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.

Introduction. Depression has become one of the mental diseases that seriously affect human health. Its mechanism is very complex, and many factors influence the condition. An imbalance of the gut microbiota is being considered as a factor that impacts the occurrence and progression of depression. Future therapies may therefore tap into this connection, treating depression through manipulation of the gut microbiome.Hypothesis/Gap Statement. Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin from Latrodectus tredecimguttatus eggs, was previously demonstrated to inhibit excessive inflammation and improve depression behaviours, suggesting that it might be able to regulate the balance of gut microbiota. The aim of this study was to explore the effects of LPS and LETX-VI on depressive behaviours and gut microbiota and to analyse correlations between changes in the gut microbiota and depressive behaviours.Methodology. A murine model of depression was established, and the effects of LPS and LETX-VI treatment on depressive behaviours and gut microbiota were investigated.Results. In the murine model, depressive behaviour was induced by LPS; the ratio of Firmicutes to Bacteroidetes (F/B) and the number of pro-inflammatory bacteria in the gut microbiota increased (P<0.01), while butyric acid-producing bacteria with anti-inflammatory effect decreased (P<0.05). Furthermore, the metabolic function of the gut microbiota was disrupted, and the level of virulence factors among gut microbiota was up-regulated (P<0.05). Association analysis showed that the changes in the composition and function of gut microbiota were closely related to the depression phenotype of mice, suggesting that the abnormal function of gut microbiota is linked to depression. However, when LETX-VI was applied before LPS injection, the LPS-induced changes in the gut microbiota were alleviated, and the depressive behaviour greatly improved.Conclusion. LETX-VI can prevent depressive behaviour by regulating the composition and/or function of the gut microbiota.

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.

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.

Nisin O is an antimicrobial peptide encoded by the human gut bacterium Blautia obeum A2-162 which has antimicrobial activity against clinically relevant organisms. The nisin O biosynthetic gene cluster (BGC) varies from other nisin BGCs as it lacks a leader-peptide cleaving protease and contains two bacterial two-component response regulator-histidine kinase (RK) systems. The dissemination of the nisin O cluster, the final proteolytic biosynthesis step and the regulation of nisin O are currently unknown and are the foci of this study. We identified six nisin O-like BGCs across Blautia, Dorea and Ruminococcus species using comparative genomics. These BGCs show evidence of genetic transfer between genera, with genes involved in transposition discovered up- and downstream of the BGCs. All nisin O-like BGCs contained two RK systems but no protease. Mining the B. obeum A2-162 genome identified candidate proteases that were cloned and used in pre-nisin O leader peptide cleavage assays. None of the candidate proteases removed the leader; however, cleavage was achieved using trypsin. To maximize the expression of the nsoA1-4 peptides, the interactions of the two RK systems with predicted promoters in the nisin O cluster were assessed using a PepI reporter assay. We observed that the PnsoR2K2 promoter was constitutively expressed, with NsoR1K1 increasing its activity, and that there was increased nsoA1-4 expression when the nisin A RK system and nisin A were present. Long-read cDNA sequencing confirmed nso gene transcription in the heterologous expression system and identified a novel, highly expressed gene. This study provides evidence that the nisin O BGC has been transferred between different gut-associated genera, with all clusters lacking a protease and containing two RK systems. We hypothesize that this BGC has lost its protease due to negative selection as a result of high trypsin concentrations in the gut. Further work is required to maximize nisin O expression for it to be used as a potential antimicrobial therapy.

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.

Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.

The microbiome of the human intestine is a regulator of health that modulates immune response and plays an important role in metabolism. The diversity, and abundance of microbiota communities in the gut have been shown to change in cirrhosis and its complications. We aimed to review the current knowledge regarding microbiota alterations in cirrhosis, its potential differences according to etiology, and its role in the development of cirrhosis complications. A systematic search of the online bibliographic database up to July 2024 was performed. Randomized controlled trials and observational and cohort studies that included a total or at least a cohort of cirrhotic adult patients were enlisted for data extraction and analysis. A total of 73 publications were included for data extraction. Alpha diversity was found to decrease in cirrhotic patients in 30/38 (78%) of the studies, while beta diversity in 20/22 (90%) presented significant differences between healthy and cirrhotic groups. Proteobacteria significantly increased in 20/27 (74%) studies, followed by Actinobacteria and Fusobacteria, while 22/25 (88%) studies found either a reduction in cirrhotic patients or increased abundance in healthy controls for Firmicutes and Bacteroidetes. The most abundant genera in hepatic encephalopathy groups were pathobionts such as Enterococcus and Streptococcus, followed by Vellionella and Escherichia. Heterogeneity was found among studies regarding Alpha diversity in hepatocellular carcinoma (HCC) as it was decreased in three studies, indifferent in five, and increased in three studies in comparison to cirrhotic non-HCC patients. The dysbiosis of the gut microbiota is associated with cirrhosis and the development of complications such as hepatic encephalopathy and hepatocellular carcinoma.

