms (e.g., reduced diversity or expansion of pathobionts), increasing evidence suggests that restoration of functional microbial networks and metabolic capacity is central to clinical response. ⁹⁸

Restoration of microbial cross-feeding networks

The gut microbiome operates as a metabolically integrated ecosystem in which microorganisms exchange substrates and metabolites, including SCFAs, amino acids, vitamins, and bile acid derivatives. Disruption of these cross-feeding interactions in UC contributes to reduced butyrate availability, impaired mucin synthesis, and increased mucosal permeability. FMT has been associated with re-expansion of SCFA-producing taxa and partial recovery of metabolic cross-feeding, which may restore butyrate-dependent colonocyte energy metabolism and support Treg differentiation via inhibition of NF-κB signaling pathways.^98,99

Reinforcement of intestinal barrier integrity

FMT may enhance epithelial barrier function through several complementary mechanisms. Increased SCFA availability promotes mucin gene expression, supports tight junction stability, and fuels epithelial regeneration. In addition, normalization of bile acid metabolism following FMT activates FXR and TGR5 signaling pathways, which enhance mucosal defense and reduce bacterial translocation and inflammation.^64,98 Experimental studies further suggest that FMT restores goblet cell function, promotes defensin synthesis, and induces epithelial autophagy, collectively supporting barrier resilience (Figure 4). ¹⁰⁰

Figure 4.

Mechanisms of action of FMT. FMT can restore intestinal homeostasis through multiple, interconnected pathways. Collectively, these mechanisms contribute to clinical and endoscopic remission and restoration of a healthy gut ecosystem.

Source: Created with Biorender.com. Demeckova, V. (2026) https://BioRender.com/ga1qr2n

FMT, fecal microbiota transplantation.

Immunomodulation

The intestinal microbiota continuously interacts with the host immune system, and dysregulation of this dialogue is central to UC pathogenesis. FMT appears to promote a shift from pro-inflammatory toward regulatory immune signaling. Restoration of microbial diversity and metabolite production has been associated with attenuation of pro-inflammatory cytokine signaling, including TNF-α, IL-6, and IL-17, alongside expansion of Tregs. Butyrate-mediated epigenetic regulation and modulation of DC activation may contribute to this effect.^98,100 Importantly, while CD is classically associated with Th1/Th17 skewing, UC exhibits a predominantly Th2-skewed inflammatory pattern. Given the reduction in IL-17 and general pro-inflammatory signals alongside Treg expansion, FMT-induced immune modulation in UC likely reflects a broad restoration of balance, attenuating both Th2 and Th17-mediated inflammation, rather than simple suppression of a single immune axis.

Colonization resistance against pathobionts

By increasing microbial diversity and restoring ecological competition, FMT may reinforce colonization resistance against opportunistic taxa implicated in UC, including adherent-invasive E. coli and sulfate-reducing bacteria such as Desulfovibrio. These bacteria produce metabolites (e.g., hydrogen sulfide, enterotoxins) that disrupt epithelial integrity and amplify mucosal inflammation. Reintroduction of keystone taxa and restoration of metabolic balance may reduce niche availability for these pathobionts and stabilize the mucosal ecosystem. ⁹⁸

Trans-kingdom contributions

Emerging evidence indicates that the efficacy of FMT is not solely mediated by bacteria. Viral, fungal, and archaeal components of the donor stool, together with microbial metabolites and host-derived factors (e.g., secretory IgA and desquamated colonocytes), may act synergistically to support therapeutic outcomes. Studies in recurrent CDI have demonstrated that sterile fecal filtrates and bacteriophage transfer can mediate therapeutic benefit, raising the possibility that similar trans-kingdom interactions may influence outcomes in UC. ⁹⁸

These observations argue for a multi-scale model of FMT action in UC. Instead of acting through a single metabolite-driven pathway, FMT appears to induce coordinated remodeling across molecular (metabolite signaling), cellular (epithelial and immune responses), strain-level (engraftment dynamics), and community-level (ecological restructuring and cross-feeding networks) dimensions. Such an integrative ecosystem perspective more accurately captures the complexity of host–microbiome interactions underlying therapeutic response.

