Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy.

Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA-microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.

The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis.

Hepatic encephalopathy (HE) is a neurological disease occurring in patients with hepatic insufficiency and/or portal-systemic blood shunting based on cirrhosis. The pathogenesis is not completely clear till now, but it is believed that hyperammonemia is the core of HE. Hyperammonemia caused by increased sources of ammonia and decreased metabolism further causes mental problems through the gut-liver-brain axis. The vagal pathway also plays a bidirectional role in the axis. Intestinal microorganisms play an important role in the pathogenesis of HE through the gut-liver-brain axis. With the progression of cirrhosis to HE, intestinal microbial composition changes gradually. It shows the decrease of potential beneficial taxa and the overgrowth of potential pathogenic taxa. Changes in gut microbiota may lead to a variety of effects, such as reduced production of short-chain fatty acids (SCFAs), reduced production of bile acids, increased intestinal barrier permeability, and bacterial translocation. The treatment aim of HE is to decrease intestinal ammonia production and intestinal absorption of ammonia. Prebiotics, probiotics, antibiotics, and fecal microbiota transplantation (FMT) can be used to manipulate the gut microbiome to improve hyperammonemia and endotoxemia. Especially the application of FMT, it has become a new treated approach to target microbial composition and function. Therefore, restoring intestinal microbial homeostasis can improve the cognitive impairment of HE, which is a potential treatment method.

Low-diversity microbiota and an increased metabolism of arginine and aromatic amino acids: a hallmark of hepatic encephalopathy in western Mexican patients with alcohol-associated cirrhosis.

AIMS: To evaluate the composition and functions of the gut microbiota in patients with decompensated alcohol-associated cirrhosis, with and without hepatic encephalopathy (HE). METHODS AND RESULTS: Faecal samples from 31 inpatients (20 with HE, 11 without HE), and from 18 age-balanced healthy controls (HC), were included. Microbial composition was determined by 16S rRNA amplicon sequencing and analysed using QIIME2. Metabolic pathways were inferred by PICRUSt2, and short-chain fatty acids (SCFAs) quantification was performed by gas chromatography. The gut microbiota of patients with HE was characterized by a diminished α-diversity, compared to no-HE (P < 0.01) and HC (P < 0.001) groups; ß-diversity also differed between HE vs no-HE patients (P < 0.05), and between HE vs HC (P < 0.001). In patients with HE, Escherichia/Shigella, Burkholderiales and Lactobacillales taxa predominated. In contrast, patients without HE were characterized by Veillonella and Bacteroides. Reduced levels of faecal SCFAs in both groups correlated with a depletion of beneficial taxa, such as Ruminococcus or Faecalibacterium. PICRUSt2 analysis showed both an enhanced catabolism of arginine through ammonia-producing pathways and chorismate biosynthesis in HE patients, a key precursor of aromatic amino acids. CONCLUSIONS: The gut microbiota of HE patients exhibits a proinflammatory dysbiotic profile, plus metabolic pathways that produce potentially neurotoxic byproducts.

Ameliorative Effect of Chitosan Oligosaccharides on Hepatic Encephalopathy by Reshaping Gut Microbiota and Gut-Liver Axis.

This study investigated the influence of chitosan oligosaccharides (COSs) on a thioacetamide-induced hepatic encephalopathy (HE) Wistar rat model. COS treatment statistically reduced the false neurotransmitters and blood ammonia in HE rats, along with the suppression of oxidative stress and inflammation. The disbalanced gut microbiota was detected in HE rats by 16S rDNA sequencing, but the abundance alterations of some intestinal bacteria at either the phylum or genus level were at least partly restored by COS treatment. According to metabolomics analysis of rat feces, six metabolism pathways with the greatest response to HE were screened, several of which were remarkably reversed by COS. The altered metabolites might serve as a bridge for the alleviated HE rats treated with COS and the enhanced intestinal bacterial structure. This study provides novel guidance to develop novel food or dietary supplements to improve HE diseases due to the potential beneficial effect of COS on gut-liver axis.

Hydrogen-producing small intestinal bacterial overgrowth is associated with hepatic encephalopathy and liver function.