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.

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.

This study aimed to investigate the effects of blackcurrant (BC) on gut microbiota abundance and composition, inflammatory and immune responses, and their relationship with bone mass changes. The effects of BC on bone mineral density (BMD), gut microbiota, and blood inflammatory and immune biomarkers were evaluated using DXA, stool and fasting blood collected from a pilot three-arm, randomized, double-blind, placebo-controlled clinical trial. Fifty-one peri- and early postmenopausal women aged 45-60 years were randomly assigned into one of three treatment groups for 6 months: control, low BC (392 mg/day) and high BC (784 mg/day); and 40 women completed the trial. BC supplementation for 6 months effectively mitigated the loss of whole-body BMD (P<.05). Six-month changes (%) in peripheral IL-1β (P=.056) and RANKL (P=.052) for the high BC group were marginally significantly lower than the control group. Six-month changes in whole-body BMD were inversely correlated with changes in RANKL (P<.01). In proteome analysis, four plasma proteins showed increased expression in the high BC group: IGFBP4, tetranectin, fetuin-B, and vitamin K-dependent protein S. BC dose-dependently increased the relative abundance of Ruminococcus 2 (P<.05), one of six bacteria correlated with BMD changes in the high BC group (P<.05), suggesting it might be the key bacteria that drove bone protective effects. Daily BC consumption for 6 months mitigated bone loss in this population potentially through modulating the gut microbiota composition and suppressing osteoclastogenic cytokines. Larger-scale clinical trials on the potential benefits of BC and connection of Ruminococcus 2 with BMD maintenance in postmenopausal women are warranted. Trial Registration: NCT04431960, https://classic.clinicaltrials.gov/ct2/show/NCT04431960.

Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD-related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury.

Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early- and late-stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD-afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries.

Patients with hepatic WD and mice with WD-related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD-related liver injury.

Individuals and mice with pronounced WD-related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD-related liver injury.

Gut dysbiosis and liver cirrhosis are two corelated complications that highly disturbs the metabolism of a normal human body. Liver cirrhosis is scarring of the hepatic tissue and gut dysbiosis is the imbalance in the microbiome of the gut. Gut dysbiosis in cirrhosis occurs due to increased permeability of the intestinal membrane which might induce immune responses and damage the normal functioning of the body. Dysbiosis can cause liver damage from cirrhosis and can further lead to liver failure by hepatocellular carcinoma. In this review we discuss if eubiosis can revert the poorly functioning cirrhotic liver to normal functioning state? A normal microbiome converts various liver products into usable forms that regulates the overgrowth of microbiome in the gut. The imbalance caused by dysbiosis retards the normal functioning of liver and increases the complications. To correct this dysbiosis, measures like use of antibiotics with probiotics and prebiotics are used. This correction of the gut microbiome serves as a ray of hope to recover from this chronic illness. In case of alcohol induced liver cirrhosis, intervention of microbes can possibly be helpful in modulating the addiction as well as associated complications like depression as microbes are known to produce and consume neurotransmitters that are involved in alcohol addiction. Hence a correction of gut liver brain axis using microbiome can be a milestone achieved not only for treatment of liver cirrhosis but also for helping alcohol addicts quit and live a healthy or at least a near healthy life.

