Fecal microbiota transplant and its usefulness in hepatic disorders: a systematic review

Search strategy

Searches were conducted via the Scopus (https://www-scopus-com-s.web.bisu.edu.cn) database, Google Scholar, Science Direct, and PubMed, with the support of an information professional. The duplicacy of data was eliminated, and the titles of the articles were thereafter assessed. Abstracts deemed pertinent to the subject of interest were selected for further consideration. The full-length papers of the shortlisted articles were evaluated against the qualifying criteria. The articles meeting the inclusion criteria were selected for the final systematic review. The study was conducted and reported in accordance with the PRISMA statement. ²⁵ The referenced studies were cross-examined for supplementary research (Supplemental Material). The manuscript was independently evaluated by all authors, and any discrepancies were reconciled through consensus among all authors.

Study selection

The search terms FMT (fecal microbiota transplantation or microbiome or microbiota), NAFLD (NAFSH or MASLD or ASLD), and Gut microbiota (microbiome or gut bacteria or microbiota or gut or probiotics or prebiotics or synbiotics), or ailments or hepatic were searched for the titles, abstracts, and keywords.

Data extraction and synthesis

A total of 267 results were extracted. Subsequently, works authored in languages other than English, published before January 1, 2010, and subsequent to January 1, 2025, or those that were review articles, were eliminated. After the initial removal, the abstracts of the remaining 161 articles were meticulously examined. Following an abstract review, papers were omitted if they were reviews, if they did not examine gut microbiota, gut–liver axis, or if they did not concentrate on diet, resulting in a total of 128 articles collected. Three articles were retrieved after manually reviewing the 217 items eliminated by Scopus, Google Scholar, PubMed, and Science Direct. Consequently, our systematic review encompassed a total of 129 publications as shown in Figure 1. Related to this review, all seven reviewers collected data from each report, and all they worked independently.

OPEN IN VIEWER

Figure 1.

PRISMA flowchart on study selection procedure.

Concept of FMT

FMT is a therapeutic approach that involves transferring stool, rich in beneficial microorganisms, from a healthy donor into the gastrointestinal tract of a patient to restore a balanced gut microbiome. The basic concept is based on the fact that the gut microbiota plays a vital role in digestion, immune regulation, and protection against harmful pathogens. ²⁶ When there is microbial imbalance—due to factors such as antibiotics, infections, or chronic diseases—it can lead to conditions like recurrent hepatic cirrhosis, hepatitis, CDI, etc. FMT helps to replenish the gut ecosystem with a diverse community of microbes, thereby restoring colonization resistance and improving gut health. ²⁷

On the advanced side, FMT is no longer seen as just a transfer of stool but as a highly specialized microbiome-based therapy. Research is uncovering how specific microbial taxa, metabolites, and functional genes within donor stool contribute to therapeutic success. This has led to the development of standardized stool banks, encapsulated microbiota preparations, and synthetic microbial consortia designed to mimic the beneficial effects of FMT without relying solely on donor material. These advancements aim to address challenges of safety, reproducibility, and scalability while making FMT a more regulated and accessible therapeutic tool. ²⁸

Moreover, FMT is being investigated beyond CDI to target a range of conditions such as inflammatory bowel disease, metabolic syndrome, liver disorders, and even neurological diseases through the gut–stomach axis, gut–liver axis, and gut–brain axis, respectively. Advanced approaches involve precision microbiome engineering, where donor selection and microbial profiling are tailored to patient-specific needs. ²⁹ The integration of metagenomics, metabolomics, and artificial intelligence into FMT research is also helping to identify predictive markers of treatment success. Thus, while the basic concept of FMT is grounded in restoring microbial balance, advanced aspects are pushing it toward a new era of personalized and mechanistic microbiome therapeutics. ³⁰

Link between gut and liver (gut–liver axis)

The gut–liver axis refers to the bidirectional communication between the gastrointestinal tract and the liver, mediated through the portal vein, immune signaling, and microbial metabolites. Since the liver receives most of its blood supply from the intestine, any disruption in gut microbiota can significantly influence liver physiology. ³¹ Dysbiosis in this case leads to increased intestinal permeability, allowing harmful microbial products such as lipopolysaccharides (LPS) to enter the portal circulation. This triggers liver inflammation, contributes to conditions like NAFLD, alcoholic liver disease (ALD), cirrhosis, and can worsen complications such as HE. ³²

FMT is gaining attention as a potential therapy as it modulates the gut–liver axis. By introducing a diverse and healthy microbiome, FMT can restore intestinal barrier function, reduce microbial translocation, and lower systemic endotoxemia. ³³ In cirrhosis, studies have shown that FMT reduces the recurrence of HE by increasing beneficial bacteria and decreasing ammonia-producing organisms. ³⁴ Similarly, in metabolic liver diseases such as NAFLD and NASH, FMT has shown potential in improving insulin sensitivity, reducing hepatic fat accumulation, and modulating bile acid metabolism, all of which are key processes influenced by the gut microbiome. ³⁵