Clinical efficacy of FMT in UC

The clinical efficacy of FMT in UC has been evaluated in an increasing number of randomized controlled trials (RCTs), yielding outcomes that range from modest to clinically meaningful remission rates (Table 4). Early pilot studies by Rossen et al. ¹⁰¹ and Moayyedi et al., ¹⁰² were among the first to evaluate the clinical efficacy of FMT as a therapeutic strategy for active UC. Although the study by Rossen et al. found no significant difference between donor-derived and autologous FMT (approximately 20%–30% remission; p = 0.51), the trial by Moayyedi et al. demonstrated higher clinical and endoscopic remission rates with weekly multidonor enemas compared with placebo (24% vs 5%; p = 0.03). These initial findings suggested that donor composition, delivery route, and dosing frequency are key determinants of efficacy. Subsequent multicenter, double-blind trials reinforced this concept. Paramsothy et al. ¹⁰³ demonstrated that an intensive 8-week multidonor regimen combining colonoscopic infusion with repeated enemas significantly increased steroid-free remission rates (27% vs 8%; p = 0.02). Similarly, Costello et al. ¹⁰⁴ confirmed superior efficacy of anaerobically prepared pooled-donor material compared with autologous FMT (32% vs 9%; p = 0.03), emphasizing the importance of preserving oxygen-sensitive commensals and standardized preparation techniques. Smaller prospective studies further refined these observations. Schierová et al. ¹⁰⁵ achieved 37% clinical remission at week 6 using repeated single-donor enemas in patients with left-sided UC, whereas Fang et al. ¹⁰⁶ reported 90% clinical and mucosal remission after a single fresh FMT compared with 50% in patients receiving standard medical therapy for recurrent disease. Collectively, these findings indicate that FMT can induce remission even under limited dosing regimens, although response durability and optimal protocols remain to be fully defined. The marked variability in remission rates across studies suggests that differences in donor characteristics, microbial community composition, and strain-level engraftment capacity may substantially influence therapeutic outcomes. Recent donor-focused analyses have demonstrated that ecological stability and species evenness of the donor microbiome are associated with improved engraftment and higher remission rates, indicating that biological donor quality may contribute to inter-trial heterogeneity.^107,108 These observations highlight that clinical efficacy cannot be interpreted independently of donor-dependent factors.

Table 4.

Clinical studies of FMT in UC.

