In patients with alcohol-associated cirrhosis, the intestinal microbiome composition is disturbed with a loss of beneficial functions and an increase in pathobionts. These changes are associated with disease severity and decompensation, due in part to the exacerbation of liver inflammation by an altered microbiome. Microbes or their antigens may translocate to the liver to potentiate the activation of immune cells and thereby contribute to inflammatory injury. Moreover, microbes may aggravate liver disease through the production of toxins or metabolites, via the effects on bile acids or the intestinal immune system.

Alcohol-related liver disease (ALD) is a major cause of mortality and disability-adjusted life years. It is not fully understood why a small proportion of patients develop progressive forms of ALD (e.g., fibrosis and cirrhosis). Differences in the metabolic processes could be behind the individual progression of ALD. Our aim was to examine differences in serum metabolome between patients with nonprogressive ALD and patients with an early form of progressive ALD.

The study had three study groups: progressive ALD (alcohol-related steatohepatitis or early-stage fibrosis, n = 50), nonprogressive ALD (simple steatosis, n = 50) and healthy controls (n = 32). Both ALD groups took part in a voluntary alcohol rehabilitation programme. A nontargeted metabolomics analysis and targeted analysis of short-chain fatty acids were done to the serum samples taken on the day of admission.

We found 111 significantly (p < 0.0005) altered identified metabolites between the study groups. Our main finding was that levels of glycine-conjugated bile acids (Cohen's d = 0.90-0.91), glutamic acid (d = 1.01), 7-methylguanine (d = 0.77) and several phosphatidylcholines (d = 0.61-0.85) were elevated in the progressive ALD group in comparison to the nonprogressive ALD group. Glycine-conjugated bile acids, glutamic acid and 7-methylguanine also positively correlated with increased levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, cell death biomarker M65 and liver stiffness.

Our results indicate that the enterohepatic cycle of glycine-conjugated bile acids, as well as lipid and energy metabolism, is altered in early forms of progressive ALD. These metabolic processes could be a target for preventing the progression of ALD.

This review articulates the significance of the gut-liver-brain axis in understanding hepatic encephalopathy (HE), emphasizing the role of gut microbiota in influencing liver and brain health. Key treatments like lactulose, rifaximin, probiotics, and fecal microbiota transplantation are examined for their ability to modulate the gut microbiome, thereby mitigating HE symptoms through reduced neurotoxin production and enhanced gut barrier integrity. The synopsis highlights both established and emerging microbial therapies, presenting them as crucial to the management and future strategies of HE. This comprehensive overview explores current therapeutic approaches alongside promising future interventions, suggesting that personalized microbiome-focused treatments may revolutionize HE management.

Hepatic encephalopathy (HE) is a frequent decompensation in patients with cirrhosis, which significantly affects morbidity and mortality. Ammonia is a major neurotoxin implicated in the pathogenesis, progression, and severity of HE, and various organs including the gut, muscle, kidney, and brain are involved in its metabolism. Therefore, therapeutic management involves reducing ammonia production and increasing its elimination from the blood and the brain. Prevention of HE in patients at high risk of first and recurrent episodes is important for prolonging survival. Various anti-ammonia therapies with synergistic and complementary actions have been attempted for overt HE and for prophylaxis of the first and recurrent episodes of HE. In the current review, we summarize the currently used and under-development pharmacotherapies/procedure(s) for HE in cirrhosis and their mechanism of action. Primary and secondary prophylaxis with monotherapies and combination therapies are also discussed.

The role of the gut-liver axis in liver cirrhosis is becoming increasingly recognized. We investigated the fecal microbiome in patients with liver cirrhosis and its potential function as a predictive biomarker of hepatic encephalopathy.

Patients were divided into either a high plasma ammonia (HPA) group or a low plasma ammonia (LPA) group according to the upper limit of normal of plasma ammonia concentration. 16S rRNA sequencing of fecal samples was performed to study how the microbiota affects the clinical symptoms of liver cirrhosis. The Stroop test was used to assess the ability of the brain to inhibit habitual behaviors.

