The impact of the fecal multidrug-resistant organism (MDRO) carriage on the gut microbiota, metabolite alterations, and cirrhosis-related complications remains unclear.

Eighty-eight patients with cirrhosis and 22 healthy volunteers were analyzed for plasma metabolites, fecal MDROs, and microbiota composition. The fecal bacterial and fungal composition was assessed using 16S ribosomal RNA and internal transcribed spacer sequencing, whereas plasma metabolomic analysis was evaluated via untargeted liquid chromatography-mass spectrometry. Predictors of cirrhosis-related outcomes, risk factors for MDRO carriage, and microbiota-metabolite correlations were analyzed.

Fecal MDRO carriage was detected in 33% of patients with cirrhosis. MDRO carriers had a higher risk of hepatic encephalopathy (HE) compared to non-carriers (20.7% vs. 3.2%, p = 0.008). Patients carrying MDROs had higher plasma lipopolysaccharide (LPS) levels, and both elevated LPS and MDRO carriage independently predicted HE occurrence within 1 year. Compared with non-carriers, MDRO carriers had higher fecal bacterial and fungal burdens and exhibited different gut microbiota compositions, characterized by increased Streptococcus salivarius and enrichment of Saccharomycetes and Candida albicans. Thirty-one metabolites differed significantly among healthy controls, and patients with cirrhosis, with and without MDRO carriage. Six metabolites were significantly correlated with specific microbial taxa in MDRO carriers. Isoaustin, a fungal-derived metabolite, was significantly elevated in MDRO carriers with HE.

Fecal MDRO carriage was associated with endotoxemia, altered gut microbiota, metabolic changes, and a higher risk of HE. It's worthy to monitor fecal MDRO colonization in cirrhosis.

Many investigations have highlighted the involvement of the intestinal microbiota in the progression of cervical cancer lesions; however, the causal link between them remains to be confirmed. We employed two-sample Mendelian randomization (MR) as a alternative to randomized controlled trials (RCTs) to explore the association between intestinal microbiota and high-risk Human Papillomavirus (HPV) infection, cervical intraepithelial neoplasia (CIN), and cervical cancer (CC). This method allowed for a detailed investigation of the underlying mechanistic interactions within the gut-cervix axis. The analysis predominantly encompassed the utilization of inverse variance weighting (IVW) and the Wald ratio test. Additionally, various sensitivity analysis methods were employed to validate the findings. We uncovered a total of 17 gut microbial taxa associated with HPV infection, 9 taxa related to CIN, and 7 taxa linked to CC. At different stages of cervical cancer lesions, various gut microbial communities play either protective or promoting roles. However, some microbial communities also act as persistent risk factors in promoting the progression of CC. Our investigation has revealed that the gut microbiota exerts a considerable impact along the entire spectrum of CC progression within the gut-cervix axis. These findings lay a foundation for prospective research focused on the utilization of gut microbiota in cervical cancer screening, prevention, and therapeutic strategies.

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.

Hepatic encephalopathy (HE) is a primary complication following transjugular intrahepatic portosystemic shunt (TIPS), but the utility of pharmacological prophylaxis for HE is unclear.

To assess the HE incidence post-TIPS across various groups and the prophylactic efficacies of various medications.

A thorough literature search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library databases from their inception to November 24, 2024, to collect data regarding HE incidence. The main outcome was HE incidence post-TIPS. A meta-analysis using a random effects model was performed to obtain odds ratios (ORs) and 95% confidence intervals. Statistical analyses were conducted using Stata and RevMan software.

This meta-analysis included nine studies with 1140 patients; 647 received pharmacological agents including lactulose, rifaximin, albumin, and l-ornithin-l-aspartate, and 493 did not (controls). (1) In the single-group meta-analysis, the control group had higher short- and long-term HE rates than the drug intervention group. Among patients with and without prior HE, the non-intervention group's HE rates were also higher; (2) Pharmacological prevention post-TIPS significantly reduced HE incidence [OR = 0.59 (0.45, 0.77), P = 0.0001]. Compared with the no prophylaxis, rifaximin reduced the risk of HE after TIPS [OR = 0.52 (0.29, 0.95), P = 0.03], but lactulose did not; (3) In patients without prior HE, pharmacological prevention significantly reduced post-TIPS HE incidence [OR = 0.62 (0.41,0.95), P = 0.03]; and (4) Network meta-analysis showed no significant differences among five prevention strategies.