Background: Parkinson's disease (PD) is a neurodegenerative disorder, and the main clinical characteristics are bradykinesia and muscle stiffness. Cognitive impairment (CI) is a prevalent non-motor manifestation observed in individuals with PD. According to disease severity, it can be divided into PD with mild cognitive impairment (MCI) and PD dementia. CI in PD patients may precede motor symptoms, and the gut microbiota plays an important role in PD pathogenesis. Therefore, gut microbiota may be one of the diagnostic targets for PD-CI. Methods: This study compared the gut microbiota of 43 PD-CI patients [Montreal Cognitive Assessment (MoCA) score < 26] and 38 PD patients without CI (MoCA ≥ 26). Patients' neuropsychological conditions, depression scale, and brain structure scanned by magnetic resonance imaging (MRI) were also recorded. The fecal metagenomic datasets of patients with PD, PD-CI, and CI only were retrieved from public databases for reanalysis to explore the relationship between PD, CI, and gut microbiota. Results: We found that the cortical thickness and the volume of the hippocampus, gray matter, and thalamus were significantly reduced among patients with PD-CI compared to PD without CI (P < 0.05). Moreover, the gut microbiome in patients with PD-CI had fewer short-chain fatty acid (SCFA) producing bacteria and more pathogenic bacteria. There were also alterations in patterns of metabolic pathway-encoding genes. Additionally, PD affected gut microbiota more than CI. Conclusion: CI may aggravate the severity of PD, but it did not drastically alter subjects' gut microbiota. This study reveals the relationship between gut microbiota, PD, and CI.

The microbiome, a complex micro-ecosystem, helps the host with various vital physiological processes. Alterations of the microbiome (dysbiosis) have been linked with several diseases, and generally, differential abundance testing between the healthy and patient groups is performed to identify important bacteria. However, providing a singular species of bacteria to an individual as treatment has not been as successful as fecal microbiota transplant therapy, where the entire microbiome of a healthy individual is transferred. These observations suggest that a combination of bacteria might be crucial for the beneficial effects. Here we provide the framework to utilize topic modeling, an unsupervised machine learning approach, to identify a community of bacteria related to health or disease. Specifically, we used our previously published gut microbiome data of patients with multiple sclerosis (MS), a neurodegenerative disease linked to a dysbiotic gut microbiome. We identified communities of bacteria associated with MS, including genera previously discovered, but also others that would have been overlooked by differential abundance testing. This method can be a useful tool for analyzing the microbiome, and it should be considered along with the commonly utilized differential abundance tests to better understand the role of the gut microbiome in health and disease.

Cholelithiasis is one of the more common complications following bariatric surgery. This may be related to the rapid weight loss during this period, although the exact mechanism of gallstone formation after bariatric surgery has not been fully elucidated.

The present literature review focuses on risk factors, prevention options and the impact of the gut microbiota on the development of gallbladder stones after bariatric surgery.

A potential risk factor for the development of cholelithiasis after bariatric surgery may be changes in the composition of the intestinal microbiota and bile acids. One of the bile acids-ursodeoxycholic acid-is considered to reduce the concentration of mucin proteins and thus contribute to reducing the formation of cholesterol crystals in patients with cholelithiasis. Additionally, it reduces the risk of both asymptomatic and symptomatic gallstones after bariatric surgery. Patients who developed gallstones after bariatric surgery had a higher abundance of Ruminococcus gnavus and those who did not develop cholelithiasis had a higher abundance of Lactobacillaceae and Enterobacteriaceae.

The exact mechanism of gallstone formation after bariatric surgery has not yet been clarified. Research suggests that the intestinal microbiota and bile acids may have an important role in this.

Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.

Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota.

A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study.

We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials.

This trial was registered with ClinicalTrials.gov (NCT05200468).

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Methylmercury (MeHg) remains a global public health issue because of its frequent presence in human food sources obtained from the water. The excretion of MeHg in humans occurs slowly with a biological half-time of 32-47 days. Short-term MeHg exposure may cause long-lasting neurotoxicity. The excretion through feces is a major route in the demethylation of MeHg. Accumulating evidence suggests that the intestinal microbiota plays an important role in the demethylation of MeHg, thereby protecting the host from neurotoxic effects. Here, we discuss recent developments on the role of intestinal microbiota in MeHg metabolism, based on in vitro cell culture experiments, experimental animal studies and human investigations. Demethylation by intestinal bacteria is the rate-limiting step in MeHg metabolism and elimination. The identity of bacteria strains responsible for this biotransformation is currently unknown; however, the non-homogenous distribution of intestinal microbiota may lead to different demethylation rates in the intestinal tract. The maintenance of intestinal barrier function by intestinal microbiota may afford protection against MeHg-induced neurotoxicity, which warrant future investigations. We also discuss studies investigating the effects of MeHg exposure on the population structural stability of intestinal microbiota in several host species. Although this is an emerging area in metal toxicity, current research suggests that a change in certain phyla in the intestinal microbiota may indicate MeHg overexposure.