Overt hepatic encephalopathy (HE) is one of the complications of liver cirrhosis (LC), which negatively affects the prognosis and quality of life of patients. Small intestinal bacterial overgrowth (SIBO) is significantly associated with LC and its complications, including HE. We investigated the relationship between SIBO and LC, and the difference between hydrogen-producing and methane-producing SIBO (H-SIBO and M-SIBO, respectively). This is a prospective cohort study of 107 cases. Breath measurements of hydrogen and methane concentrations were performed for the diagnosis of SIBO. The study cohort included 81 males with a median age of 70 (40-86) years, and SIBO was detected in 31 cases (29.0%). There were no significant differences between the SIBO positive and SIBO negative groups. Reclassification into H-SIBO (16 cases) and others (91 cases) was performed, and the Child-Pugh score was only derived in the multivariate logistic analysis (P = 0.028, odds ratio 1.39, 95% confidence interval 1.04-1.85). Furthermore, H-SIBO was significantly associated with covert HE in chi-square test (50.0% vs. 24.2%, P = 0.034). In addition, we evaluated the therapeutic response on SIBO of rifaximin in eight covert HE patients. 20% patients with M-SIBO and 67% patients with H-SIBO showed an improvement of the breath test. In conclusion, H-SIBO, but not M-SIBO, is significantly associated with liver function, and rifaximin might be more effective for covert HE with H-SIBO. Therefore, the diagnosis of SIBO, including the classification as H-SIBO and M-SIBO, might help to determine the choice of treatment for HE.

Sex is associated with differences in gut microbial composition and function in hepatic encephalopathy.

BACKGROUND & AIMS: Altered microbiota can affect the gut-liver-brain axis in cirrhosis and hepatic encephalopathy (HE), but the impact of sex on these changes is unclear. We aimed to determine differences in fecal microbiota composition/functionality between men and women with cirrhosis and HE on differing treatments. METHODS: Cross-sectional stool microbiome composition (16s rRNA sequencing) and microbial functional analyses were performed in men and women with cirrhosis, and controls. Patients with HE on rifaximin+lactulose (HE-Rif), patients with HE on lactulose only (HE-Lac) and those with cirrhosis without HE (No-HE) were compared to controls using random forest classifier. Men and women were also compared. RESULTS: A total of 761 individuals were included, 619 with cirrhosis (466 men, 153 women) and 142 controls (92 men, 50 women). Men were older and more frequently used proton pump inhibitors (PPIs), but model for end-stage liver disease score, No-HE (n = 319), HE-lac (n = 130) and HE-Rif (n = 170) proportions were similar. PPI/age-adjusted AUC of differentiation between controls vs. all cirrhosis, and controls vs. No-HE were higher within women than men, but the adjusted AUC for No-HE vs. HE-Rif was higher in men. Control vs. HE-Rif differentiation was similar across sexes. Men vs. women were different in all cirrhosis, No-HE and HE-Lac but not HE-Rif on PERMANOVA and AUC analyses. Autochthonous taxa decreased and pathobionts increased with disease progression regardless of sex. In men, Lactobacillaceae were higher in HE-Lac but decreased in HE-Rif, along with Veillonellaceae. Pathways related to glutamate and aromatic compound degradation were higher in men at all stages. Degradation of androstenedione, an estrogenic precursor, was lower in men vs. women in HE-Rif, likely enhancing feminization. CONCLUSIONS: There are differences in gut microbial function and composition between men and women with cirrhosis, which could be implicated in differential responses to HE therapies. Further studies linking these differences to sex-specific outcomes are needed. LAY SUMMARY: Patients with cirrhosis develop changes in their brain function, and men often develop feminization with disease progression. However, the interaction between sex, microbiota and disease severity is unclear. We found that as disease progressed in men, their microbial composition began to approach that observed in women, with changes in specific microbes that are associated with male hormone metabolism.

Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy.