The HE incidence after TIPS was relatively high, and the use of drugs after TIPS may reduce the HE incidence. However, research, especially large-scale randomized controlled trials, is still lacking.

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.

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.

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.

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination and cognitive impairment that reduce life quality and span. Motor incoordination is due to neuroinflammation and enhanced GABAergic neurotransmission in cerebellum. Recent reports support that probiotics, including L. casei, may improve cognitive function in different pathologies and MHE in cirrhotic patients. Extracellular vesicles (EV) are small cell-derived membrane vesicles that carry bioactive molecules released from cells, including bacteria. We hypothesized that EV from Lacticaseibacillus paracasei (LC-EV) could improve neuroinflammation, GABAergic neurotransmission and motor function in MHE. We show that LC-EV treatment reverses glial activation and neuroinflammation in cerebellum and restore motor coordination in hyperammonemic rats. Moreover, ex vivo treatment of cerebellar slices from hyperammonemic rats with LC-EV also reverses glial activation and neuroinflammation, and the enhancement of the TNFR1-S1PR2-BDNF-TrkB and TNFR1-TrkB-pAKT-NFκB-glutaminase-GAT3 pathways and of GABAergic neurotransmission. The results reported support that LC-EV may be used as a therapeutic tool to improve motor incoordination in patients with MHE.

With the rising prevalence of chronic liver diseases worldwide, there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease. Currently, the most common causes of liver disease are non-alcoholic fatty liver disease, hepatitis, and alcoholic liver disease. Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis. In this review, we analyse the relationship between the gut and liver and their significance in liver disease. This two-way relationship has interesting effects on each other in liver diseases. The gut microbiota, through its metabolites, influences the metabolism in numerous ways. Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases. Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.

Bacterial infections in patients with cirrhosis lead to a 4-fold increase in mortality. Immune dysfunction in cirrhosis further increases the risk of bacterial infections, in addition to alterations in the gut microbiome, which increase the risk of pathogenic bacteria. High rates of empiric antibiotic use contribute to increased incidence of multidrug-resistant organisms and further increases in mortality. Despite continous advances in the field, major unknowns regarding interactions between the immune system and the gut microbiome and strategies to reduce infection risk and improve mortality deserve further investigation. Here, we highlight the unknowns in these major research areas and make a proposal for a research agenda to move toward improving disease progression and outcomes in patients with cirrhosis and infections.

Gut microbiota perturbation and motor dysfunction have been reported in steatosis patients. Rats with mild liver damage (MLD) show motor dysfunction mediated by neuroinflammation and altered GABAergic neurotransmission in the cerebellum. The extracellular vesicles (EV) from mesenchymal stem cells (MSC) have emerged as a promising therapeutic proxy whose molecular basis relies partly upon TGFβ action. This study aimed to assess if MSC-EVs improve motor dysfunction in rats with mild liver damage and analyze underlying mechanisms, including the role of TGFβ, cerebellar neuroinflammation and gut microbiota. MLD in rats was induced by carbon tetrachloride administration and EVs from normal (C-EVs) or TGFβ-siRNA treated MSCs (T-EV) were injected. Motor coordination, locomotor gait, neuroinflammation and TNF-α-activated pathways modulating GABAergic neurotransmission in the cerebellum, microbiota composition in feces and microbial-derived metabolites in plasma were analyzed. C-EVs reduced glial and TNFα-P2X4-BDNF-TrkB pathway activation restoring GABAergic neurotransmission in the cerebellum and improving motor coordination and all the altered gait parameters. T-EVs also improved motor coordination and some gait parameters, but the mechanisms involved differed from those of C-EVs. MLD rats showed increased content of some Bacteroides species in feces, correlating with decreased kynurenine aside from motor alterations. These alterations were all normalized by C-EVs, whereas T-EVs only restored kynurenine levels. Our results support the value of MSC-EVs on improving motor dysfunction in MLD and unveil a possible mechanism by which altered microbiota may contribute to neuroinflammation and motor impairment. Some of the underlying mechanisms are TGFβ-dependent.