Probiotic adjuvant has promising effects in treating alcohol induced hepatitis, depression, and anxiety. This study aimed to assess the effectiveness of adjuvant probiotic use in improving the liver functions, anxiety, and depression among patients with alcohol dependence syndrome (ADS) in a tertiary care hospital in Andhra Pradesh, India. In this prospective observational design, ADS patients with or without probiotics were followed-up at one and three months after initiation of treatment. They were assessed for liver function test (LFT), anxiety by HAM-A and depression by HAM-D scale. A total of 120 patients complied with the treatment, 60 in each group, mean age being 35.0 years (SD 9.5 years). The baseline socio-demographic and clinical characteristics were similar in both the groups. Significant reduction was noted in the probiotic group for total bilirubin (Mean difference (MD) 0.18; 95 % CI: 0.04, 0.31), AST (MD 5.0; 95 % CI: 0.5, 9.5), and ALT (MD 8.6; 95 % CI: 1.4, 15.7) at one month after treatment. Both the groups showed a considerable change in anxiety and depression scores (HAM-A and HAM-D) till three months. At three months of treatment initiation, proportional improvement of severity grade to mild form in anxiety was more in the probiotic group (35 %) than the non-probiotic group (13.3 %) (p < 0.05). Hence, probiotic supplementation can significantly reduce the hepatic enzymes and depression severity in patients with alcohol dependence syndrome but demands additional robust evidence on the causal inference.

Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.

Impact of fecal colonization by multidrug-resistant organisms (MDROs) on changes in gut microbiota and associated metabolites, as well as its role in cirrhosis-associated outcomes, has not been thoroughly investigated.

Eighty-eight cirrhotic patients and 22 healthy volunteers were prospectively enrolled with analysis conducted on plasma metabolites, fecal MDROs, and microbiota. Patients were followed for a minimum of one year. Predictive factors for cirrhosis-associated outcomes were identified using Cox proportional hazards regression models, and risk factors for fecal MDRO carriage were assessed using logistic regression model. Correlations between microbiota and metabolic profiles were evaluated through Spearman's rank test.

Twenty-nine (33%) cirrhotic patients exhibited MDRO carriage, with a notably higher rate of hepatic encephalopathy (HE) in MDRO carriers (20.7% vs. 3.2%, p = 0.008). Cox regression analysis identified higher serum lipopolysaccharide levels and fecal MDRO carriage as predictors for HE development. Logistic regression analysis showed that MDRO carriage is an independent risk factor for developing HE. Microbiota analysis showed a significant dissimilarity of fecal microbiota between cirrhotic patients with and without MDRO carriage (p = 0.033). Thirty-two metabolites exhibiting significantly different expression levels among healthy controls, cirrhotic patients with and without MDRO carriage were identified. Six of the metabolites showed correlation with specific bacterial taxa expression in MDRO carriers, with isoaustin showing significantly higher levels in MDRO carriers experiencing HE compared to those who did not.

Fecal MDRO carriage is associated with altered gut microbiota, metabolite modulation, and an elevated risk of HE occurrence within a year.

Studies have linked gut microbiota dysbiosis with sleep apnea; however, no causal relationship was found in human subjects. Finding new targets for the pathophysiology of sleep apnea might be made possible by systematically investigating the causal relationship between the human gut microbiota and sleep apnea.

A two-sample Mendelian randomization analysis was conducted. The human gut microbiome composition data, spanning five taxonomic levels, were acquired from a genome-wide association study that included 18,340 participants from 24 cohorts. Genome-wide association study data for sleep apnea were obtained from the Sleep Disorder Knowledge Portal for primary analysis and the FinnGen consortium for meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy.

Using inverse-variance weighted analysis, eight microbial taxa were initially found to be substantially linked with the apnea-hypopnea index. Only three microbial taxa remained significant associations with sleep apnea when combined with the FinnGen consortium (the class Bacilli: B = 8.21%, 95% CI = 0.93%-15.49%; p = 0.03; the order Lactobacillales: B = 7.55%, 95% CI = 0.25%-4.85%; p = 0.04; the genus RuminococcaceaeUCG009: B = -21.63%, 95% CI = -41.47% to -1.80%; p = 0.03).