OBJECTIVE: Altered bacterial composition is associated with disease progression in cirrhosis but the role of virome, especially phages, is unclear. DESIGN: Cross-sectional and pre/post rifaximin cohorts were enrolled. Cross-sectional: controls and cirrhotic outpatients (compensated, on lactulose (Cirr-L), on rifaximin (Cirr-LR)) were included and followed for 90-day hospitalisations. Pre/post: compensated cirrhotics underwent stool collection pre/post 8 weeks of rifaximin. Stool metagenomics for bacteria and phages and their correlation networks were analysed in controls versus cirrhosis, within cirrhotics, hospitalised/not and pre/post rifaximin. RESULTS: Cross-sectional: 40 controls and 163 cirrhotics (63 compensated, 43 Cirr-L, 57 Cirr-LR) were enrolled. Cirr-L/LR groups were similar on model for end-stage liver disease (MELD) score but Cirr-L developed greater hospitalisations versus Cirr-LR (56% vs 30%, p=0.008). Bacterial alpha/beta diversity worsened from controls through Cirr-LR. While phage alpha diversity was similar, beta diversity was different between groups. Autochthonous bacteria linked negatively, pathobionts linked positively with MELD but only modest phage-MELD correlations were seen. Phage-bacterial correlation network complexity was highest in controls, lowest in Cirr-L and increased in Cirr-LR. Microviridae and Faecalibacterium phages were linked with autochthonous bacteria in Cirr-LR, but not Cirr-L hospitalised patients had greater pathobionts, lower commensal bacteria and phages focused on Streptococcus, Lactococcus and Myoviridae. Pre/post: No changes in alpha/beta diversity of phages or bacteria were seen postrifaximin. Phage-bacterial linkages centred around urease-producing Streptococcus species collapsed postrifaximin. CONCLUSION: Unlike bacteria, faecal phages are sparsely linked with cirrhosis characteristics and 90-day outcomes. Phage and bacterial linkages centred on urease-producing, ammonia-generating Streptococcus species were affected by disease progression and rifaximin therapy and were altered in patients who experienced 90-day hospitalisations.

Microbiome: Emerging Concepts in Patients with Chronic Liver Disease.

The gut microbiome is an exciting new area of research in chronic liver disease. It has shown promise in expanding our understanding of these complicated disease processes and has opened up new treatment modalities. The aim of this review is to increase understanding of the microbiome and explain the collection and analysis process in the context of liver disease. It also looks at our current understanding of the role of the microbiome in the wide spectrum of chronic liver diseases and how it is being used in current therapies and treatments.

Minimal Hepatic Encephalopathy: Effect of H. pylori infection and small intestinal bacterial overgrowth treatment on clinical outcomes.

The effect Helicobacter pylori (Hp) infection and small intestinal bacterial over growth (SIBO) in minimal hepatic encephalopathy (MHE) is not well understood. The aim of the study was to determine the effect of eradication of Hp infection and SIBO treatment on MHE in patients with cirrhosis. Patients with cirrhosis were enrolled and MHE was determined by psychometric tests and critical flicker frequency analysis. Hp infection and SIBO were assessed by urea breath and Hydrogen breath tests respectively in patients with cirrhosis and in healthy volunteers. Patients with Hp infection and SIBO were given appropriate treatment. At six weeks follow-up, presence of Hp infection, SIBO and MHE status was reassessed. Ninety patients with cirrhosis and equal number of healthy controls were included. 55 (61.1%) patients in the cirrhotic group were diagnosed to have underlying MHE. Among cirrhotic group, Hp infection was present in 28 with MHE (50.9%) vs. in 15 without MHE (42.8%) (p = 0.45). Similarly, SIBO was present in 17 (30.9%) vs. 11 (31.4%) (p = 0.95) in patients with and without MHE respectively. In comparison with healthy controls, patients with cirrhosis were more frequently harboring Hp and SIBO (47.7% vs. 17.7% (p < 0.001) and 31.1% vs. 4.4% (p < 0.001) respectively. On follow-up, all patients showed evidence of eradication of Hp and SIBO infection. Treatment of SIBO significantly improved the state of MHE in cirrhotics, however eradication of Hp infection did not improve MHE significantly. Additionally, patients with low Model for End-Stage Liver Disease (MELD) score and belonging to Child class B had significantly better improvement in MHE. A large number of patients with cirrhosis had either active Hp infection or SIBO with or without MHE, compared to healthy controls. Treatment of SIBO significantly improved MHE in patients with cirrhosis, whereas eradication of Hp did not affect the outcome of MHE in these patients.

Expert insights: The potential role of the gut microbiome-bile acid-brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathy.

Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the progression of hepatic encephalopathy (HE) via bile acid (BA)-mediated effects on the farnesoid X receptor. In this perspective paper, we reviewed several recently published studies that suggested a role for the gut microbiota transformation of BAs as a factor in AD and HE development/progression. We hypothesize that in addition to cholesterol elimination pathways, alteration of the gut microbiota and subsequent changes in both the serum and brain BA profiles are mechanistically involved in the development of both AD and HE, and thus, are a potential target for the prevention and treatment of the two diseases. Our understanding of the microbiome-BAs-brain axis in central nervous system disease is still evolving, and critical questions regarding the emerging links among central, peripheral, and intestinal metabolic failures contributing to brain health and disease during aging have yet to be addressed.

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis.

BACKGROUNDHepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp.METHODSTwenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT.RESULTSFMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes.CONCLUSIONGut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.TRIAL REGISTRATIONClinicaltrials.gov NCT03152188.FUNDINGNational Center for Advancing Translational Sciences NIH grant R21TR002024, VA Merit Review grant 2I0CX001076, the United Kingdom National Institute for Health Research Biomedical Facility at Imperial College London, the British Heart Foundation, Wellcome Trust, and King's College London.

Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.

OBJECTIVE: Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. METHODS: This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. RESULTS: A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. CONCLUSIONS: Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).

Microbial Profiles of Cirrhosis in the Human Small Intestine.

PURPOSE OF REVIEW: The aim of this review is to summarize the recent literature on associations of small intestinal microbial and bile acid profiles with liver cirrhosis and its complications. RECENT FINDINGS: Recent studies into the duodenal microbiome of patients with cirrhosis have linked the microbiome to certain etiologies of chronic liver disease as well as complications of cirrhosis. In particular, microbial differences in the duodenum of patients with cirrhosis have been linked to the presence of hepatic encephalopathy and varices. While the fecal microbiome of patients with liver cirrhosis is well characterized, the small intestinal microbiome of cirrhotic patients is an active area of research. This review focuses on the current understanding of the small intestinal microbiome in human cirrhosis as well as future directions of the field.

Bacteroides in colonic mucosa-associated microbiota affects the development of minimal hepatic encephalopathy in patients with cirrhosis.

BACKGROUND/PURPOSE: Gut microbiota has been associated with liver cirrhosis and, possibly, hepatic encephalopathy. However, only a few studies have examined the link between mucosa-associated microbiota (MAM) and minimal hepatic encephalopathy (MHE). Our aim was to investigate this relationship. METHODS: Twenty-four patients with cirrhosis underwent colon biopsies at our institution, between January 2014 and April 2015. Patterns of microbial colonization were examined using 16S rRNA gene sequences. MHE was diagnosed using the Neuropsychological Test. RESULTS: Ten (41.7%) of the 24 patients were diagnosed as having MHE. There was no significant difference in the diversity of gut microbiota by sampling locations between those with and without MHE. However, the diversity of the gut microbiota and the proportion of the genus Bacteroides decreased as a function of declining liver function. We divided patients into those with the highest proportion of the genus Bacteroides (Bacteroides-dominant group; n = 9) and into a Bacteroides non-dominant group (n = 15). In the Bacteroides-dominant group, only 1 patient (11.1%) was diagnosed as having MHE, with the incidence rate of MHE being significantly lower in the Bacteroides-dominant group than in the non-dominant group (p = 0.019). The Child-Pugh score (p = 0.05) and use of proton-pump inhibitors (p = 0.015) were negatively correlated to the proportion of Bacteroides. Furthermore, the proportion of the family Clostridiaceae was significantly higher in the Bacteroides-dominant group than in the non-dominant group (p = 0.078). CONCLUSIONS: The decrease in microbial diversity and genus Bacteroides in MAM is a risk factor for MHE in patients with liver cirrhosis.

Predicting Clinical Outcomes of Cirrhosis Patients With Hepatic Encephalopathy From the Fecal Microbiome.