The therapeutic promise of FMT in the gut–liver axis lies not only in restoring microbial balance but also in reshaping host–microbe interactions to support liver health. However, clinical applications remain at an early stage, with concerns about safety, patient variability, and long-term effects. Future directions include the use of targeted microbial consortia, precision probiotics, and metabolite-based therapies derived from FMT. Overall, FMT represents an innovative strategy to harness the gut–liver axis, providing a novel microbiome-centered approach to prevent and manage chronic liver diseases in an effective way. ³⁶

Rationale for using FMT in liver diseases

The rationale for using FMT in liver diseases stems from the intimate relationship of the gut–liver axis. The liver receives nearly 70% of its blood supply from the intestine through the portal vein, which means that microbial products, metabolites, and inflammatory mediators from the gut have a direct impact on hepatic function. ³⁷ Dysbiosis, or imbalance in the gut microbial ecosystem, has been implicated in the pathogenesis of multiple liver diseases, including NAFLD, ALD, cirrhosis, and HE. By restoring microbial diversity and functionality, FMT addresses one of the root causes of liver disease progression and disrupted host–microbe interactions. ³⁸ In cirrhosis, gut barrier dysfunction and bacterial translocation are major drivers of complications such as spontaneous bacterial peritonitis and HE. Traditional therapies such as lactulose and rifaximin provide symptomatic relief but often fail to restore long-term microbial balance.^39,40 FMT offers a biological solution by increasing beneficial microbial species, reducing pathogenic bacteria, and lowering systemic endotoxemia. ⁴¹ Clinical studies have shown that patients with cirrhosis receiving FMT experience fewer episodes of HE, improved cognitive function, and enhanced quality of life. This evidence suggests a potential therapeutic role of FMT beyond symptomatic management; however, its classification as a disease-modifying intervention remains to be established through larger, long-term clinical studies. ⁴²

FMT is also being explored in metabolic liver disorders such as NAFLD and NASH, conditions driven by obesity, insulin resistance, and systemic inflammation. The gut microbiome influences lipid metabolism, bile acid signaling, and inflammatory pathways, all of which play a critical role in fatty liver disease. ⁴³ By altering the gut microbial composition, FMT has the potential to reduce liver fat accumulation, improve insulin sensitivity, and decrease pro-inflammatory cytokines. Though clinical data are still preliminary, this approach could complement lifestyle interventions and emerging pharmacotherapies for NAFLD, making FMT a valuable component of integrative liver disease management. ⁴⁴ While whole-stool transplants carry challenges related to safety, standardization, and scalability, they provide proof of concept that modifying the gut microbiota can improve liver outcomes. This has spurred research into developing next-generation therapies such as defined microbial consortia, live biotherapeutics, and metabolite-based drugs designed to target the gut–liver axis. Therefore, the rationale for using FMT in liver diseases is not only grounded in current clinical benefits but also in its potential to pave the way for safer, more targeted, and personalized microbiome-based therapies in hepatology. ⁴⁵

Historical perspective

The history of FMT is both ancient and modern, reflecting a practice that has evolved from traditional remedies to evidence-based medicine. The earliest recorded use of fecal material as a therapeutic agent dates back to the 4th century, where physician Ge Hong described the use of “yellow soup,” a suspension of human stool, for treating severe diarrhea and food poisoning. Similar practices were later reported in veterinary medicine, where fecal material was used to treat digestive disorders in animals. Though primitive, these historical accounts reveal an early understanding of the therapeutic value of restoring gut balance through microbial transfer. ⁴⁶

In modern medicine, the concept of FMT re-emerged in the mid-20th century. In 1958, Ben Eiseman and colleagues published the first documented case series and mentioned that patients with fulminant pseudomembranous colitis were successfully treated using fecal enemas. This milestone established the clinical utility of FMT in managing severe gastrointestinal infections. ⁴⁷ However, it was not until the late 20th and early 21st centuries, with the rise of recurrent CDI and the limitations of antibiotic therapy, that FMT gained broader recognition. Clinical studies consistently demonstrated cure rates above 80%–90% for recurrent CDI, positioning FMT as one of the most effective treatments in modern gastroenterology. ⁴⁸

Over the past two decades, advancements in microbiome science, molecular sequencing, and bioinformatics have propelled FMT into the spotlight of medical research. ⁴⁹ Regulatory agencies and professional societies have also begun to develop guidelines for donor screening, preparation, and administration methods, reflecting the growing acceptance of FMT as a mainstream therapy for chronic diseases. Thus, from its ancient origins to its current status as a cutting-edge therapeutic approach, the history of FMT underscores the enduring importance of the gut microbiome in human health and disease. ⁹