Gut microbiota (GM) affects the progression and response to treatment in liver diseases. The GM composition is diverse and associated with different etiologies of liver diseases. Notably, alterations in GM alterations are observed in patients with portal hypertension (PH) secondary to cirrhosis, with hepatitis B virus (HBV) infection being a major cause of cirrhosis in China. Thus, understanding the role of GM alterations in patients with HBV infection-related PH is essential.

To evaluate GM alterations in patients with HBV-related PH after transjugular intrahepatic portosystemic shunt (TIPS) placement.

This was a prospective, observational clinical study. There were 30 patients (with a 100% technical success rate) recruited in the present study. Patients with esophagogastric variceal bleeding due to HBV infection-associated PH who underwent TIPS were enrolled. Stool samples were obtained before and one month after TIPS treatment, and GM was analyzed using 16S ribosomal RNA amplicon sequencing.

One month after TIPS placement, 8 patients developed hepatic encephalopathy (HE) and were assigned to the HE group; the other 22 patients were assigned to the non-HE group. There was no substantial disparity in the abundance of GM at the phylum level between the two groups, regardless of TIPS treatment (all, P > 0.05). However, following TIPS placement, the following results were observed: (1) The abundance of Haemophilus and Eggerthella increased, whereas that of Anaerostipes, Dialister, Butyricicoccus, and Oscillospira declined in the HE group; (2) The richness of Eggerthella, Streptococcus, and Bilophila increased, whereas that of Roseburia and Ruminococcus decreased in the non-HE group; and (3) Members from the pathogenic genus Morganella appeared in the HE group but not in the non-HE group.

Intestinal microbiota-related synergism may predict the risk of HE following TIPS placement in patients with HBV-related PH. Prophylactic microbiome therapies may be useful for preventing and treating HE after TIPS placement.

Cirrhosis, a pathological stage that develops from various chronic liver diseases, is characterized by liver fibrosis, pseudolobular formation, and chronic inflammation. When it progresses to the decompensated phase, the mortality rate of cirrhosis can reach 80%. The role of gut microbiota in the progression of liver diseases has received significant attention. Numerous studies have shown that regulating gut microbiota has significant therapeutic effects on preventing and reversing liver cirrhosis. This article reviewed the mechanisms by which gut microbiota influence liver cirrhosis, explaining the effective therapeutic effects of traditional Chinese medicine. Through multi-directional regulation involving signaling pathways, gut microbiota diversity, and restoration of intestinal barrier function, traditional Chinese medicine has been promising in ameliorating liver cirrhosis, providing treatment options and pharmacological guidance for the occurrence and development of liver cirrhosis.

There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated.

This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results.

The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis.

Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.

Hepatic encephalopathy is a common and serious complication of decompensated cirrhosis. It can considerably contribute to economic burden and impaired quality of life. However, its pathogenesis remains unclear.

In this study, we aimed to visually analyse the research status and development trends in hepatic encephalopathy pathogenesis using bibliometrics and knowledge mapping. Information regarding publications between 1978 and 2022 were obtained from the Web of Science Core Collection. CiteSpace was used to analyse and present data by year, author, institution, country, journal, reference, and keyword.

A total of 1578 publications on hepatic encephalopathy pathogenesis in patients with cirrhosis were retrieved from Web of Science Core Collection. A gradual increasing trend in annual publications has occurred. The collaborative network analysis results suggest the United States of America, the University of London, and Bajaj, Jasmohan S as the most influential country, institution, and author, respectively, in this research field. Notably, China appeariiuis to be the most promising country. Research on 'hepatology' garners the most significant papers in the field. Combined with reference co-citation and keyword co-occurrence analyses, we found that ammonia metabolism, gut microbiota, sarcopenia, and trace elements will become future research frontiers that are likely to be explored for a considerable length of time.

Future research directions in HE pathogenesis may target modulating the ammonia metabolism, the gut microbiota, sarcopenia, and trace elements.

Portal hypertension has cerebral consequences via its causes and complications, namely hepatic encephalopathy (HE), a common and devastating brain disturbance caused by liver insufficiency and portosystemic shunting. The pathogenesis involves hyperammonemia and systemic inflammation. Symptoms are disturbed personality and reduced attention. HE is minimal or grades I to IV (coma). Bouts of HE are episodic and often recurrent. Initial treatment is of events that precipitated the episode and exclusion of nonhepatic causes. Specific anti-HE treatment is lactulose. By recurrence, rifaximin is add-on. Anti-HE treatment is efficacious also for prophylaxis, but emergence of HE marks advanced liver disease and a dismal prognosis.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward.