Totally, 21 subjects were enrolled. Among the 18 patients with liver cirrhosis, 14 were male, the age range was 42-56 years, and the plasma ammonia level range was 20-125.9 μmol/l. The Stroop test showed more severe cognitive impairment in HPA than in LPA individuals. At the same time, there were significant differences in fecal microbiome characteristics between the two groups, characterized by a further increase in the abundance of the Proteobacteria phylum in the gut (especially aerobic Enterobacteriaceae ). Function predictions of Phylogenetic Investigation of Communities by Reconstruction of Unobserved States in the microbiome further explained the increase in the Enterobacteriaceae -dominated polyamine synthesis pathway in the gut microbiome of HPA groups.

Cirrhotic patients with hyperammonemia have a specific fecal bacterial composition (characterized via expansion of Enterobacteriaceae ). The ability to bio-synthesize polyamines that Enterobacteriaceae possesses is likely to be a key factor in the elevation of plasma ammonia.

Transjugular intrahepatic portosystemic shunts (TIPSs) are generally used for the management of complications of portal hypertension in patients with decompensated cirrhosis. However, hepatic encephalopathy (HE), which impairs neuropsychiatric function and motor control, remains the primary adverse effect of TIPS, limiting its utility. Prompt prevention and treatment of post-TIPS HE are critical, as they are strongly associated with readmission rates and poor quality of life. This review focuses on the main pathophysiological mechanisms underlying post-TIPS HE, explores advanced biomarkers and predictive tools, and discusses current management strategies and future directions to prevent or reverse HE following TIPS. These strategies include preoperative patient assessment, individualized shunt diameter optimization, spontaneous portosystemic shunt embolization during the TIPS procedure, postoperative preventive and therapeutic measures such as nutrition management, medical therapy, fecal microbiota transplantation, and stent reduction.

Acute pancreatitis (AP) is a common and potentially severe gastrointestinal condition characterized by acute inflammation of the pancreas. The pathophysiology of AP is multifactorial and intricate, involving a cascade of events that lead to pancreatic injury and systemic inflammation. The progression of AP is influenced by many factors, including genetic predispositions, environmental triggers, and immune dysregulation. Recent studies showed a critical involvement of the gut microbiota in shaping the immune response and modulating inflammatory processes during AP. This review aims to provide a comprehensive overview of the emerging role of gut microbiota and probiotics in AP. We analyzed the implication of gut microbiota in pathogenesis of AP and the modification during an acute attack. The primary goals of microbiome-based therapies, which include probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and enteral nutrition, are to alter the composition of the gut microbial community and the amount of metabolites derived from the microbiota. By resetting the entire flora or supplementing it with certain beneficial organisms and their byproducts, these therapeutic approaches aim to eradicate harmful microorganisms, reducing inflammation and avoiding bacterial translocation and the potential microbiota-based therapeutic target for AP from nutrition to pre- and probiotic supplementation to fecal transplantation.

Weightlessness-induced bone loss (WIBL) refers to the reduction of bone mass and the decline of bone resistance to load in a weightless environment. However, current treatment strategies aimed at increasing bone mass are associated with various limitations and side effects, highlighting the urgent need for safer and more effective therapeutic options to address WIBL.

We aimed to further explore the potential mechanism of the anti-WIBL effect of Atractylodes macrocephalon polysaccharide1-1(AMP1-1). To find a better way to treat WIBL and provide new insights for the development of therapeutic drugs for this condition.

Firstly, the anti-weightlessness bone loss of AMP1-1 was verified by micro-computed tomography (Micro-CT), three-point mechanical bending test and Western Blot (WB). Subsequently, the intestinal barrier was examined using histopathology, immunohistochemistry (IHC), and WB. Finally, validation experiments were performed using fecal microbiota transplantation (FMT). After FMT, 16S rDNA sequencing was used to analyze the gut microbiota composition in the rat feces.

AMP1-1 was able to inhibit WIBL by enhancing bone mass, improving toughness, and increasing osteogenic activity. Meanwhile, AMP1-1 reduced peripheral 5-HT content by restoring enterochromaffin cell function through gut microbiota regulation and tight junction repair. FMT of rat fecal microbiota after gavage of AMP1-1 into tail suspension rats still has the effects of regulating gut microbiota, repairing intestinal barrier and reducing bone loss.