Mechanisms of action and routes of administration

The therapeutic effects of FMT are primarily driven by its ability to restore microbial gut balance and diversity within the gut microbiome. In conditions such as recurrent CDI, prolonged antibiotic use disrupts the normal gut flora, allowing pathogenic bacteria to dominate. ⁷ FMT replenishes beneficial microbial populations, which compete with pathogens for nutrients and adhesion sites, secrete antimicrobial compounds, and restore colonization resistance. This re-established microbial ecology helps to suppress harmful organisms, reduces inflammation, and promotes mucosal healing, thereby directly alleviating symptoms of infection and inflammation in the gastrointestinal tract and in liver as well. ⁵⁰

Another important mechanism involves the strengthening of the intestinal barrier and reduction of microbial translocation. ⁵¹ Dysbiosis often impairs the integrity of the gut epithelium, leading to a “leaky gut” that allows bacterial products like LPS to enter systemic circulation. ⁵² FMT enhances the abundance of short-chain fatty acid (SCFA)-producing bacteria such as Faecalibacterium prausnitzii and Bifidobacterium, which improve epithelial tight junction function and lower gut permeability. This results in decreased systemic inflammation and has profound implications for diseases where endotoxemia plays a role, such as metabolic syndrome, autoimmune conditions, and complicated liver disorders. ⁵³

The mechanisms of FMT in liver diseases are linked to the gut–liver axis. Restoring microbial balance reduces the load of endotoxins and ammonia-producing bacteria reaching the liver via the portal vein, thereby lowering hepatic inflammation and improving outcomes in cirrhosis and HE. ⁵⁴ In metabolic liver diseases such as NAFLD and NASH, FMT influences bile acid metabolism, glucose regulation, and lipid homeostasis through microbial metabolites. These changes improve insulin sensitivity, reduce liver fat accumulation, and modulate immune pathways, highlighting how gut microbial modulation can directly benefit liver physiology. ⁵⁵

Additionally, FMT exerts systemic effects by reshaping host–microbe interactions at the metabolic and immunological level. Restored microbial communities produce metabolites such as SCFAs, secondary bile acids, and tryptophan derivatives that regulate host immunity, energy metabolism, and neuroendocrine signaling. These systemic changes explain why FMT is being investigated not only for gastrointestinal and liver diseases but also for neurological, metabolic, and autoimmune disorders. Thus, the basic mechanisms of FMT involve a complex interplay of microbial competition, barrier restoration, immune modulation, and metabolic regulation together forming the foundation of its therapeutic potential across human ailments, including those of hepatic disorders.^56,57

Safety and regulatory aspects

FMT carries out both therapeutic promise and distinct safety risks for patients with liver disease. The principal safety concerns are transmission of infectious agents (including multidrug-resistant organisms), exacerbation of systemic inflammation, and unpredictable effects in immunocompromised or decompensated cirrhotic patients. ⁵⁸ Regulatory agencies have already documented serious adverse events. The U.S. Food and Drug Administration (FDA) issued safety alerts after recipients developed infections (including ESBL-producing Escherichia coli) traced to donor material, and has published guidance on additional donor testing (including for enteropathogenic and shigatoxin-producing E. coli, SARS-CoV-2 considerations during the pandemic, and other emerging risks). These events underscore that the stakes are especially high in liver patients, many of whom have impaired immune defenses and altered gut barrier function that increase susceptibility to translocated pathogens. ⁵⁹

In addition to the risk of pathogen transmission, emerging evidence suggests that FMT can also result in region-specific microbiome mismatches in the gastrointestinal tract, with unintended systemic effects. As shown in DeLeon et al.’s paper, colonic anaerobic microbes with high prevalence upon engraftment into the small intestine result in long-lasting changes in intestinal identity genes (Gata4, Gata6), immune activation signatures, host metabolic processes, and even hepatic transcriptomic signatures. This paper points out that gut microbes are regionally differentiated, and in the event of non-indigenous microbiota colonization of the small bowel, chronic metabolic and immunomodulatory imbalances can be experienced via the gut–liver axis. These results are especially applicable to patients with liver disease, where there is already an abnormal intestinal ecology, compromised barrier function, and immune dysregulation, which may increase these unwanted effects. ⁶⁰ Because of those risks, donor selection, screening, and processing are the cornerstone of safe FMT practice. Best practices described in the literature and by expert groups include comprehensive clinical questionnaires, blood and stool testing for pathogens (including multidrug-resistant organisms, enteric pathogens, and relevant viruses), exclusion criteria for donors with recent antibiotic exposure or high-risk behaviors, and repeated/periodic rescreening of stool and blood for active donors. ⁶¹ The literature based upon translational applications highlight how extensive screening reduces risk but also raises costs and reduces available donations, forcing many centers to balance feasibility against safety. For liver disease trials and treatments, many centers adopt even more stringent screening and monitoring because recipients of FMT for example, those with decompensated cirrhosis or awaiting transplant) are at elevated risk for complications. ⁶²