The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.

Chronic liver disease (CLD) is a persistent public health burden, with over one billion cases reported worldwide. In most cases, the progression of CLD is slow and undulating with end-stage liver disease developing at variable time points depending on the underlying etiology of the disease. The concept of reversibility or halting progression to end stage liver disease is recent and various medications are in the pipeline which influence the progression of CLD. Non-invasive tests for monitoring of CLD may have the potential to avoid the morbidity and mortality related to invasive procedures. However, their applicability and validation in pediatrics requires further development and a coordinated effort by large pediatric liver centres. Recent advances in metabolomics and modern molecular technologies have led to an understanding of the interaction between gut microbiome liver axis and gut dysbiosis contributing to liver diseases. In the future, modifying the gut microbiome has the potential to change the outcome and significantly reduce the morbidity associated with CLD. This article focuses on newer modalities and concepts in the management of CLD, which may help develop strategies to prevent its progression to end-stage liver disease and associated morbidity/mortality.

Fecal microbiota transplantation (FMT) offers a potential treatment avenue for hepatic encephalopathy (HE) by leveraging beneficial bacterial displacement to restore a balanced gut microbiome. The prevalence of HE varies with liver disease severity and comorbidities. HE pathogenesis involves ammonia toxicity, gut-brain communication disruption, and inflammation. FMT aims to restore gut microbiota balance, addressing these factors. FMT's efficacy has been explored in various conditions, including HE. Studies suggest that FMT can modulate gut microbiota, reduce ammonia levels, and alleviate inflammation. FMT has shown promise in alcohol-associated, hepatitis B and C-associated, and non-alcoholic fatty liver disease. Benefits include improved liver function, cognitive function, and the slowing of disease progression. However, larger, controlled studies are needed to validate its effectiveness in these contexts. Studies have shown cognitive improvements through FMT, with potential benefits in cirrhotic patients. Notably, trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care. Although evidence is promising, challenges remain: Limited patient numbers, varied dosages, administration routes, and donor profiles. Further large-scale, controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy. While FMT holds potential for HE management, ongoing research is needed to address these challenges, optimize protocols, and expand its availability as a therapeutic option for diverse hepatic conditions.

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.

Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well.

Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed.

After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers.

There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

Background: Hepatic encephalopathy (HE) caused by cirrhosis has severe consequences on an individual's lifespan, leading to long-term liver complications and potentially life-threatening outcomes. Despite recent interest in this condition, the effectiveness of secondary prophylaxis involving rixafimin, lactulose, or L-ornithine L-aspartate (LOLA) may be hindered by the unique microbial profiles each patient possesses. Methods: Thus, in this manuscript, we aimed to search, identify, and gather all randomized controlled trials (RCTs) published between 2000-2023 (November) in four major academic databases such as PubMed, ISI Web of Science, Scopus, and ScienceDirect by using a controlled terminology and web strings that reunite six main keywords. We complementarily retrieved data on the ongoing RCTs. Results: Regardless of the relatively high number of results displayed (n = 75), 46.66% (n = 35) were initially deemed eligible after the first evaluation phase after removing duplicates, n = 40 (53.34%). At the second assessment stage, we eliminated 11.42% (n = 4) studies, of which n = 22 finally met the eligibility criteria to be included in the main body of the manuscript. In terms of RCTs, otherwise found in distinct stages of development, n = 3 target FMT and n = 1 probiotics. Conclusions: Although we benefit from the necessary information and technology to design novel strategies for microbiota, only probiotics and synbiotics have been extensively studied in the last decade compared to FMT.