Study (year, country)	Design/N	FMT protocol (route, dose, donor)	Patient type/total dose of FMT	Main result (remission/response)	Safety notes/remarks
Rossen et al., 2015 101 (Netherlands)	Double-blind phase II RCT; n = 50	2 infusions via nasoduodenal tube; healthy single-donor vs autologous	Mild-to-moderate active UC/240	No significant difference between donor and autologous FMT	Early phase II RCT with limited power; no direct FMT-related serious adverse events; donor variability suspected; route of administration may influence outcomes
Moayyedi et al., 2015 102 (Canada)	Double-blind RCT; n = 75	Weekly enemas ×6; multi-donor	Active UC/300	Higher remission with FMT notable “super-donor” effect	Marked donor-to-donor variability; generally safe with rigorous donor screening; rare serious adverse events reported
Paramsothy et al., 2017 103 (Australia)	Multicenter double-blind RCT; n = 85	Intensive multi-donor FMT: colonoscopy + enemas 5×/week for 8 weeks	Active UC/1537,5	Multidonor intensive FMT induced significantly higher steroid-free remission	Intensive schedule and pooled donors improved efficacy compared to previous less frequent or single-donor protocols.
Costello et al., 2019 104 (Australia)	Multicenter double-blind RCT; n = 73	Anaerobically prepared pooled-donor FMT: colonoscopy + 2 enemas/7 days	Mild-to-moderate active UC/100	Donor FMT superior to autologous FMT	Short-duration, high-quality anaerobic preparation protocol was effective and safe with similar adverse event rates between groups.
Schierová et al. 2020 105 ; (Czech Republic)	Prospective RCT, n = 16	Enema (50 g stool in 150 mL saline), applied five times in week 1 and once weekly until week 6	Active left-sided UC/500	Clinical and endoscopic remission achieved in a subset of patients	No adverse events reported during treatment or 6 weeks after; small sample, single-donor design.
Fang et al., 2021 106 (China)	Prospective RCT pilot; n = 20	Single fresh FMT (lower GIT)	Recurrent active UC/50	High remission rates following single fresh FMT	Small size and single-center design; striking induction effect of single fresh FMT.
Crothers et al., 2021 109 (USA)	Double-blind RCT pilot; n = 12	FMT by colonoscopy followed by 12 weeks of daily oral frozen encapsulated FMT	Mild-to-moderate active UC/90	No clear superiority over placebo in small cohort	Daily oral cFMT was found to be safe and well tolerated, with high adherence and no treatment-emergent adverse events related to FMT; Challenges included home storage of frozen capsules.
Březina et al., 2021 110 (Czech Republic)	Multicenter open-label RCT; n = 45	5 FMT enemas in first week, then weekly enemas for 5 weeks	Mild-to-moderate left-sided UC/350-500 g	Clinical improvement observed alongside mesalazine	Good safety profile, well tolerated; comparable adverse events
Haifer et al., 2022, 111 Australia	Double-blind, RCT; n = 35	Oral lyophilized FMT capsules daily for 8 weeks after 2-week antibiotic treatment	active UC/ns	Oral FMT induced steroid-free clinical and endoscopic remission
Kedia et al., 2022 112 (India)	Open-label RCT; n = 73	Multidonor FMT (lower GIT) + AID	Mild-to-moderate active UC/350	Combination therapy superior to standard medical therapy	Highlights a synergistic effect between diet and microbiome manipulation, presenting a cost-effective and safe approach.
Sarbagili Shabat et al., 2022 113 (Israel and Italy)	Blinded RCT; n = 62	Day 0 colonoscopic FMT 200 mL to right colon, plus 100 mL enemas on Days 2 and 14	Mild-to-moderate active UC/130	Modest remission rates; diet alone showed notable benefit	No serious adverse effects; diet may have an under-appreciated role in the treatment of UC
Tkach et al., 2022 114 (Ukraine)	Open-label RCT; n = 53	Single colonoscopic FMT as add-on to SMT (mesalazine)	Mild-to-moderate active UC /200–300	Improved clinical and microbiological outcomes with adjunctive FMT	Single colonoscopic FMT as add-on to mesalazine improves clinical and microbiological parameters and is safe and well tolerated.
Lahtinen et al., 2023 115 (Finland)	Double-blind RCT; n = 48	Single-dose FMT via colonoscopy into cecum	UC in clinical remission/30	No significant benefit in long-term maintenance	Single FMT dose via colonoscopy was ineffective in maintaining remission in UC during 12-month follow-up. No serious adverse events.
Gogokhia et al., 2025 116 (USA)	Double-blind RCT; n = 27	Single 250 mL of FMT by colonoscopy ± psyllium fiber supplementation (5 g) twice a day	Mild-to-moderate UC/ns	Single-dose FMT improved short-term outcomes; fiber had no additive effect	Fiber supplementation had no significant added benefit. FMT well tolerated.
Microbiotica COMPOSER-1, 2023 117 (European study)	Multicenter double-blind phase Ib RCT; n ~ 29 (recruited)	Oral capsule MB310, containing 8 live gut commensal bacterial strains, once a day/12 weeks + standard care	Active, mild-to-moderate UC/ns	Ongoing trial assessing strain-level engraftment and efficacy	First precision microbiome tailored trial; explores strain-level engraftment and impacts on UC
Allegretti et al., 2025, 118 (USA)	Open-label multicenter phase III; n = 74 IBD (UC + CD) with recurrent CDI	Rebyota®; single rectal dose	Adults with IBD (UC and CD) and recurrent CDI/150 mL	Demonstrated safety and microbiome restoration in IBD cohort	Safety-focused study

AID, anti-inflammatory diet; CDI, Clostridioides difficile infection; FMT, fecal microbiota transplantation; GIT, gastrointestinal tract; IBD, inflammatory bowel disease; LBP, Live Biotherapeutic Product; ns, not specified; RCT, randomized controlled trial; SMT, standard medical therapy; UC, ulcerative colitis.