Our results demonstrate that AMP1-1 exerts a protective effect against WIBL in rats, potentially by modulating 5-HT content and 5-HT-related metabolism in bone tissue through microbiota-gut-bone axis. This study is the first to elucidate the mechanism of AMP1-1 in mitigating WIBL through the perspective of the microbiota-gut-bone axis. Moreover, this research integrates plant extract research with the issue of bone loss induced by microgravity (aerospace medicine), thereby opening new avenues for natural drug research.

The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.

Numerous factors are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which are responsible for its development and progression as an independent entity, but also thanks to their simultaneous action. This is explained by the hypothesis of multiple parallel hits. These factors are insulin resistance, lipid metabolism alteration, oxidative stress, endoplasmic reticulum stress, inflammatory cytokine liberation, gut microbiota dysbiosis or gut-liver axis activation. This is a systematic review which has an aim to show the connection between intestinal microbiota and the role of its disbalance in the development of NAFLD. The gut microbiota is made from a wide spectrum of microorganisms that has a systemic impact on human health, with a well-documented role in digestion, energy metabolism, the stimulation of the immune system, synthesis of essential nutrients, etc. It has been shown that dysbiosis is associated with all three stages of chronic liver disease. Thus, the modulation of the gut microbiota has attracted research interest as a novel therapeutic approach for the management of NAFLD patients. The modification of microbiota can be achieved by substantial diet modification and the application of probiotics or prebiotics, while the most radical effects are observed by fecal microbiota transplantation (FMT). Given the results of FMT in the context of metabolic syndrome (MetS) and NAFLD in animal models and scarce pilot studies on humans, FMT seems to be a promising treatment option that could reverse intestinal dysbiosis and thereby influence the course of NAFLD.

Transjugular intrahepatic portosystemic shunt (TIPS) placement alleviates portal hypertension symptoms. Hepatic encephalopathy (HE) is a common complication of TIPS, impacting patient quality of life and the healthcare burden. Post-TIPS HE is associated with portosystemic shunting, elevated blood ammonia levels, and inflammation. Increasing attention has been given to the liver and intestinal circulation in recent years. An imbalance in intestinal microecology plays a role in the occurrence of HE and may be a new target for treatment. This review discusses the causes, diagnosis, and treatment strategies for post-TIPS HE and focuses on exploring treatment strategies and their relationships with the gut microbiota, suggesting an innovative approach to address this complication.

Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

The Gut Microbiome-Liver-Brain Axis is a relatively novel construct with promising potential to enhance our understanding of Alcohol Use Disorder (AUD), and its therapeutic approaches. Significant alterations in the gut microbiome occur in AUD even before any other systemic signs or symptoms manifest. Prolonged and inappropriate alcohol consumption, by affecting the gut microbiota and gut mucosa permeability, is thought to contribute to the development of behavioral and cognitive impairments, leading to Alcohol-Related Liver Disorders and potentially progressing into alcoholic cirrhosis, which is often associated with severe cognitive impairment related to neurodegeneration, such as hepatic encephalopathy and alcoholic dementia. The critical role of the gut microbiota is further supported by the efficacy of FDA-approved treatments for hepatic encephalopathy in alcoholic cirrhosis (i.e., lactulose and rifaximin). To stimulate new research, we hypothesize that interactions between a maladaptive stress response and a constitutional predisposition to neurodegeneration underlie the progression of AUD to conditions of Alcohol-Related Clinical Concerns with severe cognitive impairment, which represent a significant and costly burden to society. Early identification of AUD individuals at risk for developing these conditions could help to prioritize integrated therapeutic interventions targeting different substrates of the Gut Microbiome-Liver-Brain axis. Specifically, addiction medications, microbiome modulators, stress-reducing interventions, and, possibly soon, novel agents that reduce hepatic steatosis/fibrosis will be discussed in the context of digitally supported integrated therapeutic approaches. The explicit goal of this AUD treatment performed on the early stage of the disorder would be to reduce the transition from AUD to those conditions of Alcohol-Related Common Clinical Concerns associated with severe cognitive impairment, a strategy recommended for most neurological neurodegenerative disorders.