The gut microbiome plays a key role in influencing several pathways and functions involved in human health, including metabolism, protection against infection, and immune regulation. Perturbation of the gut microbiome is recognised as a pathogenic factor in several gastrointestinal and extraintestinal disorders, and is increasingly considered as a therapeutic target in these conditions. Faecal microbiota transplantation (FMT) is the transfer of the microbiota from healthy screened stool donors into the gut of affected patients, and is a well-established and highly effective treatment for recurrent Clostridioides difficile infection. Despite the mechanisms of efficacy of FMT not being fully understood, it has been investigated in several chronic noncommunicable disorders, with variable results. This review aims to give an overview of mechanisms of efficacy of FMT in chronic noncommunicable disorders, and to paint the current landscape of its investigation in these medical conditions, including inflammatory bowel disease (IBD), chronic liver disorders, and also extraintestinal autoimmune conditions.

Neurofilament light chain protein (NfL) levels reflect neuronal damage in several neurological diseases and have been proposed as a possible biomarker. Plasma extracellular vesicles (EVs) could play an important role as mediators of the inflammatory changes associated with inducing minimal hepatic encephalopathy (MHE) in cirrhotic patients. This study investigated the association of NfL levels in plasma and EVs with the presence of MHE in cirrhotic patients, and with responses to rifaximin treatment. The NfL levels in plasma and EVs were assessed in 71 patients with liver cirrhosis (40 with MHE and 31 without MHE) and 26 controls. A total of 31 patients with MHE received rifaximin treatment. We examined changes in NfL levels in plasma and EVs before and after 6 months of rifaximin treatment. The NfL measures were correlated with cognitive alterations and plasma inflammatory cytokines. MHE patients showed increased plasma levels of NfL, which were reverted after rifaximin treatment in patients who responded to treatment. The NfL content in EVs also showed a reversal pattern in MHE patients treated with rifaximin. In multivariable analyses, NfL levels were independently associated with the presence of MHE. We also showed that patients with high levels of both ammonia and fractalkine had significantly higher NfL levels than patients with low levels of least one of these parameters. Rifaximin treatment in MHE patients showed promising results in improving axonal damage, suggesting that rifaximin may have therapeutic benefits against disease progression in MHE.

The composition, viability and metabolic functionality of intestinal microbiota play an important role in human health and disease. Studies on intestinal microbiota are often based on fecal samples, because these can be sampled in a non-invasive way, although procedures for sampling, processing and storage vary. This review presents factors to consider when developing an automated protocol for sampling, processing and storing fecal samples: donor inclusion criteria, urine-feces separation in smart toilets, homogenization, aliquoting, usage or type of buffer to dissolve and store fecal material, temperature and time for processing and storage and quality control. The lack of standardization and low-throughput of state-of-the-art fecal collection procedures promote a more automated protocol. Based on this review, an automated protocol is proposed. Fecal samples should be collected and immediately processed under anaerobic conditions at either room temperature (RT) for a maximum of 4 h or at 4 °C for no more than 24 h. Upon homogenization, preferably in the absence of added solvent to allow addition of a buffer of choice at a later stage, aliquots obtained should be stored at either -20 °C for up to a few months or -80 °C for a longer period-up to 2 years. Protocols for quality control should characterize microbial composition and viability as well as metabolic functionality.

Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.

Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.

There is growing evidence that gut microbiota dysbiosis is linked to the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), from the initial stage of disease until the progressive stage of nonalcoholic steatohepatitis (NASH) and the final stage of cirrhosis. Conversely, probiotics, prebiotics, and synbiotics have shown promise in restoring dysbiosis and lowering clinical indicators of disease in a number of both preclinical and clinical studies. Additionally, postbiotics and parabiotics have recently garnered some attention. The purpose of this bibliometric analysis is to assess recent publishing trends concerning the role of the gut microbiome in the progression of NAFLD, NASH and cirrhosis and its connection with biotics. The free access version of the Dimensions scientific research database was used to find publications in this field from 2002 to 2022. VOSviewer and Dimensions' integrated tools were used to analyze current research trends. Research into the following topics is expected to emerge in this field: (1) evaluation of risk factors which are correlated with the progression of NAFLD, such as obesity and metabolic syndrome; (2) pathogenic mechanisms, such as liver inflammation through toll-like receptors activation, or alteration of short-chain fatty acids metabolisms, which contribute to NAFLD development and its progression in more severe forms, such as cirrhosis; (3) therapy for cirrhosis through dysbiosis reduction, and research on hepatic encephalopathy a common consequence of cirrhosis; (4) evaluation of diversity, and composition of gut microbiome under NAFLD, and as it varies under NASH and cirrhosis by rRNA gene sequencing, a tool which can also be used for the development of new probiotics and explore into the impact of biotics on the gut microbiome; (5) treatments to reduce dysbiosis with new probiotics, such as Akkermansia, or with fecal microbiome transplantation.