Recent innovations in formulation and delivery have expanded the therapeutic scope of FMT. Haifer et al. ¹¹¹ showed that lyophilized oral FMT capsules achieved corticosteroid-free clinical and endoscopic remission in 53% of recipients versus 15% in the placebo group at week 8 (p = 0.027). Maintenance dosing sustained remission through week 56, demonstrating that encapsulated FMT can be both effective and practical. In contrast, Lahtinen et al. ¹¹⁵ reported that a single colonoscopic FMT failed to maintain remission in quiescent UC during 12-month follow-up (54% vs 41% placebo; p = 0.66), suggesting that repeated administrations may be required for long-term benefit.

Combination strategies have produced particularly encouraging results. In an open-label RCT, Kedia et al. ¹¹² reported that multidonor FMT combined with an anti-inflammatory diet (AID) was superior to optimized medical therapy in inducing clinical response, remission, and deep mucosal healing (p ⩽ 0.03). This synergistic approach supports the hypothesis that dietary modulation enhances microbial engraftment and functional recovery of the gut ecosystem. However, a separate trial assessing donor preconditioning with an AID was terminated early for futility, showing low remission rates (FMT 11.8%, FMT + diet 21%, diet alone 40%), indicating that not all diet–microbiome interactions provide additive benefits. ¹¹³ Interestingly, the AID alone achieved the highest remission rate, underscoring the strong impact of dietary modulation on gut microbiota and mucosal healing.

Recent and ongoing trials continue to refine FMT protocols. Tkach et al. ¹¹⁴ demonstrated that adjunctive colonoscopic FMT combined with mesalazine improved both clinical outcomes and microbial diversity in mild-to-moderate UC without serious adverse events. Likewise, Brˇezina et al. ¹¹⁰ confirmed the safety and feasibility of repeated single-donor FMT administered over 6 weeks, and Crothers et al. ¹⁰⁹ showed that oral frozen FMT capsules are a practical option for maintenance therapy. The most recent trial by Gogokhia et al. ¹¹⁶ provided proof of concept that donor selection and prebiotic fiber can influence strain-level engraftment after FMT. Although a single-dose FMT achieved significant clinical efficacy in mild-to-moderate UC compared with placebo, fiber supplementation conferred no additional clinical benefit, suggesting that dietary components may modulate microbial integration rather than immediate therapeutic response. Moreover, ongoing precision-designed trials such as Microbiotica COMPOSER-1 (2025) ¹¹⁷ aim to evaluate defined microbial consortia with known strain composition to overcome donor variability and improve the predictability of outcomes.

Recent meta-analyses provide quantitative confirmation of the therapeutic potential of FMT in UC, while also highlighting its limitations and variability across study designs. A comprehensive analysis by Feng et al., ¹¹⁹ which included 13 RCTs (n = 580), showed that FMT significantly improved both clinical remission (p < 0.00001) and endoscopic remission (p = 0.001) compared with control groups, without a significant increase in serious adverse events (p = 0.96). Subgroup analyses revealed that non-oral administration, multidonor preparations, and higher total doses (⩾300 g) were associated with greater efficacy, whereas older trials or those using smaller inocula (<300 g) showed weaker effects. These findings emphasize the critical role of dosing, donor diversity, and delivery route in optimizing therapeutic benefit.

The most recent systematic review and meta-analysis (14 RCTs; n = 600), confirmed that patients treated with FMT had significantly higher odds of achieving both combined clinical and endoscopic remission (p < 0.0001) as well as clinical remission alone (p = 0.0002) compared with controls. ¹²⁰ Importantly, oral formulations and multidonor preparations produced the most favorable outcomes. Pretreatment with methotrexate, biologics, or corticosteroids was associated with improved remission rates, suggesting that combining microbiota modulation with anti-inflammatory therapy may enhance efficacy. The overall safety profile remained acceptable, with no increase in post-treatment colitis or other serious adverse events.