BACKGROUND & AIMS: Gut dysbiosis plays a role in hepatic encephalopathy (HE), while its relationship at the acute episode of overt HE (AHE), the disease progression and clinical outcomes remains unclear. We aimed to identify AHE-specific microbiome and its association to patients' outcomes. METHODS: We profiled fecal microbiome changes for a cohort of 62 patients with cirrhosis and AHE i) before treatment, ii) 2-3 days after medication and iii) 2-3 months after recovery, and three control cohorts i) healthy individuals, patients with ii) compensated or iii) decompensated cirrhosis. RESULTS: Comparison of the microbiome shift from compensated, decompensated cirrhosis, AHE to recovery revealed the AHE-specific gut-dysbiosis. The gut microbiome diversity was decreased during AHE, further reduced after medication, and only partially reversed during the recovery. The relative abundance of Bacteroidetes phylum in the microbiome decreased, whereas that of Firmicute, Proteobacteria and Actinobacteria increased in patients during AHE compared with those with compensated cirrhosis. A total of 70 operational taxonomic units (OTUs) were significantly different between AHE and decompensated cirrhosis abundances. Of them, the abundance of Veillonella parvula increased the most during AHE via a metagenomics recovery of the genomes. Moreover, the relative abundances of three (Alistipes, Bacteroides, Phascolarctobacterium) and five OTUs (Clostridium-XI, Bacteroides, Bacteroides, Lactobacillus, Clostridium-sedis) at AHE were respectively associated with HE recurrence and overall survival during the subsequent one-year follow-up. CONCLUSIONS: AHE-specific gut OTUs were identified that may be involved in HE development and able to predict clinical outcomes, providing new strategies for the prevention and treatment of HE recurrence in patients with cirrhosis.

The rise of Clostridioides difficile infections and fall of associated mortality in hospitalized advanced cirrhotics.

BACKGROUND & AIMS: Cirrhotics are at increased risk of Clostridioides difficile infection (CDI) and its associated high morbidity and mortality. However, the impact of CDI in cirrhotics over time remains unclear. This study analyses prevalence and mortality in CDI in hospitalized patients with advanced cirrhosis over 15 years and identifies trends. METHODS: Using the Nationwide Inpatient Sample (NIS) from 1998 to 2014, 3 049 696 weighted patients with advanced cirrhosis (defined as evidence of decompensation or oesophageal varices) were identified using a validated algorithm of ICD-9-CM codes and included in the study. Trends were analysed using Cochran Armitage test and joinpoint regression and compared to the general population. Multivariable logistic regression was performed controlling for risk factors that affect mortality in cirrhotics. RESULTS: CDI prevalence in advanced cirrhotics increased from 0.8% to 2.6%, annual percent change (APC) 8.8% (compared to 7.6% for the general population), while CDI-related mortality decreased from 20.7% to 11.3%, APC -3.4% (compared to -2.0% for the general population), from 1998 to 2014. CDI independently increased mortality in advanced cirrhotics (OR 1.47, P < 0.001) and was associated with acute kidney injury (AKI) (OR 2.09, P < 0.001), which itself significantly increased mortality (OR 4.54, P < 0.001). Hepatic encephalopathy and Hispanic ethnicity were interestingly associated with a lower prevalence of CDI. CONCLUSIONS: CDI is increasingly common in advanced cirrhotics, but on the contrary, its associated mortality is decreasing. Despite improvements in outcomes in patients with advanced cirrhosis, CDI is associated with an increased mortality, driven by AKI, and therefore, requires aggressive identification and therapy.

Long-Term Effect of Rifaximin with and without Lactulose on the Active Bacterial Assemblages in the Proximal Small Bowel and Faeces in Patients with Minimal Hepatic Encephalopathy.

BACKGROUND: Gut microbiota play an essential role in the pathogenesis of hepatic encephalopathy (HE). Treatment strategies are directed to modulate intestinal microbiota profiles and their function by the administration of the non-absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin, which are required for long terms, but little is known on their long-term effect on gut microbiota composition and function. AIM: To characterize the active bacterial assemblages in duodenum and faeces in patients with minimal HE (MHE) before, during and after long-term therapy with rifaximin. METHODS: We analysed the microbiota composition in 5 patients with liver cirrhosis and MHE treated either with rifaximin 550 mg bid alone continuously for a period of 3 months or combined with lactulose 30-60 mL daily for 3 months. In addition to clinical assessments of HE, biopsies from duodenum and stool samples were analysed for their specific bacterial community applying NGS after RNA isolation before treatment, after 3 months of treatment and 3 months after the end of treatment. RESULTS: All 5 patients had a significant improvement of their MHE. Bacterial communities were different and distinct in duodenal samples and faeces. No statistically significant changes were found in the bacterial community profile at the different time points. CONCLUSION: Rifaximin therapy with and without lactulose over a period of 3 months does not affect the bacterial community composition. The improvement of HE with rifaximin is lasting also after the end of treatment and therefore a prolonged effect on microbiota metabolic function is suggested.