Patients with liver cirrhosis show hyperammonemia and peripheral inflammation and may show hepatic encephalopathy with cognitive impairment, reproduced by rats with chronic hyperammonemia. Peripheral inflammation induces neuroinflammation in hippocampus of hyperammonemic rats, altering neurotransmission and leading to cognitive impairment. Extracellular vesicles (EVs) may transmit pathological effects from the periphery to the brain. We hypothesized that EVs from peripheral blood would contribute to cognitive alterations in hyperammonemic rats. The aims were to assess whether EVs from plasma of hyperammonemic rats (HA-EVs) induce cognitive impairment and to identify the underlying mechanisms. Injection of HA-EVs impaired learning and memory, induced microglia and astrocytes activation and increased TNFα and IL-1β. Ex vivo incubation of hippocampal slices from control rats with HA-EVs reproduced these alterations. HA-EVs increased membrane expression of TNFR1, reduced membrane expression of TGFβR2 and Smad7 and IκBα levels and increased IκBα phosphorylation. This led to increased activation of NF-κB and IL-1β production, altering membrane expression of NR2B, GluA1 and GluA2 subunits, which would be responsible for cognitive impairment. All these effects of HA-EVs were prevented by blocking TNFα, indicating that they were mediated by enhanced activation of TNFR1 by TNFα. We show that these mechanisms are very different from those leading to motor incoordination, which is due to altered GABAergic neurotransmission in cerebellum. This demonstrates that peripheral EVs play a key role in the transmission of peripheral alterations to the brain in hyperammonemia and hepatic encephalopathy, inducing neuroinflammation and altering neurotransmission in hippocampus, which in turn is responsible for the cognitive deficits.

Hepatitis C virus (HCV) infection is commonly comorbid with opioid dependence (OD). We wanted to compare the neurocognitive functions of OD subjects with or without HCV [HCV (+), HCV (-)] and healthy controls (HC).

We recruited 40 adult subjects (age 18-55 years) in each group. HCV(+) group had a detectable viral load. Subjects with HIV or hepatitis B infection, head injury, epilepsy, or comorbid mental illness were excluded. We administered Standard Progressive Matrices (SPM), Wisconsin Card Sorting Test, Iowa Gambling Task (IGT), trail-making tests A and B, and verbal and visual N-back tests (NBT) one week after opioid abstinence. The group differences in cognitive performance were adjusted for age and years of education. Effect size (ES) is expressed as Cohen's D.

The HCV(+) and HCV(-) groups did not differ in potential effect modifiers (age and years of education) or confounders (age of opioid initiation, duration of use, dependence severity, tobacco use, and cannabis use) of neuropsychological functioning. HCV(+) showed significantly poorer performance than HCV(-) in SPM (P = 0.006; ES = 0.72). Both HCV(+) and HCV(-) performed worse than controls in IGT(P < 0.001; ES = 0.8) and visual NBT[P < 0.01 and ES > 1 for total errors]; HCV(+) had a larger ES of group difference than HCV(-). HCV(+) had higher error scores in verbal NBT than control.

HCV(+) has poorer general intellectual ability and reasoning than HCV(-) persons and controls. Chronic HCV infection causes a higher magnitude of dysfunction in decision-making and visual working memory in opioid-dependent individuals.

To investigate whether non-alcoholic fatty liver disease (NAFLD) increases the risk of dementia or cognitive impairment.

A systematic search of the literature in the PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, and Web of Science databases was conducted, covering the period from the inception of each database to 22 May 2022. Statistical analysis of non-alcoholic fatty liver disease and the risk of cognitive impairment or dementia based on data extracted from each article was performed using Stata software v. 16.0. The quality of this study was assessed using the Newcastle-Ottawa Scale (NOS) for assessing the quality of cohort and case-control studies and the American Agency for Healthcare Research and Quality (AHRQ) methodology checklist for assessing the quality of cross-sectional studies. Funnel plots and the Egger's test were used to assess publication bias.