Collectively, pooled evidence indicates that FMT induces clinical remission in approximately 30%–50% of patients with active UC, depending on donor selection, delivery route, total dose, and concomitant therapies. However, long-term maintenance of remission and standardization of protocols remain key challenges. Future trials should focus on optimizing multidonor, orally delivered, and adjunctive FMT strategies to achieve durable mucosal healing and reproducible clinical outcomes.

Factors influencing the efficacy of FMT

While RCTs and meta-analyses consistently demonstrate that FMT can induce clinical and endoscopic remission in active UC, therapeutic response remains heterogeneous. This variability suggests that FMT efficacy is not uniform but depends on specific microbial, immunological, and ecological determinants.

Microbial and functional determinants of therapeutic response

Recent high-quality analyses have shifted the conceptual understanding of FMT from a non-specific microbial replacement strategy toward a precision ecosystem intervention. A meta-analysis rest-ricted to double-blind RCTs confirmed that FMT significantly increases the likelihood of combined clinical and endoscopic remission compared with placebo, without excess serious adverse events. ¹²¹ However, subgroup analyses did not identify a single procedural variable (fresh vs frozen, single vs pooled donor, upper vs lower route) that uniformly predicted response, suggesting that donor–recipient microbial compatibility and functional restoration are more critical than protocol alone. Longitudinal microbial profiling has demonstrated that sustained remission is associated with restoration of axa belonging to families Ruminococcaceae and Lachnospiraceae and enrichment of butyrate-producing taxa, including F. prausnitzii, Roseburia spp., Anaerobutyricum hallii (formerly Eubacterium hallii), Coprococcus eutactus, and Anaerostipes caccae. ¹²² These taxa contribute to the increased abundance of butyryl-CoA:acetate CoA-transferase genes and enhanced SCFA production capacity. In contrast, non-responders and patients who subsequently relapse frequently exhibit persistent enrichment of Bacteroidota, Pseudomonadota, and mucolytic species such as Mediterraneibacter gnavus (formerly Ruminococcus gnavus), which has been associated with barrier disruption and ongoing inflammatory signaling. Importantly, strain-level analyses indicate that successful FMT is characterized not by complete microbiome replacement but by transfer of a responder-specific transferable microbiota. Among these strains, IgA-coated Odoribacter splanchnicus has emerged as a mechanistically relevant bacterium enriched in responders. ¹²³ Experimental colonization models demonstrate that this species induces IL-10-dependent regulatory T-cell responses and confers protection against colitis via SCFA receptor-dependent pathways, providing direct mechanistic support for FMT-induced immunomodulation. Beyond the bacterial component, recent studies have expanded the understanding of therapeutic determinants to include the intestinal virome. Longitudinal virome analysis in the RESTORE-UC trial demonstrated that, in contrast to bacterial communities, viral engraftment following FMT is often limited and transient. Jansen et al. ¹²⁴ reported that although allogenic FMT temporarily shifted the recipient virome toward the donor configuration, this effect was modest and primarily driven by Microviridae phages, with minimal durable engraftment of donor Caudoviricetes phages. Importantly, colonic inflammation exerted a stronger influence on virome structure than FMT itself, leading to a phenomenon termed “virome drift,” characterized by progressive divergence of the recipient virome over time. These findings suggest that mucosal inflammation may create ecological constraints that limit stable phage engraftment in UC. Complementary evidence from fecal microbiota filtrate transfer (FMFT), which contains viral particles but no intact bacteria, further supports the biological relevance of phage transfer. Junca et al. ¹²⁵ demonstrated that while FMFT did not result in stable establishment of predominant donor viruses, it induced significant remodeling of the recipient virome. In contrast, full FMT led to detectable donor virus establishment that correlated with the predicted bacterial hosts transferred during the same procedure, indicating coordinated bacterial–phage engraftment dynamics. Experimental data provide mechanistic support for a causal role of phages in modulating disease severity. In a human microbiota-associated mouse model, Sinha et al. ¹²⁶ showed that virus-like particles derived from UC patients altered gut bacterial composition and exacerbated dextran sulfate sodium (DSS)-induced colitis. Notably, administration of UC-derived phages increased pro-inflammatory cytokine production and shortened colon length, effects that were dependent on intact viral particles. These findings indicate that disease-associated phages are not merely passive biomarkers of dysbiosis but may actively shape bacterial communities and amplify intestinal inflammation.