Novel therapies are needed to treat HE, and microbiome modulation is a promising target. VE303 is a defined consortium of 8 purified, clonal bacterial strains, known to produce metabolites that may be beneficial in HE. We evaluated the safety and efficacy of VE303 to treat HE.

We performed a single-center, randomized, placebo-controlled trial of VE303 in adult patients with a history of overt HE (NCT04899115). Eligible patients were taking lactulose and rifaximin, had no recent systemic antibiotics, and had MELD ≤20. All patients received 5 days of oral vancomycin followed by randomization to 14 days of VE303 or placebo (2:1). The primary endpoints were incidence of serious adverse events and change in psychometric HE score (PHES) from baseline to 4 weeks after treatment. Stool samples underwent metagenomic sequencing and metabolite quantification.

Eighteen patients completed the trial, 56% men, with a mean age of 59 years and a mean MELD of 11. Patients who received VE303 had a mean change in PHES of +1.5 versus -1.0 in those who received a placebo (p=0.20). Two of the 12 patients who received VE303 had at least 1 serious adverse event (all overt HE hospitalizations), compared with 0/6 patients who received a placebo. In the patients who received VE303, 2 of 8 strains engrafted in >50% of patients. Both VE303 strain engraftment and increased stool butyrate production had a trend toward improved PHES.

VE303 was well tolerated in patients with cirrhosis and a history of overt HE, leading to the engraftment of certain VE303 strains and a higher percentage of patients with improved PHES.

This article discusses the findings presented by Zhang et al. They analyzed the risk factors and clinical characteristics associated with Klebsiella pneumoniae infection in patients with liver cirrhosis treated at a hospital in Beijing. In this article, we focus on the connection between chronic kidney disease and the intestinal microbiota, and propose microbiota transplantation as a potential treatment for this patient group. We also examine an intriguing phenomenon related to hepatic encephalopathy, and provide insights into the future research.

Liver cirrhosis is a progressive disease with high mortality. Gut microbiota derangement, increased gut permeability, bacterial translocation and chronic inflammation all drive disease progression. This trial aims to investigate whether faecal microbiota transplantation (FMT) may improve the disease course in patients with acute decompensation of liver cirrhosis.

In this Danish, multicentre, randomised, double-blinded, placebo-controlled trial, 220 patients with acute decompensation of liver cirrhosis and a Child-Pugh score≤12 will be randomised (1:1) to oral, encapsulated FMT or placebo in addition to standard of care. Before the intervention, the patients will be examined and biological samples obtained, and this is repeated at 1 and 4 weeks and 3, 6 and 12 months after the intervention. The primary outcome is the time from randomisation to new decompensation or death. Secondary endpoints include mortality, number of decompensation events during follow-up and changes in disease severity and liver function.

The Central Denmark Region Research Ethics Committee approved the trial protocol (no. 1-10-72-302-20). The results will be published in an international peer-reviewed journal, and all patients will receive a summary of the results.

ClinicalTrials.gov study identifier NCT04932577.

The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or "immune paralysis" caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.

Up to 50-70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut-liver-brain axis and identify a promising therapeutic and predictive target for HE.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic disorder worldwide in both adults and children. It is well established that MASLD represents the hepatic manifestation of the metabolic syndrome whose definition includes the presence of obesity, type 2 diabetes (T2D), dyslipidemia, hypertension and hypercoagulability. All these conditions contribute to a chronic inflammatory status which may impact on blood brain barrier (BBB) integrity leading to an impaired function of central nervous system (CNS).

Since the mechanisms underlying the brain-liver-gut axis derangement are still inconclusive, the present narrative review aims to make a roundup of the most recent studies regarding the cognitive decline in MASLD also highlighting possible therapeutic strategies to reach a holistic advantage for the patients.

Due to its ever-growing prevalence, the MASLD-related mental dysfunction represents an enormous socio-economic burden since it largely impacts on the quality of life of patients as well as on their working productivity. Indeed, cognitive decline in MASLD translates in low concentration and processing speed, reduced memory, sleepiness but also anxiety and depression. Chronic systemic inflammation, hyperammonemia, genetic background and intestinal dysbiosis possibly contribute to the cognitive decline in MASLD patients. However, its diagnosis is still underestimated since the leading mechanisms are multi-faceted and unexplained and do not exist standardized diagnostic tools or cognitive test strategies. In this scenario, nutritional and lifestyle interventions as well as intestinal microbiota manipulation (probiotics, fecal transplantation) may represent new approaches to counteract mental impairment in these subjects. In sum, to face the "mental aspect" of this multifactorial disease which is almost unexplored, cognitive tools should be introduced in the management of MASLD patients.