The regulatory landscape for FMT is evolving and differs across jurisdictions, which affects how FMT is offered for hepatic indications. In the United States, the FDA has taken a cautious approach—while recognizing the clinical value of FMT for recurrent C. difficile, it treats fecal microbiota products as biologic/medical products that may require investigational new drug (IND) oversight or compliance with specific guidance, especially for indications beyond CDI; the agency has published multiple safety alerts and information updates. ⁶³ In Europe, the regulatory response has been heterogeneous (due to member states and European Medicines Agency (EMA) discussions), and horizon-scanning reports recommend clearer frameworks for classification (such as stool as tissue, a medicinal product, or something in between), standardized donor registries, and harmonized requirements. This fragmented regulatory landscape means that clinicians and researchers planning FMT for liver disease must navigate local regulations, obtain the necessary approvals (INDs or equivalent), and adhere to institution-level infection control policies. ⁶⁴ Practical implications and future directions focus on risk mitigation and standardization to make FMT safer for liver patients. ⁶⁵ Clinically, FMT used in HE and other liver trials has shown promising signals but also requires careful patient selection, pre- and post-procedure monitoring, and clear informed-consent discussion about infectious and unknown risks. ⁶⁶ From the pharmaceutical and regulatory perspective, the field is moving toward defined microbial consortia, freeze-dried or encapsulated standardized products, and rigorous stool-bank quality systems that allow reproducibility and regulatory compliance—approaches intended to lower infectious risk and satisfy regulators. Until such standardized, approved products become widely available, current practice should emphasize stringent donor screening, transparent regulatory approvals (IND or local equivalent), and multidisciplinary oversight when treating vulnerable liver patients. ⁶⁷

Regulatory developments and guidelines

The growing clinical application of FMT has prompted regulatory agencies worldwide to develop comprehensive frameworks ensuring its safety, efficacy, and ethical administration. Initially, FMT emerged as an experimental therapy for recurrent CDIs, often administered under compassionate-use provisions. However, as its therapeutic potential expanded to conditions such as inflammatory bowel disease, metabolic syndrome, and hepatic disorders, the need for formal regulatory oversight became evident. Agencies such as the U.S. FDA, the EMA, and India’s Central Drugs Standard Control Organization have since initiated structured guidelines to govern donor screening, stool processing, storage, and clinical use. In the U.S., FMT is currently regulated under the category of a “biological product” or “live biotherapeutic product,” and its clinical application outside of recurrent CDI typically requires an IND application. ⁶⁸

Recent regulatory trends emphasize the standardization and quality assurance of FMT products. While selecting an appropriate donor, we have to think about comprehensive screening for infectious agents, antibiotic resistance, metabolic abnormalities, and emerging pathogens, with repeated testing before and after stool donation. Furthermore, processing laboratories must follow Good Manufacturing Practice conditions to ensure sterility, traceability, and reproducibility. Biobanking of donor material and detailed recordkeeping are also becoming mandatory in many countries to maintain transparency and enable post-treatment monitoring. The move toward synthetic microbiota and defined microbial consortia has further highlighted the need for clear distinctions between traditional FMT, standardized microbial therapeutics, and genetically engineered live biotherapeutic agents, each requiring specific regulatory pathways. ⁹

Looking forward, harmonization of global regulatory standards will be crucial for advancing FMT into mainstream medical practice. International collaborations among health agencies, academic researchers, and pharmaceutical developers are likely to produce unified frameworks for clinical trials, data reporting, and patient follow-up. Ethical considerations—such as informed consent, equitable donor selection, and long-term monitoring of recipients—will remain central to regulatory evolution. As synthetic and personalized microbiome-based therapies emerge, there is a need to balance innovation with safety, adapting existing frameworks to accommodate next-generation FMT approaches. Ultimately, these developments aim to transition FMT from an experimental intervention into a rigorously controlled, evidence-based therapeutic modality that meets the highest standards of modern clinical practice. ⁶⁹

Anatomy and physiology of the gut–liver axis

The gut–liver axis includes a dynamic, bidirectional communication system that integrates the gastrointestinal tract and the liver through anatomical, vascular, metabolic, and immunological pathways. ⁷⁰ Anatomically, the portal vein forms the most critical connection between these organs, as it drains nutrient-rich and microbe-derived blood from the intestines directly into the liver. This anatomical arrangement ensures that the liver acts as the first line of defense against dietary antigens, toxins, and microbial products, regulating the metabolic homeostasis based on signals received from the gut. Thus, the gut–liver axis is both a surveillance and regulatory system and is considered as essential for maintaining host health. ⁷¹