These data support a conceptual shift in the understanding of FMT efficacy in UC. Therapeutic success appears to depend on functional restoration of SCFA-producing microbial networks, strain-level engraftment of immunoregulatory taxa, suppression of pro-inflammatory microbial signatures, and donor–recipient ecological compatibility. Integration of taxonomic, functional, and virome profiling into future clinical trials may enable improved donor selection and stratified therapeutic strategies.

Procedural determinants of FMT efficacy

Although microbial determinants are central, procedural and regulatory factors also substantially influence therapeutic outcomes.

Donor selection and screening

Beyond microbial composition, donor-related factors remain critical. Currently, there are no universally accepted criteria for FMT donor selection. Donors may be relatives, spouses, close contacts, or unrelated healthy volunteers identified through structured recruitment programs. Given the potential risk of transmitting infectious or immune-mediated conditions, rigorous donor evaluation is fundamental to patient safety. Screening protocols include detailed medical history, physical examination, and comprehensive blood and stool testing for infectious agents. Exclusion criteria commonly encompass infectious diseases, gastrointestinal disorders, autoimmune conditions, metabolic syndrome, malignancy, neurological disorders, and recent antibiotic or microbiota-modulating therapy. Assessment of travel history, high-risk behaviors, prior hospitalizations, surgeries, transfusions, and relevant family history is also essential. ¹²⁷

According to the Second Rome Consensus Conference, donors should undergo repeated reassessment throughout the donation period—typically prior to each donation or at defined intervals—to confirm continued eligibility. In addition, a post-donation follow-up evaluation (approximately 3 weeks after donation) is recommended to exclude interval infections. These safety standards are most effectively implemented within structured stool bank systems, which ensure systematic documentation, traceability, and quality control. ¹²⁸

The concept of the “super donor,” an individual whose microbiota yields superior clinical response rates, has gained attention in UC trials. Moreover, several randomized studies have reported favorable outcomes using pooled multidonor preparations, potentially due to increased microbial diversity and functional redundancy. However, consensus statements caution that pooling may complicate traceability, regulatory oversight, and safety monitoring. Thus, the decision to use single-donor versus multidonor material should carefully balance potential efficacy advantages against methodological and safety considerations, particularly in multicenter trials.^128,129 Importantly, emerging mechanistic evidence indicates that donor superiority is not attributable to a single dominant bacterial species but rather to broader ecological properties of the donor microbiome. In a longitudinal metagenomic and metabolomic analysis of two donors with markedly different therapeutic efficacy (100% vs 36% remission rates), Haifer et al. ¹⁰⁸ demonstrated that the effective donor exhibited remarkable long-term microbiome stability and significantly higher species evenness. These community-level characteristics were associated with enhanced strain-level engraftment in recipients and distinct metabolic signatures validated through untargeted metabolomics, suggesting that community resilience and functional coherence represent critical determinants of donor efficacy.

Similarly, data from single-donor FMT studies indicate that a well-characterized donor enriched in SCFA-producing taxa can achieve substantial remission rates, challenging the assumption that pooled multidonor preparations are inherently superior. Levast et al. ¹⁰⁷ reported that donor-specific microbial features, rather than donor number per se, may drive therapeutic outcomes, further supporting the concept that ecological quality and functional capacity outweigh simple increases in diversity. These findings suggest that donor selection should progressively evolve from a predominantly safety-oriented screening strategy toward integrative microbial, metabolic, and strain-level profiling. Assessment of microbiome stability, species evenness, and functional engraftment potential may improve predictability of therapeutic response and support precision-based FMT approaches in UC.