The gut microbiome is associated with hepatic encephalopathy (HE), but research results on the gut microbiome characteristics of patients with liver cirrhosis with and without HE are inconsistent.

To study the gut microbiota characteristics of patients with liver cirrhosis with and without HE.

We searched the PubMed, Web of Science, EMBASE, and Cochrane databases using two keywords, HE, and gut microbiome. According to the inclusion and exclusion criteria, suitable literature was screened to extract data on the diversity and composition of the fecal microbiota in patients with liver cirrhosis with and without HE. The data were analyzed using RevMan and STATA.

Seventeen studies were included: (1) A meta-analysis of 7 studies revealed that the Shannon index in liver cirrhosis patients with HE was significantly lower than that in patients without HE [-0.20, 95% confidence interval (CI): -0.28 to -0.13, I2 = 20%]; (2) The relative abundances of Lachnospiraceae (-2.73, 95%CI: -4.58 to -0.87, I2 = 38%) and Ruminococcaceae (-2.93, 95%CI: -4.29 to -1.56, I2 = 0%) in liver cirrhosis patients with HE was significantly lower than those in patients without HE; (3) In patients with HE, Enterococcus, Proteobacteria, Enterococcaceae, and Enterobacteriaceae proportions increased, but Ruminococcaceae, Lachnospiraceae, Prevotellaceae, and Bacteroidetes proportions decreased; (4) Differences in the fecal metabolome between liver cirrhosis patients with and without HE were detected; and (5) Differential gut microbiomes may serve as diagnostic and prognostic tools.

The gut microbiomes of patients with liver cirrhosis with and without HE differ. Some gut microbiomes may distinguish liver cirrhosis patients with or without HE and determine patient prognosis.

Inflammatory bowel disease is a chronic inflammatory condition predominantly affecting the intestines, encompassing both ulcerative colitis and Crohn disease (CD). As one of the most common gastrointestinal disorders, CD's pathogenesis is closely linked with the intestinal microbiota. Recently, fecal microbiota transplantation (FMT) has gained attention as a potential treatment for CD, with the effective reestablishment of intestinal microecology considered a crucial mechanism of FMT therapy. This article synthesizes the findings of population-based cohort studies to enhance our understanding of gut microbial characteristics in patients with CD. It delves into the roles of "beneficial" and "pathogenic" bacteria in CD's development. This article systematically reviews and compares data on clinical response rates, remission rates, adverse events, and shifts in bacterial microbiota. Among these studies, gut microbiome analysis was conducted in only 7, and a single study examined the metabolome. Overall, FMT has demonstrated a partial restoration of typical CD-associated microbiological alterations, leading to increased α-diversity in responders and a moderate shift in patient microbiota toward the donor profile. Several factors, including donor selection, delivery route, microbial state (fresh or frozen), and recipient condition, are identified as pivotal in influencing FMT's effectiveness. Future prospective clinical studies with larger patient cohorts and improved methodologies are imperative. In addition, standardization of FMT procedures, coupled with advanced genomic techniques such as macroproteomics and culture genomics, is necessary. These advancements will further clarify the bacterial microbiota alterations that significantly contribute to FMT's therapeutic effects in CD treatment, as well as elucidate the underlying mechanisms of action.

Preventing hepatic encephalopathy (HE) recurrence in cirrhosis, which is associated with an altered gut-liver-brain axis, is an unmet need. Benefits of fecal microbiota transplantation (FMT) have been shown in phase I studies, but route and dose-related questions remain.