Sleep apnea may lead to gut dysbiosis as significant reductions in butyrate-producing bacteria and increases in lactate-producing bacteria. By integrating genomes and metabolism, the evidence that three microbiome species are causally linked to sleep apnea may offer a fresh perspective on the underlying mechanisms of the condition.

The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.

Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients.

We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR.

In the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients.

In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

Gut dysbiosis is present in chronic hepatitis B virus (HBV) infection. In this study, we integrated microbiome and metabolome analysis to investigate the role of gut microbiome in virological response to nucleos(t)ide analogues (NAs) treatment.

Chronic HBV patients were prospectively recruited for steatosis and fibrosis assessments via liver elastography, with full-length 16S sequencing performed to identify the compositional gut microbiota differences. Fasting plasma bile acids were quantified by liquid chromatography-tandem mass spectrometry.

All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-Bacteroides, c-Blautia, and c-Prevotella. Patients with c-Bacteroides had a higher plasma ursodeoxycholic acids (UDCA) level and an increase in 7-alpha-hydroxysteroid dehydrogenase (secondary bile acid biotransformation) than other clusters. In NAs-treated patients (n = 84), c-Bacteroides was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-Bacteroides clusters (OR 3.49, 95% CI 1.43-8.96, p = 0.01). c-Blautia was positively associated with advanced fibrosis (OR 2.74, 95% CI 1.09-7.31, p = 0.04). No such associations were found in treatment-naïve patients. Increased Escherichia coli relative abundance (0.21% vs. 0.03%, p = 0.035) was found in on-treatment patients (median treatment duration 98.1 months) with advanced fibrosis despite HBV DNA undetectability. An enrichment in l-tryptophan biosynthesis was observed in patients with advanced fibrosis, which exhibited a positive correlation with Escherichia coli.

Collectively, unique bacterial signatures, including c-Bacteroides and c-Blautia, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment.

This study was supported by the Guangdong Natural Science Fund (2019A1515012003).

The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients.

This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages.

The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism.

This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression.

Clinicaltrials.gov, number NCT04339725.

Portal hypertension (PH) is a complex clinical challenge with severe complications, including variceal bleeding, ascites, hepatic encephalopathy, and hepatorenal syndrome. The gut microbiota (GM) and its interconnectedness with human health have emerged as a captivating field of research. This review explores the intricate connections between the gut and the liver, aiming to elucidate how alterations in GM, intestinal barrier function, and gut-derived molecules impact the development and progression of PH. A systematic literature search, following PRISMA guidelines, identified 12 original articles that suggest a relationship between GM, the gut-liver axis, and PH. Mechanisms such as dysbiosis, bacterial translocation, altered microbial structure, and inflammation appear to orchestrate this relationship. One notable study highlights the pivotal role of the farnesoid X receptor axis in regulating the interplay between the gut and liver and proposes it as a promising therapeutic target. Fecal transplantation experiments further emphasize the pathogenic significance of the GM in modulating liver maladies, including PH. Recent advancements in metagenomics and metabolomics have expanded our understanding of the GM's role in human ailments. The review suggests that addressing the unmet need of identifying gut-liver axis-related metabolic and molecular pathways holds potential for elucidating pathogenesis and directing novel therapeutic interventions.

Patients with decompensated cirrhosis face poor prognosis and increased mortality risk. Rifaximin, a non-absorbable antibiotic, has been shown to have beneficial effects in preventing complications and improving survival in these patients. However, the underlying mechanisms of rifaximin's effects remain unclear.

We obtained fecal samples from decompensated cirrhotic patients undergoing rifaximin treatment and controls, both at baseline and after 6 months of treatment. Shotgun metagenome sequencing profiled the gut microbiome, and untargeted metabolomics analyzed fecal metabolites. Linear discriminant and partial least squares discrimination analyses were used to identify differing species and metabolites between rifaximin-treated patients and controls.