Complications of Cirrhosis in Primary Care: Recognition and Management of Hepatic Encephalopathy.

Approximately 3.7% of patients in primary care settings have chronic liver disease, and 18% with chronic liver disease in the specialty care setting have cirrhosis. For cirrhotic patients without complications, prognosis is generally favorable; increased morbidity and mortality are observed when complications (i.e., hepatic encephalopathy [HE]) occur. HE occurs in up to 70% of patients with cirrhosis. Neurologic signs in HE span a wide spectrum, from those not easily apparent (covert) to more clinically obvious signs (overt). Providers should consider overt HE in patients with cirrhosis and signs of impaired cognition, confusion, consciousness and/or personality changes, and/or impaired memory. Overt HE treatment includes identifying and treating precipitating factors and reducing bacterial-derived toxin loads. For acute overt HE, lactulose is first-line treatment. To prevent HE recurrence, lactulose plus rifaximin is recommended. Patients with cirrhosis and HE often present in primary care; recognizing and properly managing HE are important in this setting.

Clinical impact of microbiome in patients with decompensated cirrhosis.

Cirrhosis is an increasing cause of morbidity and mortality. Recent studies are trying to clarify the role of microbiome in clinical exacerbation of patients with decompensated cirrhosis. Nowadays, it is accepted that patients with cirrhosis have altered salivary and enteric microbiome, characterized by the presence of dysbiosis. This altered microbiome along with small bowel bacterial overgrowth, through translocation across the gut, is associated with the development of decompensating complications. Studies have analyzed the correlation of certain bacterial families with the development of hepatic encephalopathy in cirrhotics. In general, stool and saliva dysbiosis with reduction of autochthonous bacteria in patients with cirrhosis incites changes in bacterial defenses and higher risk for bacterial infections, such as spontaneous bacterial peritonitis, and sepsis. Gut microbiome has even been associated with oncogenic pathways and under circumstances might promote the development of hepatocarcinogenesis. Lately, the existence of the oral-gut-liver axis has been related with the development of decompensating events. This link between the liver and the oral cavity could be via the gut through impaired intestinal permeability that allows direct translocation of bacteria from the oral cavity to the systemic circulation. Overall, the contribution of the microbiome to pathogenesis becomes more pronounced with progressive disease and therefore may represent an important therapeutic target in the management of cirrhosis.

Multiple bacterial infections increase the risk of hepatic encephalopathy in patients with cirrhosis.

OBJECTIVE: Patients with liver cirrhosis (LC) are at increased risk for bacterial infections. It is not fully understood how exposure to infections induces further development of hepatic encephalopathy (HE). This study estimated risks of infection associated with HE among patients with LC. METHODS: A nested case-control study of 14,428 adult patients with LC was performed using the population-based Longitudinal Health Insurance Database 2000 in Taiwan. Cases were cirrhotic patients who developed HE during follow-up. Controls were matched to each case by age at LC diagnosis (±2 years), sex, Charlson Comorbid index score, year of LC, and follow-up time with a 1:1 ratio. A multivariate logistic regression model was used to determine and compare the odds of developing HE based on exposure to various risk factors, including site of infection, cirrhosis-related complications, Helicobacter pylori eradication therapy, and peptic ulcer bleeding. Patient survival was evaluated using the time-dependent Cox regression model. RESULTS: Cirrhotic patients with HE (n = 714) and without HE (n = 714) were matched to compare risks. Infections and more frequent yearly infections were significantly associated with increased risk of HE. Independent predictors of HE included spontaneous bacterial peritonitis (aOR, 5.13; 95% CI, 3.03-8.69), sepsis (aOR, 2.54; 95% CI, 1.82--3.53), and biliary tract infection (aOR, 2.03; 95% CI, 1.2-3.46), controlling for confounders. CONCLUSION: Frequent infections are associated with increased risk of HE in cirrhotic patients. More frequent exposure to infection increases the risk of HE and mortality rates. Appropriate prevention of infection and the use of antibiotics for cirrhotic patients at risk for HE are needed.