Probiotics can modulate gut microbiota, intestinal permeability, and immune response and could therefore improve cognitive dysfunction and help avoid potential consequences, such as falls, in patients with cirrhosis. The aim of this study was to evaluate the effect of a multistrain probiotic on cognitive function, risk of falls, and inflammatory response in patients with cirrhosis. Consecutive outpatients with cirrhosis and cognitive dysfunction (defined by a Psychometric Hepatic Encephalopathy Score [PHES] < −4) and/or falls in the previous year were randomized to receive either a sachet of a high‐concentration multistrain probiotic containing 450 billion bacteria twice daily for 12 weeks or placebo. We evaluated the changes in cognitive function (PHES); risk of falls (Timed Up and Go [TUG] test, gait speed, and incidence of falls); systemic inflammatory response; neutrophil oxidative burst; intestinal barrier integrity (serum fatty acid–binding protein 6 [FABP‐6] and 2 [FABP‐2] and zonulin and urinary claudin‐3); bacterial translocation (lipopolysaccharide‐binding protein [LBP]); and fecal microbiota. Thirty‐six patients were included. Patients treated with the probiotic (n = 18) showed an improvement in the PHES ( P = 0.006), TUG time ( P = 0.015) and gait speed ( P = 0.02), and a trend toward a lower incidence of falls during follow‐up (0% compared with 22.2% in the placebo group [n = 18]; P = 0.10). In the probiotic group, we observed a decrease in C‐reactive protein ( P = 0.01), tumor necrosis factor alpha ( P = 0.01), FABP‐6 ( P = 0.009), and claudin‐3 ( P = 0.002), and an increase in poststimulation neutrophil oxidative burst ( P = 0.002). Conclusion: The multistrain probiotic improved cognitive function, risk of falls, and inflammatory response in patients with cirrhosis and cognitive dysfunction and/or previous falls.

The progression of cirrhosis is associated with alterations in the composition of the gut microbiome. To assess microbial translocation, we compared the serum microbial composition of patients with and without ascites and characterized the ascitic fluid microbiome using 16S rDNA high-throughput sequencing data. A complex and specific microbial community was detected in the serum and ascitic fluid of patients with cirrhosis but barely detectable in the serum of healthy controls. The serum microbiome of patients with ascites presented higher levels of lipopolysaccharide binding protein, a marker of microbial translocation, associated with higher diversity and relative abundance of Clostridiales and an unknown genus belonging to the Cyanobacteria phylum compared to patients without ascites. The composition of the fecal microbiome was also more altered in patients with than without ascites, confirming previous studies on fecal microbiome. We propose that alteration of the serum and fecal microbiome composition be considered indicators of cirrhosis progression.

Background and Aim Frailty is increasingly recognized as a major prognostic factor in cirrhosis in addition to conventional liver insufficiency scores. The aim was to compare the prevalence and characteristics of frailty between patients with cirrhosis and controls, and to analyse its prognostic value. Methods We included outpatients with cirrhosis and age‐ and gender‐matched non‐cirrhotic controls. Frailty was defined according to the Fried frailty criteria. In patients with cirrhosis, we analysed the ability of the degree of frailty to predict a composite endpoint, consisting of hospitalization, admission to a long‐term care centre, falls or death. Results We included 135 patients with cirrhosis and 135 controls. The prevalence of frailty was higher among patients with cirrhosis: 35 (25.9%) frail, 74 (54.8%) pre‐frail and 26 (19.2%) robust vs 14 (10.4%) frail, 67 (49.6%) pre‐frail and 54 (40%) robust (P < .001) in controls. This difference was mainly as a result of decreased muscle strength in patients with cirrhosis. During follow‐up, frail patients with cirrhosis showed a higher probability of composite endpoint, hospitalization and falls than pre‐frail and robust cirrhotic patients but mortality was similar. MELD‐Na score and frailty were independent predictive factors for hospitalization, frailty for falls, and MELD‐Na score and albumin for survival. Vitamin D deficiency and increased cystatin C were associated with frailty. Conclusions Frailty was more frequent in outpatients with cirrhosis than in controls, mainly because of a decrease in muscle strength, and it could be a predictive factor for hospitalization and falls in these patients.

Background:Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours.Methods:A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days.Results:The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child–Pugh score showed a statistically significant ammonia decrease in Child–Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0–120 hours in the OP group [40.16 μmol/l (37.7–42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54–126);p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed.Conclusions:OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child–Pugh A and B patients. OP appeared well tolerated.

Ascitic neutrophils from cirrhotic patients with spontaneous bacterial peritonitis (SBP) exhibit an impaired oxidative burst that could facilitate bacterial infection. However, the influence of the cell-free ascitic fluid of these patients on neutrophil function has not been investigated. To analyze this influence, we determined the ascitic levels of cytokines, resistin, and lactoferrin and their association with neutrophil function, disease severity score, and SBP resolution. We analyzed NETosis induction by microscopy and oxidative burst by the flow cytometry of healthy neutrophils cultured in ascitic fluid from cirrhotic patients with sterile ascites (SA) and with SBP before and after antibiotic treatment. Resistin, IL-6, IL-1 receptor antagonist, IL-1β, and lactoferrin levels were measured in ascitic fluids and supernatants of cultured neutrophils and PBMCs by ELISA. Upon stimulation, healthy neutrophils cultured in SBP ascitic fluid produced lower NETosis and oxidative burst than those cultured in SA. Ascitic resistin levels were negatively correlated with NETosis, oxidative burst, and ascitic glucose levels; and positively correlated with the model for end-stage liver disease score. After an E. coli or TNF-α stimulus, neutrophils were the major resistin producers. Resistin indirectly reduced the oxidative burst of neutrophils and directly reduced the inflammatory phenotype of monocytes and TNF-α production. Bacterial-induced resistin production can down-regulate the inflammatory response of macrophages and neutrophil function in ascitic fluid. Consequently, this down-regulation may jeopardize the elimination of bacteria that translocate to ascitic fluid in patients with cirrhosis.