We performed a phase II randomized, placebo-controlled, double-blind, clinical trial of capsule and enema FMT in patients with cirrhosis and HE on lactulose and rifaximin. Participants were randomized into four groups (3 active doses; 2 active and 1 placebo dose; 1 active and 2 placebo doses; 3 placebo doses). Each patient received two capsules and one enema (either placebo or FMT) and were followed for 6 months. The primary outcome was FMT-related (serious) adverse events ([s]AEs)/AEs using intention-to-treat analysis. Secondary outcomes were HE recurrence, all-cause hospitalizations, death, donor engraftment, and quality-of-life. FMT was from a vegan or omnivorous donor.

We enrolled 60 patients (15/group) with similar baseline characteristics. FMT was safe without any FMT-related SAEs/AEs. Overall SAEs (p = 0.96) or death (p = 1.0) were similar. There were significant differences in HE recurrence between groups (p = 0.035, Cramer's V = 0.39). On post hoc analysis, recurrence was highest in the all-placebo vs. any FMT group (40% vs. 9%; odds ratio 0.15, 95% CI 0.04-0.64). Within the FMT groups, HE recurrence rates were similar regardless of route, doses, or donor type. Quality of life improved in FMT-recipient groups. Engraftment was highest in those with high pre-FMT Lachnospiraceae and lower in those whose HE recurred.

In patients with cirrhosis and HE on maximal therapy, FMT regardless of dose, route, or donor was safe without any FMT-related AEs. On post hoc analysis, HE recurrence was highest in the placebo-only group and linked with lower baseline Lachnospiraceae and reduced donor engraftment.

Patients with hepatic encephalopathy (HE) already on maximal therapy could have recurrences, which worsen prognosis and are not prioritized for liver transplant. In this phase II, double-blind, randomized, placebo-controlled trial in patients with cirrhosis and prior overt HE, we found that fecal microbiota transplant (FMT) was safe and well tolerated regardless of route of delivery (oral or enema), number of doses (1 through 3), or donor type (vegan or omnivorous). HE recurrence, which was a key secondary endpoint, was different between groups and, on post hoc analysis, lowest in groups that received any FMT. Donor engraftment was higher in those with higher relative abundance of Lachnospiraceae, which was associated with lower HE recurrence.

The human gut mycobiome, a minor but integral component of the gut microbiome, has emerged as a significant player in host homeostasis and disease development. While bacteria have traditionally been the focus of gut microbiome studies, recent evidence suggests that fungal communities (mycobiota) may also play a crucial role in modulating health, particularly in neuropsychiatric disorders.

This review aims to provide a comprehensive overview of current knowledge on the relationship between the gut mycobiome and neuropsychiatric disorders, exploring the potential of targeting fungal communities as a novel therapeutic strategy.

We summarized recent findings from metagenomic analyses that characterize the diversity and composition of gut mycobiota and discuss how these communities interact with the host and other microorganisms via the gut-brain axis. Key methodologies for studying mycobiota, such as high-throughout sequencing and bioinformatics approaches, were also reviewed to highlight advances in the field.

Emerging research links gut mycobiota dysbiosis to conditions such as schizophrenia, Alzheimer's disease, autism spectrum disorders, bipolar disorder, and depression. Studies indicate that specific fungal populations, such as Candida and Saccharomyces, may influence neuroinflammation, gut permeability and immune responses, thereby affecting mental health outcomes.

Understanding the gut mycobiome's role in neuropsychiatric disorders opens new avenues for therapeutic interventions, including antifungal treatments, probiotics, and dietary modifications. Future research should integrate multi-omics approaches to unravel the complex interkingdom interactions within the gut ecosystem, paving the way for personalized medicine in mental health care.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). The strong association between gut and liver inflammation has driven several pathogenic hypotheses to which the intestinal microbiome is proposed to contribute. Pilot studies of faecal microbiota transplantation (FMT) in PSC and IBD are demonstrated to be safe and associated with increased gut bacterial diversity. However, the longevity of such changes and the impact on markers of disease activity and disease progression have not been studied. The aim of this clinical trial is to determine the effects of repeated FMT as a treatment for PSC-IBD.

FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO) is a phase IIa randomised placebo-controlled trial to assess the efficacy and safety of repeated colonic administration of FMT in patients with non-cirrhotic PSC-IBD. Fifty-eight patients will be recruited from six sites across England and randomised in a 1:1 ratio between active FMT or FMT placebo arms. FMT will be manufactured by the University of Birmingham Microbiome Treatment Centre, using stool collected from rigorously screened healthy donors. A total of 8 weekly treatments will be delivered; the first through colonoscopic administration (week 1) and the remaining seven via once-weekly enema (up to week 8). Participants will then be followed on a 12-weekly basis until week 48 from the first treatment visit. The primary efficacy outcome will be to determine the effect of FMT on serum alkaline phosphatase values over time (end of study at 48 weeks). Key secondary outcomes will be to evaluate the impact of FMT on other liver biochemical parameters, PSC risk scores, circulating and imaging markers of liver fibrosis, health-related quality of life measures, IBD activity and the incidence of PSC-related clinical events. Key translational objectives will be to identify mucosal metagenomic, metatranscriptomic, metabolomic and immunological pathways associated with the administration of FMT.

The protocol was approved by the South Central-Hampshire B Research Ethics Committee (REC 23/SC/0147). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.

The trial was registered at ClinicalTrials.gov on 23 February 2024 (NCT06286709). Weblink: Study Details | FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis | ClinicalTrials.gov.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.

Incidence of a number of liver diseases has increased. Gut microbiota serves a role in the pathogenesis of hepatitis, cirrhosis and liver cancer. Gut microbiota is considered 'a new virtual metabolic organ'. The interaction between the gut microbiota and liver is termed the gut‑liver axis. The gut‑liver axis provides a novel research direction for mechanism of liver disease development. The present review discusses the role of the gut‑liver axis and how this can be targeted by novel treatments for common liver diseases.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

The gut microbiota has a complex relationship with the human host and is key to maintaining health. Disruption of the healthy diverse gut microbial milieu plays an important role in the pathogenesis of several diseases including Clostridioides difficile infection (CDI), inflammatory bowel disease, irritable bowel syndrome, alcohol-related liver disease and metabolic-dysfunction associated steatotic liver disease (MASLD). Fecal microbiota transplantation (FMT) is highly effective in treating CDI, though its utility in other diseases is still being explored.

In this narrative review, we explore the role of gut microbiota in liver diseases, focusing on key changes in the microbial composition and function. We summarize current evidence on the role of FMT, identifying gaps in current research and outlining future directions for investigation. We comprehensively searched PubMed through 15 October 2024 to identify relevant studies.

While data from available studies shows promise, more research is necessary before we can use FMT for liver diseases. Key areas that require further study are - determining the optimal FMT regimen for each disease, establishing efficacy and safety with larger clinical trials, ensuring safe and equitable access to the FMT product and mechanistic insights into the reasons for success or failure of FMT.

The last two decades have witnessed an explosion of microbiome research, including in hepatology, with studies demonstrating altered microbial composition in liver disease. More recently, efforts have been made to understand the association of microbiome features with clinical outcomes and to develop therapeutics targeting the microbiome. While microbiome therapeutics hold much promise, their unique features pose certain challenges for the design and conduct of clinical trials. Herein, we will briefly review indications for microbiome therapeutics in cirrhosis, currently available microbiome therapeutics, and the biological pathways targeted by these therapies. We will then focus on the best practices and important considerations for clinical trials of gut microbiome therapeutics in cirrhosis.

Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE.

Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE.

A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.

Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients' needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy.

We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at - 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH - such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) - to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management.

We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS.

In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa - to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH's pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof.

The online version contains supplementary material available at 10.1007/s13167-024-00381-5.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

The global COVID-19 pandemic, which began in 2019, is still ongoing. SARS-CoV-2, also known as the severe acute respiratory syndrome coronavirus 2, is the causative agent. Diarrhea, nausea, and vomiting are common GI symptoms observed in a significant number of COVID-19 patients. Additionally, the respiratory and GI tracts express high level of transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme-2 (ACE2), making them primary sites for human microbiota and targets for SARS-CoV-2 infection. A growing body of research indicates that individuals with COVID-19 and post-acute COVID-19 syndrome (PACS) exhibit considerable alterations in their microbiome. In various human disorders, including diabetes, obesity, cancer, ulcerative colitis, Crohn's disease, and several viral infections, the microbiota play a significant immunomodulatory role. In this review, we investigate the potential therapeutic implications of the interactions between host microbiota and COVID-19. Microbiota-derived metabolites and components serve as primary mediators of microbiota-host interactions, influencing host immunity. We discuss the various mechanisms through which these metabolites or components produced by the microbiota impact the host's immune response to SARS-CoV-2 infection. Additionally, we address confounding factors in microbiome studies. Finally, we examine and discuss about a range of potential microbiota-based prophylactic measures and treatments for COVID-19 and PACS, as well as their effects on clinical outcomes and disease severity.