We included 7 studies comprising 891,562 individuals from 6 countries, which were published between 2020 and 2022. The pooling analysis showed that a history of NAFLD was associated with cognitive impairment [odds ratio (OR) = 1.44; 95% CI: 1.17-1.78; heterogeneity (I 2) = 0%; P = 0.001]. A history of NAFLD was not associated with an increased risk of all-cause dementia (OR = 1.03; 95% CI: 0.97-1.09; I 2 = 84.7%; P = 0.341) or Alzheimer disease (OR = 0.95; 95% CI: 0.83-1.09; I 2 = 61.0%; P = 0.489). In contrast, NAFLD was associated with an obvious reduction of the risk of vascular dementia (OR = 0.88; 95% CI: 0.79-0.98; I 2 = 0.0%; P = 0.020). In the subgroup analysis, male and female patients with NAFLD showed an equal risk of dementia or cognitive impairment. The risk of dementia or cognitive impairment in the cross-sectional study (OR = 1.49; 95% CI: 1.19-1.88; I 2 = 0.0%; P = 0.001) was slightly higher than that in the retrospective cohort (OR = 1.03; 95% CI: 0.97-1.09; I 2 = 84.3%; P = 0.294).

NAFLD was associated with an increased risk of cognitive impairment and a decreased risk of vascular dementia. More studies are needed to clarify the pathophysiological mechanism underlying the association between NAFLD and dementia or cognitive impairment.

https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: CRD42022334492.

Microplastics (MPs), which are emerging environmental pollutants, remain uncertainties in their toxic mechanism. MPs have been linked to severe liver metabolic disorders and neurotoxicity, but it is still unknown whether the abnormal metabolites induced by MPs can affect brain tissue through the liver-brain axis. Exposed to MPs of chickens results in liver metabolic disorders and increased glutamine and glutamate synthesis. The relative expression of glutamine in the C group was -0.862, the L-PS group was 0.271, and the H-PS group was 0.592. The expression of tight junction proteins in the blood-brain barrier (BBB) was reduced by PS-MPs. Occludin protein expression decreased by 35.8%-41.2%. Claudin 3 decreased by 19.6%-42.3%, and ZO-1 decreased by 28.3%-44.6%. Excessive glutamine and glutamate cooperated with PS-MPs to inhibit the Nrf2-Keap1-HO-1/NQO1 signaling pathway and triggered autophagy-dependent ferroptosis and apoptosis. GPX protein expression decreased by 30.9%-38%. LC3II/LC3I increased by 54%, and Caspase 3 increased by 45%. Eventually, the number of Purkinje cells was reduced, causing neurological dysfunction. In conclusion, this study provides new insights for revealing the mechanism of nervous system damaged caused by PS-MPs exposed in chickens.

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut-hepatic-brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.

Liver fibrosis is a reversible pathological process, and its prevention and treatment hold great significance for patients with chronic liver disease. This study combined 16S rRNA analysis of gut microbiota and serum metabolomics to explore the mechanism of curcumol's effect on liver fibrosis in mice. The results clarified the relationship between the gut microbiota and metabolites in the process of liver fibrosis.

In this study, we randomly divided mice into a control group, a model group, and a curcumol treatment group to analyze the pathological changes in the liver tissue as well as the activities of the toll-like receptor 4 (TLR4)/nuclear factory kappa B (NF-κB) signaling pathway and inflammatory factors, such as tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-8. The gut microbiota were analyzed by 16 S rRNA sequencing, and serum metabolites were examined by liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis.

Molecular biological testing found that curcumol could significantly improve the pathological changes of the liver tissue and inhibit the occurrence of liver inflammation. Intestinal flora testing found that curcumol could significantly change the abundances of Veillonellaceae, Prerotella_oulorum, and Alistipes_finegoldii. Metabolomics analysis found that curcumol's antihepatic fibrosis effect may be related to its regulation of arachidonic acid metabolism. Correlation analysis suggested that curcumol regulated the abundances of Bacteroidota and Bacteroides and participated in the metabolism of Prostaglandin B2.

When liver fibrosis occurs, the intestinal flora and metabolic network are altered. The effect of curcumol on liver fibrosis may be related to its regulation of intestinal flora and the resulting interference with metabolic pathways, thereby reducing liver inflammation.