The physiology of the gut–liver axis is largely shaped by the intestinal microbiota, which produces metabolites such as SCFAs, bile acid derivatives, and tryptophan metabolites. These compounds influence liver function by modulating glucose and lipid metabolism, regulating bile acid synthesis, and controlling immune responses. ⁷² For example, SCFAs help maintain epithelial barrier integrity and exert anti-inflammatory effects, while bile acids act as signaling molecules through receptors such as FXR and TGR5, influencing hepatic lipid and glucose metabolism. In this way, microbial metabolites act as biochemical messengers within the gut–liver axis. ⁷³

Another important physiological aspect is the role of the intestinal barrier. A healthy gut lining, reinforced by tight junction proteins and mucus, prevents the harmful bacteria and endotoxins such as LPS from translocating into the bloodstream. ⁷⁴ When barrier function is compromised—a phenomenon often referred to as “leaky gut”—microbial products can reach the liver via the portal vein. This triggers immune activation, inflammation, and oxidative stress in hepatocytes and Kupffer cells, leading to liver injury. Thus, gut barrier integrity is central to the physiology of the gut–liver connection. ⁷⁵

Immunologically, the gut–liver axis represents a tightly regulated balance between tolerance and defense. The gut-associated lymphoid tissue (GALT) constantly samples luminal contents, educating immune cells to distinguish between harmless dietary components, commensal microbes, and pathogenic threats. ⁷⁶ Signals from GALT are transmitted to the liver, where resident immune cells, including Kupffer cells and hepatic stellate cells, respond accordingly. This immune crosstalk ensures protection against infections while preventing excessive inflammation. Disruption of this balance contributes to chronic inflammatory liver diseases, showcasing the immunophysiological importance of the axis. ⁷⁷

Finally, the gut–liver axis plays a crucial role in the pathophysiology of various hepatic disorders, such as NAFLD, ALD, cirrhosis, and HE. In these conditions, dysbiosis, increased intestinal permeability, and altered microbial metabolite profiles drive liver inflammation, fibrosis, and metabolic dysfunction. ⁷⁸ Conversely, the liver influences the gut by altering bile acid secretion and antimicrobial peptide production, which shape microbial composition. This bidirectional relationship underscores the complexity of the gut–liver axis, making it a vital target for therapeutic interventions such as probiotics, prebiotics, and FMT. ⁷⁹

Dysbiosis in liver disease

Dysbiosis, defined as an imbalance in the composition and function of the gut microbiota, plays a central role in the development and progression of liver diseases. Under normal conditions, the gut harbors a diverse community of commensal bacteria that contribute to digestion, immune regulation, and maintenance of epithelial barrier integrity. ⁸⁰ In liver disease, however, microbial diversity is reduced, with a decline in beneficial species such as F. prausnitzii and Bifidobacterium, accompanied by an overgrowth of pathogenic bacteria, including Enterobacteriaceae and Enterococcus. This imbalance contributes to increased intestinal permeability, impaired metabolic regulation, and a pro-inflammatory environment that negatively impacts the liver through the gut–liver axis. ⁸¹

In cirrhosis, dysbiosis is particularly pronounced and manifests as decreased populations of autochthonous bacteria that produce SCFAs, alongside enrichment of urease- and endotoxin-producing organisms. These alterations promote ammonia accumulation and bacterial translocation, leading to complications such as HE and spontaneous bacterial peritonitis. ⁸² Similarly, in NAFLD and NASH, dysbiosis contributes to altered bile acid metabolism, increased LPS load, and activation of hepatic Toll-like receptors, which drive inflammation and fibrosis. Thus, dysbiosis is not merely an accompanying feature but a pathogenic driver in chronic liver disorders. ⁸³

Beyond direct microbial effects, dysbiosis in liver disease disrupts host–microbe metabolic interactions. Reduced SCFA production impairs epithelial tight junctions, while changes in bile acid-modifying bacteria alter bile acid pools and signaling through receptors such as FXR and TGR5, worsening insulin resistance and hepatic steatosis. Additionally, shifts in tryptophan-metabolizing bacteria impair production of indole derivatives that normally exert anti-inflammatory and barrier-protective effects. Together, these metabolic and immune consequences of dysbiosis underscore its importance in liver disease pathogenesis and highlight why microbiome-targeted therapies, including probiotics, prebiotics, and FMT, are increasingly being explored as promising treatment strategies.