Hepatic encephalopathy (HE) represents a critical complications of end-stage liver disease, serving as an independent predictor of mortality among patients with cirrhosis. Despite effective treatment with rifaximin, some patients with HE still progress to recurrent episodes, posing a significant therapeutic challenge. Recurrent HE is defined as experiencing two or more episodes within a 6-month period. Previous research has suggested that FMT may emerge as a promising treatment for recurrent HE. However, there remains a critical need to explore the optimal dosage. This trial aims to abscess the efficacy and safety of two FMT dosages: 800 ml or 400 ml total bacterial count, including mortality and quality of life.

This multicenter, prospective, randomized controlled trial will enroll 100 eligible patients from 31 hospitals in China. Participants will be randomly assigned in a 1:1 ratio to either the high-dose group (800 ml total bacterial count) or the low-dose group (400 ml total bacterial count). The primary objective is to assess the efficacy and safety of both dosages on outcomes at 24 and 48 weeks, including mortality and quality of life.

If either or both dosages of FMT demonstrate safe and effective treatment of recurrent HE, leading to improve quality of life and survival at 24 and 48 weeks, this trial would address a significant gap in the management of recurrent HE, carrying innovative and clinically significant implications.

NCT05669651 on ClinicalTrials.gov. Registered on 29 December 2022. CHiCTR2200067135 on China Registered Clinical Trial Registration Center. Registered on 27 December 2022.

Over the last few decades, there have been tremendous advances in our understanding of the role of the gut microbiome in cirrhosis and the clinical sequelae that follow. Progressive dysbiosis and immune dysregulation occur in patients with cirrhosis. In fact, alterations in the gut microbiome occur long before a diagnosis of cirrhosis is made. Understandably, our attention has recently been diverted toward potential modulators of the gut microbiome and the gut-liver axis as targets for treatment. The goal of this review is to highlight the utility of manipulating the gut microbiome with a focus on fecal microbiome transplantation (FMT) in patients with cirrhosis. In addition, we will provide an overview of disease-specific microbial alterations and the resultant impact this has on cirrhosis-related complications.

Liver disease is among the top ten causes of death globally. With studies suggesting a link between gut microbiota (GM) and liver disease.

We selected summary statistics data from the largest available whole-genome association study (n = 13,266) of GM by the MiBioGen consortium as the exposure, and obtained liver disease-related data from IEU Open GWAS and The NHGRI-EBI GWAS Catalog. A two-sample Mendelian Randomization (MR) analysis employing various methods, to establish the causal relationship between GM and five liver diseases. Meanwhile, single-cell RNA sequencing data were used to examine Prevotella-related genes expression under healthy and disease liver.

The IVW analysis indicate a causal relationship between GM and liver diseases, with Prevotella exhibiting a protective effect in all five liver diseases: Alcoholic liver disease (OR:0.81,95% confidence interval:0.66-1.00,P IVW = 0.0494); Cirrhosis (OR: 0.85,95% confidence interval: 0.73-0.99,P IVW = 0.0397); Hepatic failure, not elsewhere classified (OR:0.60,95% confidence interval:0.37-0.95,P IVW = 0.0305); Benign neoplasm:Liver (OR:0.39,95% confidence interval:0.2-0.75,P IVW = 0.0046); Malignant neoplasm of liver, primary (OR:0.41, 95% confidence interval:0.18-0.93,P IVW = 0.0334). The single-cell results suggest differential expression of Prevotella-related genes between liver disease patients and healthy individuals.

Our MR results show a causal relationship between the GM and liver disease. Prevotella displays a notable protective effect. This finding may enhance the precision of GM-based therapies and offer new insights for clinical research.