Sleep disturbances are prevalent in patients with minimal hepatic encephalopathy (MHE). This study aimed to evaluate the association between sleep disturbances and altered gut microbiota in patients with MHE caused by hepatitis B-related liver cirrhosis.

Ninety-eight and 45 patients with MHE were included in exploration and validation cohorts, respectively. Sleep disturbances were assessed using the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Microbiota in fecal samples were analyzed via amplicon sequencing of bacterial 16S ribosomal RNA genes.

The gut microbiomes of MHE patients with sleep disturbances were characterized by lower bacterial diversity and distinct bacterial composition. Relative abundances of Streptococcus salivarius and Veillonella were independent predictors of sleep disturbances in MHE patients and well-distinguished MHE patients with and without sleep disturbances in both the exploration and validation cohorts. Moreover, the relative abundances of S. salivarius were positively correlated with plasma ammonia levels, and functional modules associated with protein digestion and absorption and lipopolysaccharide biosynthesis were enriched in the microbiomes of MHE patients with sleep disturbances.

Both S. salivarius and Veillonella were associated with sleep disturbances in patients with MHE caused by hepatitis B-related liver cirrhosis.

Gut microbiota performs indispensable functions in the pathophysiology of alcoholic hepatitis (AH). We investigated the effects of Lacticaseibacillus rhamnosus R0011 and Lactobacillus helveticus for gut microbial restoration toward eubiosis in patients with AH. A multicenter, double-blind, and randomized trial was conducted. Probiotics (n = 44) and placebo (n = 45) groups received, during 7 days, L. rhamnosus R0011/L. helveticus R0052 at 120 mg/day and placebo. All patients were hospitalized to ensure abstinence. Liver function, lipopolysaccharide level, and stool analysis were evaluated in patients before and after 7 days of treatment. At baseline, the dominant bacteria were Gram-negative in both groups which decreased after the probiotics treatment and exhibited a significant reduction in lipopolysaccharide level (p < 0.001). The probiotics ameliorated the Child−Pugh scores (p < 0.001). Furthermore, the probiotics group showed a decline in the levels of alanine aminotransferase and gamma-glutamyltranspeptidase (p < 0.05). The probiotics changed the gut microbial composition at various taxonomical levels. The proportion of Bacteroidetes (147%) was increased after 7 days of probiotics supplementation while Proteobacteria (30%) and Fusobacteria (0%) were decreased. Administration of L. rhamnosus R0011 and L. helveticus R0052 conceivably associated with restoration of gut microbiome in AH patients and improved AH by modulating the gut−liver axis.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The present study explores the clinical efficacy of probiotics in the treatment of patients with NAFLD by conducting a systematic search of relevant databases. The RevMan 5.4 software was used to evaluate the effects of probiotics on liver function (i.e. alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], lipid metabolism, blood glucose, inflammatory factors [e.g. tumor necrosis factor-α, TNF-α] and body mass index [BMI]) in patients with NAFLD. A total of 18 high-quality studies were included in the final meta-analysis. The results of the meta-analysis showed that the use of probiotics in the adjuvant treatment of patients with NAFLD improved liver function and reduced ALT levels (mean difference [MD]: -0.07; 95% confidence interval [CI]: -12.95, -7.19), AST levels (MD: -11.90; 95% CI: -16.55, -7.25) and GGT levels (MD: -8.61; 95% CI: -14.74, -2.48); additionally, the treatment effect was more obvious when the treatment time exceeded 12 weeks. Probiotic therapy reduced patients' triglyceride levels (MD: -9.71; 95% CI: -18.39, -1.03) and total cholesterol levels (MD: -22.31; 95% CI: -25.41, -19.21). Probiotic treatment improved patients' levels of fasting blood (MD: -8.22; 95% CI: -12.25, -4.20), insulin (MD: -2.68; 95% CI: -4.94, -0.41) and insulin resistance (MD: -0.72; 95% CI: -1.21, -0.24). Probiotic adjuvant therapy for patients with NAFLD reduced their BMI by approximately 1.67 (95% CI: -2.93, -0.41) and TNF-α levels. The adjuvant treatment of NAFLD with probiotics has a positive clinical effect, which is influenced by treatment time.