Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally-derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5 month follow-up in outpatient cirrhotic men with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5-days of broad-spectrum antibiotic pre-treatment then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35 and 150 post-randomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAE). Secondary outcomes were AEs, cognition, microbiota and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed till study-end. FMT with antibiotic pre-treatment was well-tolerated. Eight (80%) SOC participants had a total of 11 SAE compared to two (20%) FMT participants with SAEs (both FMT-unrelated, p=0.02). Five SOC and no FMT participants developed further HE (p=0.03). Cognition improved in FMT, but not SOC group. MELD score transiently worsened post-antibiotics, but reverted to baseline post-FMT. Post-antibiotics, beneficial taxa and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusions: FMT from a rationally selected donor reduced hospitalizations, improved cognition and dysbiosis in cirrhosis with recurrent HE.

ObjectiveComorbid conditions are associated with poor prognosis in COVID-19. Registry data show that patients with cirrhosis may be at high risk. However, outcome comparisons among patients with cirrhosis+COVID-19 versus patients with COVID-19 alone and cirrhosis alone are lacking. The aim of this study was to perform these comparisons.DesignA multicentre study of inpatients with cirrhosis+COVID-19 compared with age/gender-matched patients with COVID-19 alone and cirrhosis alone was performed. COVID-19 and cirrhosis characteristics, development of organ failures and acute-on-chronic liver failure (ACLF) and mortality (inpatient death+hospice) were compared.Results37 patients with cirrhosis+COVID-19 were matched with 108 patients with COVID-19 and 127 patients with cirrhosis from seven sites. Race/ethnicity were similar. Patients with cirrhosis+COVID-19 had higher mortality compared with patients with COVID-19 (30% vs 13%, p=0.03) but not between patients with cirrhosis+COVID-19 and patients with cirrhosis (30% vs 20%, p=0.16). Patients with cirrhosis+COVID-19 versus patients with COVID-19 alone had equivalent respiratory symptoms, chest findings and rates of intensive care unit transfer and ventilation. However, patients with cirrhosis+COVID-19 had worse Charlson Comorbidity Index (CCI 6.5±3.1 vs 3.3±2.5, p<0.001), lower presenting GI symptoms and higher lactate. Patients with cirrhosis alone had higher cirrhosis-related complications, maximum model for end-stage liver disease (MELD) score and lower BiPAP/ventilation requirement compared with patients with cirrhosis+COVID-19, but CCI and ACLF rates were similar. In the entire group, CCI (OR 1.23, 95% CI 1.11 to 1.37, p<0.0001) was the only variable predictive of mortality on multivariable regression.ConclusionsIn this multicentre North American contemporaneously enrolled study, age/gender-matched patients with cirrhosis+COVID-19 had similar mortality compared with patients with cirrhosis alone but higher than patients with COVID-19 alone. CCI was the only independent mortality predictor in the entire matched cohort.

Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single-blind, placebocontrolled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End-Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide-binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow-up with SOC maintenance was performed until 5 months. FMTassigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/ HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post-FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E-cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin-6 (P = 0.02) and serum LBP (P = 0.009) reduced post-FMT. EncephalApp performance improved post-FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.

Background/aimsIntestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.Methods/designWe analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.ResultsIn ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.ConclusionsIn ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

Chronic opioid use in cirrhosis is associated with increased endotoxemia, dysbiosis and all-cause readmissions.

Cirrhosis is associated with brain dysfunction known as hepatic encephalopathy (HE). The mechanisms behind HE are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. We aimed to define the individual contribution of specific gut bacterial taxa towards astrocytic and neuronal changes in brain function using multi-modal MRI in patients with cirrhosis. 187 subjects (40 controls, 147 cirrhotic; 87 with HE) underwent systemic inflammatory assessment, cognitive testing, stool microbiota analysis and brain MRI analysis. MR spectroscopy (MRS) changes of increased Glutamate/glutamine, reduced myo-inositol and choline are hyperammonemia-associated astrocytic changes, while diffusion tensor imaging (DTI) demonstrates changes in neuronal integrity and edema. Linkages between cognition, MRI parameters and gut microbiota were compared between groups. We found that HE patients had a significantly worse cognitive performance, systemic inflammation, dysbiosis and hyperammonemia compared to controls and cirrhotics without HE. Specific microbial families (autochthonous taxa negatively and Enterobacteriaceae positively) correlated with MR spectroscopy and hyperammonemia-associated astrocytic changes. On the other hand Porphyromonadaceae, were only correlated with neuronal changes on DTI without linkages with ammonia. We conclude that specific gut microbial taxa are related to neuronal and astrocytic consequences of cirrhosis-associated brain dysfunction.

BaCKgRoUND aND aIMS: Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach.appRoaCH aND ReSUltS: In this phase 1, doubleblind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/ creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/ isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT. CoNClUSIoNS:This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT. (Hepatology 2021;73:1688-1700.A lcohol use disorder (AUD) and alcoholassociated cirrhosis are major causes of morbidity and mortality. (1) Continued alcohol misuse in the setting of end-organ damage, such as cirrhosis, can hasten disease progression. Therefore, therapies that encourage alcohol abstinence or reduce alcohol misuse are relevant. Pharmaco-therapies for craving in alcohol-associated cirrhosis have yielded partial success and focus largely on neuromodulation. (2) AUD is associated with major changes in the gut-brain axis, which is worsened with the occurrence of cirrhosis. (3) In addition, other studies

NCT01458990.