Preparation of fecal material

Considerable heterogeneity exists in stool processing protocols. Typically, stool is collected on the day of transplantation, diluted in sterile saline or water, homogenized, and filtered to obtain a uniform microbial suspension. ¹³⁰ Although various diluents have been evaluated, comparative evidence remains limited, and no universal protocol has been established. In contrast to earlier practices involving same-day administration, the Second Rome Consensus strongly recommends that stool donation and administration should not occur on the same day. Instead, donations should be processed and stored within stool biobanks, allowing sufficient time for thorough screening and microbial quality assessment. Moreover, frozen fecal preparations are preferred over fresh material for both clinical practice and research, as freezing preserves microbial stability, reduces infectious risk, and facilitates batch standardization. Collected fecal suspensions can be safely stored at −80°C for up to 2 years without evidence of clinically relevant loss of efficacy. ¹²⁸

The implementation of stool banks has therefore become central to FMT standardization. The United European Gastroenterology (UEG) Working Group recommends that stool banks operate within standardized regulatory frameworks aligned with the EU Tissue and Cells Directive, ensuring long-term traceability and biosafety. ¹³¹ Within several European regulatory systems, donor stool is classified as a human tissue transplant product, ensuring traceability and safety oversight while maintaining clinical accessibility. Donor material must remain in quarantine until post-donation screening confirms safety. The UEG group further emphasizes that stool donation should remain a voluntary, non-commercial activity, and that all records must be retained for at least 30 years to allow long-term traceability. Safety aliquots should be preserved for retrospective analysis for up to 10 years post-transplantation. ¹³¹

Although stool banks are operational in multiple countries, international harmonization of regulatory frameworks remains incomplete.^17,132,133 Continued efforts toward global standardization are expected to enhance inter-study comparability, methodological rigor, and safe clinical implementation of FMT in UC.

Route of administration and dosing regimens

FMT can be administered through several routes, including the upper gastrointestinal tract (via nasogastric or nasojejunal tube, or upper endoscopy) and the lower gastrointestinal tract (via colonoscopy or retention enema). ¹²⁷ The route of delivery influences microbial engraftment, mucosal exposure, and patient acceptability. According to the Second Rome Consensus, ¹²⁸ colonoscopic infusion is considered the preferred induction approach in active UC, frequently followed by repeated rectal enemas. This strategy ensures direct delivery of donor microbiota onto inflamed colonic mucosa and has been associated with higher rates of clinical and endoscopic remission compared with upper gastrointestinal administration in several trials. For maintenance therapy, less invasive delivery methods are recommended. Repeated enemas or oral lyophilized FMT capsules represent the most practical and patient-friendly options. The Consensus suggests maintenance regimens at approximately 4-week intervals, with treatment durations extending up to 24–52 weeks depending on study design and clinical response. Oral capsule formulations provide additional practical advantages, including standardized dosing, simplified administration, and enhanced storage stability, which are particularly relevant in chronic diseases such as UC requiring repeated interventions.

Optimization of delivery route and dosing intensity represents a critical determinant of FMT efficacy in UC, underscoring the need for protocol standardization across clinical trials.

Recipient-related factors

In addition to donor and procedural variables, recipient-related factors significantly affect the therapeutic success of FMT. ¹³⁴ Baseline gut microbial diversity, inflammatory burden, disease duration, and concurrent therapies (such as corticosteroids, immunosuppressants, or biologics) may all affect microbial engraftment and therapeutic response. ¹³⁵ Preconditioning strategies, including bowel lavage or antibiotic pretreatment, have been proposed to enhance donor microbiota colonization. ¹³⁶ However, evidence supporting their routine use in UC remains inconsistent, and their impact on long-term remission has not been definitively established. ¹³⁷ Emerging longitudinal analyses indicate that higher baseline microbial α-diversity and relative enrichment of SCFA-producing taxa are associated with improved clinical remission rates following FMT. In contrast, low-diversity microbiome configurations enriched in Pseudomonadota, Fusobacteriota (formerly Fusobacteria), M. gnavus, or Segatella copri (formerly Prevotella copri) have been associated with treatment non-response. ¹³⁵ Importantly, successful engraftment does not appear to require complete microbial replacement. Rather, donor–recipient ecological compatibility and functional integration of key microbial networks seem to be critical determinants of therapeutic success. ¹³⁸ These findings underscore the importance of donor–recipient matching and the integration of microbial and metabolic profiling into FMT protocols to improve efficacy and reproducibility. Further stratified trials are warranted to identify patient subgroups most likely to benefit from FMT.