Hepatic encephalopathy

HE represents the most extensively studied indication for FMT in chronic liver disease. The pathophysiology of HE is closely linked to dysbiosis, characterized by an overrepresentation of urease-producing taxa, such as Enterobacteriaceae and Streptococcaceae, and a depletion of beneficial butyrate-producing families, including Ruminococcaceae and Lachnospiraceae. This imbalance contributes to ammonia accumulation, systemic inflammation, and impaired gut–brain axis signaling, which exacerbate neurocognitive decline. ¹⁸ Landmark trials have demonstrated the potential of FMT to reverse these abnormalities. Bajaj et al. ⁸⁴ reported in a pilot randomized controlled trial (RCT) that cirrhotic patients with recurrent HE who received colonoscopic FMT from a donor enriched in beneficial taxa experienced significant reductions in hospitalization and HE recurrence, along with improved psychometric performance and microbial diversity restoration. Recently it has been confirmed these benefits using encapsulated FMT in cirrhotic patients, showing improvements in cognitive outcomes, decreased plasma ammonia levels, and sustained engraftment of donor microbiota. ¹⁸ More recently, Hunag et al., ⁸⁵ emphasized in their synthesis that donor selection, frequency of administration, and delivery routes are key determinants of efficacy. In contrast, Zhang et al. ⁸⁶ demonstrated in preclinical models that FMT ameliorates intestinal barrier dysfunction and systemic inflammation. Together, these findings suggest that FMT represents a promising adjunctive therapy in recurrent HE, although larger multicenter RCTs are needed to confirm long-term safety and durability of response.

Alcoholic liver disease

FMT has also been investigated in ALD, where profound gut dysbiosis and intestinal permeability play major roles in disease progression. Patients with ALD exhibit reduced commensal taxa such as F. prausnitzii and Bifidobacteria, alongside enrichment of pathogenic organisms including Enterococcus faecalis, which facilitate ethanol metabolism, acetaldehyde accumulation, and hepatocyte injury. ⁸⁷ Subsequent analyses highlighted that survival benefit correlated with donor microbial richness, underscoring the importance of donor selection. Wu et al. ⁸⁸ further discussed these findings and concluded that while early clinical evidence is encouraging, the lack of controlled trials prevents definitive conclusions. Overall, FMT appears to offer survival advantages in severe ALD, where therapeutic options are limited; however, robust randomized evidence is still required to guide clinical application. ⁸⁹

Non-alcoholic fatty liver disease

The role of the gut microbiome in NAFLD has become increasingly evident, with characteristic microbial alterations including a reduction in butyrate-producing bacteria, an increase in ethanol-producing organisms, and enrichment of proinflammatory Proteobacteria. ⁹⁰ These changes drive hepatic steatosis through mechanisms involving insulin resistance, lipogenesis, and endotoxin-mediated hepatic inflammation. ⁸⁶ Clinical exploration of FMT in NAFLD remains in its infancy, but early findings are promising. Vrieze et al. ⁹¹ provided landmark evidence by demonstrating that lean donor FMT in obese males improved peripheral insulin sensitivity, mediated by an increase in butyrate-producing taxa. More recently, Rinott et al. ⁹² conducted a RCT in NAFLD patients and reported that lean donor FMT led to a significant reduction in hepatic fat content compared with autologous controls. Recently some researchers ⁹³ also highlighted supportive preclinical evidence showing reductions in hepatic steatosis and inflammation following FMT. While these data suggest potential effects on metabolic and hepatic surrogate endpoints, further multicenter studies are needed to define optimal donor characteristics, treatment frequency, and long-term outcomes.^94,95

Cirrhosis and related complications

Cirrhosis is characterized by profound intestinal dysbiosis, impaired gut barrier integrity, and endotoxemia, which collectively drive systemic inflammation and contribute to complications such as spontaneous bacterial peritonitis, variceal hemorrhage, and HE. FMT has been explored as a strategy to restore microbial balance and may have a role in reducing complications, although evidence remains limited. ⁹⁶ Bajaj et al. ⁹⁷ showed in an open-label study that cirrhotic patients receiving FMT experienced fewer hospitalizations and improvement in Model for End-Stage Liver Disease (MELD) scores compared with standard care. Philips et al. (2022) confirmed improvements in neurocognition and systemic ammonia levels in cirrhotic patients treated with oral FMT capsules. ⁹⁸ Although these findings suggest a potential role for FMT as an adjunctive therapy in advanced cirrhosis, variability in donor selection and treatment regimens highlights the need for standardized protocols and larger randomized studies.