Forty-two patients were enrolled and divided into two groups (26 patients in the rifaximin group and 16 patients in the control group). The gut microbiome's beta diversity changed in the rifaximin group but remained unaffected in the control group. We observed 44 species with reduced abundance in the rifaximin group, including Streptococcus_salivarius, Streptococcus_vestibularis, Haemophilus_parainfluenzae, etc. compared to only four in the control group. Additionally, six species were enriched in the rifaximin group, including Eubacterium_sp._CAG:248, Prevotella_sp._CAG:604, etc., and 14 in the control group. Furthermore, rifaximin modulated different microbial functions compared to the control. Seventeen microbiome-related metabolites were altered due to rifaximin, while six were altered in the control group.

Our study revealed distinct microbiome-metabolite networks regulated by rifaximin intervention in patients with decompensated cirrhosis. These findings suggest that targeting these specific metabolites or related bacteria might be a potential therapeutic strategy for decompensated cirrhosis.

The gut-liver axis has emerged as a focal point in chronic liver disorders, prompting more research into the role of the gut microbiota in liver cirrhosis. In individuals with liver cirrhosis, changes in the structure and function of the gut microbiota are closely tied to clinical prognosis. However, there is a scarcity of bibliometric evaluations conducted in this particular field.

This study is aiming to conduct a complete analysis of the knowledge structure and centers pertaining to gut microbiota in liver cirrhosis using bibliometric methods. Publications on gut microbiota and liver cirrhosis from 2001 to 2023 are sourced from the Web of Science Core Collection. For the bibliometric analysis, we employ VOSviewer, CiteSpace, and the R package "bibliometrix".

Our study encompasses a comprehensive collection of 3109 articles originating from 96 countries, with notable contributions from leading nations such as the United States and China. The quantity of publications concerning the gut microbiota of liver cirrhosis rises annually. The University of California San Diego, Virginia Commonwealth University, Zhejiang University are the primary research institutions. World Journal of Gastroenterology publishes the most papers in this field, while hepatology is the most frequently co-cited journal. These publications come from a total of 15,965 authors, and the most prolific authors are Bajaj Jasmohan S., Schnabl Bernd and Gillevet Patrick M., while the most co-cited authors are Bajaj Jasmohan S., Younossi Zobair M., and Reiner Wiest. In addition, "dysbiosis", "gut microbiota", "intestinal barrier", "fecal microbiota transplantation", and "complement-system" are the primary keywords of research trends in recent years.

This study offering a comprehensive insight into the research dynamics surrounding gut microbiota in patients with liver cirrhosis. It delineates the current research frontiers and hotspots, serving as a valuable guide for scholars.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with a high incidence of complications in the mid and late stages of gestation. This study investigates differences in the composition of intestinal flora among pregnant women diagnosed with ICP, employing Illumina MiSeq high-throughput sequencing technology.

This case-control study obtained patient data from the hospital information system (HIS) and the laboratory information system (LIS). Fecal samples were collected from 25 pregnant women who did not undergo intestinal preparation before delivery between December 2020 and March 2021. Whole-genome analysis was performed. PCR was used to amplify the 16S rRNA V3-V4 variable region, which was then sequenced. Alpha and beta diversity were computed, and the maternal intestinal flora's abundance and composition characteristics were analyzed. Differences in intestinal flora between the two sample groups were examined.

Bacteroides and Proteobacteria exhibited positive correlations with TBIL and IBIL. Betaproteobacteria, Gammaproteobacteria, and Erysipeiotrichi showed positive correlations with TBIL, IBIL, and DBIL, while Lactobacillus, Delftia, and Odoribacter demonstrated positive correlations with ALT.

The ICP group displayed significantly higher levels of total bile acid and ALT compared to the control group. The intestinal flora composition comprised four primary phyla: Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. ICP patients exhibited a lower relative abundance of intestinal flora across different levels of community composition when compared to the control group. Specific correlations between certain intestinal flora and clinical liver parameters were identified.

Leptospirosis, a re-emerging zoonotic disease, remains a significant global health concern, especially amid floods and disasters such as the Kakhovka Dam destruction. As is known, the stress that occurs in the conditions of military conflicts among civilian and military personnel significantly affects susceptibility to infectious diseases and possibly even influences their course. This review aims to explore how the gut microbiome and stress mediators (such as catecholamines and corticosteroids) might impact the leptospirosis disease course. The review opens new horizons for research by elucidating the connections between the gut microbiome, stress, and leptospirosis.

Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.

Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/β diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.