Safety considerations

Although FMT is generally considered safe and well-tolerated, potential safety concerns remain, particularly regarding the risk of infectious disease transmission and immune-mediated complications. Most adverse events reported in FMT trials are mild and transient, including abdominal discomfort, bloating, diarrhea, and low-grade fever. However, rare but serious complications have been documented. The FDA issued a safety alert following cases of extended-spectrum β-lactamase-producing E. coli sepsis in two immunocompromised recipients of investigational FMT, one of whom subsequently died. ¹³⁹ This incident led to mandatory screening for multidrug-resistant organisms (MDROs) and reinforced the necessity for stringent donor evaluation protocols. According to the Second Rome Consensus, donor screening must include repeated testing for enteric pathogens and MDROs, and stool material should be quarantined until repeat testing confirms safety. ¹²⁸ Similarly, the UEG Working Group ¹³¹ emphasized that stool banks must comply with rigorous biosafety and quality management standards, maintaining long-term traceability and post-treatment monitoring. Such regulatory frameworks are particularly critical in UC, where recipients frequently receive immunosuppressive or biologic therapies. Beyond infectious risks, non-infectious adverse events have been reported, including transient worsening of UC activity, low-grade fever, constipation, or exacerbation of extraintestinal manifestations.^140,141 Although typically self-limited, theoretical concerns remain regarding long-term immune modulation resulting from the transfer of donor-derived microbial metabolites or immune-active components. The durable immunological consequences of FMT in UC remain insufficiently characterized and require longitudinal investigation.

FMT should therefore be performed under strict clinical supervision, preferably within research or hospital settings where emergency care and microbiological control are available. The Rome Consensus recommends follow-up for at least 12 months after FMT to monitor for delayed adverse events and microbiota instability. Comprehensive reporting of both beneficial and adverse outcomes—including relapse, non-response, or unexpected systemic events—is essential to refine safety surveillance.

Emerging data further suggest that FMT may carry increased risk or reduced efficacy in specific subgroups, including severely immunocompromised patients, individuals with advanced hepatic disease, or those undergoing intensive immunosuppressive regimens.^142–144 Accordingly, patient selection in UC should incorporate assessment of immune status, comorbidities, and concomitant therapies. Absolute contraindications include active systemic infection, severe neutropenia, or gastrointestinal perforation.

To enhance both efficacy and safety, current research is shifting toward next-generation microbiota-based therapeutics designed to replicate the beneficial effects of FMT while minimizing infectious and procedural risks. These include defined microbial consortia, spore-based formulations, and engineered LBPs produced under strict manufacturing and safety standards.^145–147 Recent international position statements ¹⁴⁸ emphasize that development of LBPs requires rigorous strain-level characterization, including genomic sequencing, phenotypic profiling, toxicological testing, genetic stability monitoring, GMP-compliant production, and structured post-marketing surveillance. This transition marks a conceptual evolution from empirical fecal transplantation toward mechanistically defined, standardized microbial therapeutics for UC.

Conclusion

UC arises from a complex interplay among host genetic susceptibility, epithelial barrier dysfunction, immune dysregulation, and microbial imbalance. Accumulating evidence positions the gut microbiota as a central modulator of disease activity rather than a passive bystander, underscoring its therapeutic relevance. Consequently, FMT offers a unique strategy capable of hitting multiple therapeutic targets simultaneously: restoring ecological balance, reinforcing epithelial barrier function, and alleviating mucosal inflammation. Although clinical potential is evident, widespread application remains limited by variability in donor selection, preparation protocols, and patient response. Future progress will depend on deeper mechanistic insight into host–microbiome interactions and rigorous standardization. The transition toward next-generation strategies—including defined microbial consortia, spore-based preparations, and engineered LBPs—promises safer, more predictable, and personalized modulation. Ultimately, integrating these therapeutics into precision medicine frameworks may transform microbiome restoration from an experimental adjunct into a structured, mechanism-driven cornerstone of UC management.