Although a number of studies have shown an increase in MELD scores in the aftermaths of FMT, there is a need to make a distinction between statistical significance and clinical significance. ⁹⁹ Any statistically significant changes in MELD scores can indicate aspects of laboratory parameters of serum bilirubin, creatinine, and INR, which can be measured, but which do not necessarily yield any clinical benefit to a patient. ¹⁰⁰ Clinically, even minor changes in MELD score (by 1–2 points) cannot have significant effects on prognosis, transplant prioritization, or patient survival, especially in patients with severe cirrhosis. On the other hand, this is because greater reductions (⩾3–5 points) are more perceived to be of clinical value since it can be taken to mean better hepatic functioning, less chances of decompensation, and overall better prognosis. ¹⁰¹

Reported improvements in MELD scores in FMT must thus be viewed with skepticism in view of underlying disease severity, duration of follow-up, and related clinical outcomes including rates of hospitalization, incidences of HE, and survival. It is worth noting that certain studies have shown significant improvements in MELD with modest hospitalization and recurrence of encephalopathy indicating that clinical benefits of FMT might go beyond the traditional biochemical scoring methods. ¹⁰² This creates the risk of using MELD score as a surrogate endpoint relying on a single type of interventions based on microbiomes. The next round of research must include a composite clinical outcome and a more extended follow-up so as to capture the actual therapeutic effect of FMT on liver disease progression.

Primary sclerosing cholangitis

Data on the application of FMT in primary sclerosing cholangitis (PSC) remain limited. Dysbiosis in PSC has been linked to altered bile acid metabolism, immune dysregulation, and intestinal inflammation. ¹⁰³ Case reports have suggested transient improvements in pruritus and liver biochemistry following FMT, which may be related to modulation of bile acid signaling and reductions in endotoxemia. Pilot studies are underway, but PSC remains an investigational indication for FMT. ¹⁰⁴

Clinical trials and evidence summary

Clinical trials of FMT across hepatic disorders highlight its therapeutic potential but also reveal methodological heterogeneity. ¹⁰⁸ In HE, Bajaj et al. ⁸⁴ and Philips et al. (2022) demonstrated reduced recurrence, improved cognition, and restoration of microbial diversity with colonoscopic and capsule-based FMT, respectively. ⁹⁸ In ALD, Philips et al. ¹⁰⁹ showed improved survival in severe alcoholic hepatitis where corticosteroids were contraindicated. For NAFLD, Vrieze et al. ⁹¹ and Rinott et al. ⁹² provided early proof-of-concept that lean donor FMT improves insulin sensitivity and reduces liver fat content. Cirrhosis-related studies ⁹⁷ (Philips et al., 2022) further demonstrated reduced hospitalizations and metabolic improvements (Table 1). ¹¹⁰ Collectively, these trials suggest that FMT is a feasible and generally well-tolerated intervention in selected settings.

OPEN IN VIEWER

Table 1.

Clinical trials and evidence summary.

Author/year	Disorder	Design/population	Route	Key findings	Safety	Reference
Bajaj et al., 2017	HE in cirrhosis	Pilot RCT, n = 20	Colonoscopy	↓ The recurrence, ↓ hospitalization, ↑ cognition, ↑ and diversity	Safe	(84)
Philips et al., 2017	ALD (severe AH)	Pilot, steroid-ineligible	Nasojejunal	↑ 90-day survival, ↑ diversity, ↓ inflammation	Well-tolerated	(109)
Bajaj et al., 2019	Cirrhosis	Open-label, n = 50	Colonoscopy	↓ hospitalizations, improved MELD	Safe	(97)
Philips et al., 2022	HE in cirrhosis	Open-label, n = 30	Oral capsule	Improved cognition, ↓ ammonia, ↑ and diversity	Safe	(98)
Vrieze et al., 2012	NAFLD/MetS	RCT, n = 18 obese men	Duodenal	↑ insulin sensitivity, ↑ SCFA producers	Safe	(91)
Rinott et al., 2021	NAFLD	RCT, n = 24	Capsule	↓ Liver fat, improved microbiota	Safe	(92)

ALD, alcoholic liver disease; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; RCT, randomized controlled trial; SCFA, short-chain fatty acid.

Next-generation FMT (synthetic microbiota)

Next-generation FMT, often referred to as synthetic microbiota or defined microbial consortia, represents a significant advancement over traditional stool-based FMT. ² Instead of transferring entire fecal material from a donor, which carries variability and potential safety risks, synthetic microbiota involves deliberately combining well-characterized, cultured bacterial strains that collectively mimic the functional and compositional benefits of a healthy gut microbiome. These defined microbial cocktails are designed to restore microbial diversity, re-establish metabolic balance, and suppress pathogenic bacteria with improved precision and reproducibility. ³⁶ The development of such formulations relies heavily on metagenomic and metabolomic analyses to identify key bacterial taxa and their roles in maintaining gut and systemic health.

This next-generation approach offers multiple advantages, including enhanced safety, standardization, and regulatory compliance. Unlike conventional FMT, which faces ethical and logistical challenges related to donor screening and pathogen transmission, synthetic microbiota can be manufactured under controlled laboratory conditions, ensuring consistency and minimizing infection risks. ¹³¹ Furthermore, targeted microbial consortia can be tailored to specific diseases like recurrent CDI, inflammatory bowel disease, or even hepatic and metabolic disorders—thereby offering a more personalized therapeutic option. As research progresses, synthetic FMT is expected to evolve into a precision-microbiome therapy, bridging microbiology, bioengineering, and clinical medicine for safer and more effective modulation of the gut ecosystem. ¹³²

Personalized microbiome-based therapies

The future of FMT lies in its transition from a generalized therapeutic approach to a personalized microbiome-based therapy. ¹³³ With the advancement of metagenomics, metabolomics, and systems biology, clinicians can now profile an individual’s gut microbiome in great detail, identifying unique microbial signatures associated with specific diseases or therapeutic responses. This precision enables the customization of FMT formulations tailored to each patient’s microbial composition and health status. ¹³⁴ Personalized FMT could thus optimize microbial compatibility between donor and recipient, enhance engraftment efficiency, and reduce adverse reactions. Moreover, by integrating artificial intelligence and big data analytics, it will become possible to predict optimal microbial combinations and delivery methods for specific pathological conditions such as HE, inflammatory bowel disease, obesity, and metabolic disorders. ¹¹²

In the coming years, personalized microbiome-based interventions will likely expand beyond traditional stool transplants toward rationally designed microbial therapeutics. These may include engineered bacterial strains with defined functions, phage-based therapies targeting harmful microbes, and microbial metabolite supplementation to restore functional balance in the gut–liver or gut-brain axes. Regulatory frameworks and ethical guidelines will need to evolve alongside these innovations to ensure safety, efficacy, and quality control. Ultimately, the convergence of precision medicine and microbiome science is expected to redefine FMT—from a crude microbial transfer to a scientifically engineered, patient-specific therapy capable of addressing complex, multifactorial diseases with unprecedented accuracy.

FMT beyond bacteria—Role of virome and mycobiome

Basically, FMT has been viewed primarily as a bacterial therapy aimed at restoring gut microbial balance. However, emerging research reveals that the gut ecosystem extends far beyond bacteria—it also includes viruses (the virome) and fungi (the mycobiome), both of which play critical roles in maintaining intestinal and systemic health. ¹³⁵ The virome, composed largely of bacteriophages, modulates bacterial populations and gene exchange, influencing microbial stability and immune responses. Similar to microbiome and virome, the mycobiome contributes to nutrient metabolism, immune modulation, and the maintenance of mucosal integrity. Dysbiosis within these non-bacterial communities has been linked to various diseases, including severe liver disorders and metabolic syndrome-related problems. Recognizing their functional importance, future FMT strategies are expected to consider the holistic restoration of the gut ecosystem—integrating bacterial, viral, and fungal components for more comprehensive and durable therapeutic outcomes. ¹³⁶

In the future, multi-kingdom FMT may become a new paradigm for microbiome therapy. Advanced omics technologies—metagenomics, viromics, and mycobiomics—are already enabling the identification of key viral and fungal taxa involved in health and disease. This knowledge will allow the development of refined microbial formulations that include not only beneficial bacteria but also selected phages to control pathogenic microbes and commensal fungi to promote gut resilience. Engineered bacteriophages could be harnessed to modulate bacterial composition precisely, while synthetic fungal consortia might restore metabolic and immunological balance. Such multi-component FMTs could provide superior efficacy in complex disorders where bacterial interventions alone have shown limited success.

From a translational perspective, incorporating virome and mycobiome elements into FMT presents both opportunities and challenges. Standardization, safety assessment, and regulatory acceptance of non-bacterial components will require rigorous investigation. Ethical and biosafety considerations also need to be addressed as the potential for horizontal gene transfer, pathogenic activation, and long-term ecological effects. Nonetheless, the integration of the virome and mycobiome into next-generation FMT represents a forward-looking step toward truly ecosystem-level therapeutics. As our understanding of the gut microbiome deepens, future FMTs are likely to evolve into precision-designed microbial ecosystems—engineered consortia of bacteria, viruses, and fungi that collectively restore homeostasis and promote health across multiple organ systems. ¹³⁷

In this review, binary clinical outcomes such as recurrence of HE, hospitalization rates, and survival were primarily summarized using risk ratios or proportions. Continuous outcomes—including liver fat content, ammonia levels, insulin sensitivity, MELD score changes, microbial diversity indices, inflammatory markers, and metabolic parameters—were described using mean differences, percentage changes, or absolute score changes. Microbiome-related outcomes (e.g., abundance of taxa, SCFA levels) were presented through relative abundance differences rather than pooled effect measures due to heterogeneity. Overall, outcomes were synthesized narratively using the effect measures most appropriate to each data type reported across included studies.