Gut-liver axis in cirrhosis:Are hemodynamic changes a missing link?

Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease,especially cirrhosis.This introduces the concept of the gut-liver axis,which can be imagined as a chain connected by several links.Gut dysbiosis,small intestinal bacterial overgrowth,and intestinal barrier alteration lead to bacterial translocation,resulting in systemic inflammation.Systemic inflammation further causes vasodilation,arterial hypotension,and hyperdynamic circulation,leading to the aggravation of portal hypertension,which contributes to the development of complications of cirrhosis,resulting in a poorer prognosis.The majority of the data underlying this model were obtained initially from animal experiments,and most of these correlations were further reproduced in studies including patients with cirrhosis.However,despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development,the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied.They remain a missing link in the gut-liver axis and a challenge for future research.

Effect of probiotics on hemodynamic changes and complications associated with cirrhosis:A pilot randomized controlled trial

BACKGROUND Bacterial translocation exacerbates the hyperdynamic circulation observed in cirrhosis and contributes to a more severe disease course.Probiotics may reduce bacterial translocation and may therefore be useful to redress the circulatory imbalance.AIM To investigate the effect of probiotics on hemodynamic parameters,systemic inflammation,and complications of cirrhosis in this randomized placebocontrolled trial.METHODS This single-blind randomized placebo-controlled study included 40 patients with Child-Pugh class B and C cirrhosis;24 patients received probiotics(Saccharomyces boulardii)for 3 mo,and 16 patients received a placebo over the same period.Liver function and the systemic hemodynamic status were evaluated pre-and postintervention.Echocardiography and simultaneous blood pressure and heart rate monitoring were performed to evaluate systemic hemodynamic indicators.Cardiac output and systemic vascular resistance were calculated.RESULTS Following a 3-mo course of probiotics in comparison to the control group,we observed amelioration of hyperdynamic circulation[a decrease in cardiac output(P=0.026)and an increase in systemic vascular resistance(P=0.026)]and systemic inflammation[a decrease in serum C-reactive protein levels(P=0.044)],with improved liver function[an increase in serum albumin(P=0.001)and a decrease in the value of Child-Pugh score(P=0.001)]as well as a reduction in the severity of ascites(P=0.022),hepatic encephalopathy(P=0.048),and cholestasis[a decrease in serum alkaline phosphatase(P=0.016)and serum gamma-glutamyl transpeptidase(P=0.039)activity]and an increase in platelet counts(P<0.001)and serum sodium level(P=0.048).CONCLUSION Probiotic administration was associated with amelioration of hyperdynamic circulation and the associated complications of cirrhosis.

Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis

BACKGROUND Gut dysbiosis is common in cirrhosis.AIM To study the influence of gut dysbiosis on prognosis in cirrhosis.METHODS The case-control study included 48 in-patients with cirrhosis and 21 healthy controls.Stool microbiome was assessed using 16S ribosomal ribonucleic acid gene sequencing.We used modified dysbiosis ratio(MDR):[Bacilli(%)+Proteobacteria(%)]/[Clostridia(%)+Bacteroidetes(%)].Patients with MDR more the median made up the group with severe dysbiosis,others did the group with nonsevere dysbiosis.The follow-up period was 4 years.RESULTS The mortality rate of patients with severe dysbiosis was significantly higher than that of patients with non-severe dysbiosis(54.2%vs 12.5%;P=0.001).The presence of severe dysbiosis was independent risk factors for death[hazard ratio=8.6×(1.9-38.0);P=0.005].The abundance of Enterobacteriaceae(P=0.002),Proteobacteria(P=0.002),and Lactobacillaceae(P=0.025)was increased and the abundance of Firmicutes(P=0.025)and Clostridia(P=0.045)was decreased in the deceased patients compared with the survivors.The deceased patients had a higher MDR value than the survivors[0.131×(0.069-0.234)vs 0.034×(0.009-0.096);P=0.004].If we applied an MDR value of 0.14 as the cutoff point,then it predicted patient death within the next year with a sensitivity of 71.4%and a specificity of 82.9%[area under the curve=0.767×(0.559-0.974)].MDR was higher in patients with cirrhosis than in health controls[0.064×(0.017-0.131)vs 0.005×(0.002-0.007);P<0.001],and in patients with decompensated cirrhosis than in patients with compensated cirrhosis[0.106×(0.023-0.211)vs 0.033×(0.012-0.074);P=0.031].MDR correlated negatively with prothrombin(r=-0.295;P=0.042),cholinesterase(r=-0.466;P=0.014)and serum albumin(r=-0.449;P=0.001)level and positively with Child–Turcotte–Pugh scale value(r=0.360;P=0.012).CONCLUSION Gut dysbiosis is associated with a poorer long-term prognosis in cirrhosis.

Probiotics in hepatology:An update

The gut-liver axis plays an important role in the pathogenesis of various liver diseases.Probiotics are living bacteria that may be used to correct disorders of this axis.Notable progress has been made in the study of probiotic drugs for the treatment of various liver diseases in the last decade.It has been proven that probiotics are useful for hepatic encephalopathy,but their effects on other symptoms and syndromes of cirrhosis are poorly studied.Their effectiveness in the treatment of metabolic associated fatty liver disease has been shown both in experimental models and in clinical trials,but their effect on the prognosis of this disease has not been described.The beneficial effects of probiotics in alcoholic liver disease have been shown in many experimental studies,but there are very few clinical trials to support these findings.The effects of probiotics on the course of other liver diseases are either poorly studied(such as primary sclerosing cholangitis,chronic hepatitis B and C,and autoimmune hepatitis)or not studied at all(such as primary biliary cholangitis,hepatitis A and E,Wilson's disease,hemochromatosis,storage diseases,and vascular liver diseases).Thus,despite the progress in the study of probiotics in hepatology over the past decade,there are many unexplored and unclear questions surrounding this topic.

Immune disorders and rheumatologic manifestations of viral hepatitis

Infection with hepatotropic viruses is not limited to the liver and can lead to the development of various immunological disorders(the formation of cryoglobulins,rheumatoid factor,antinuclear antibodies,autoantibodies specific for autoimmune hepatitis and primary biliary cholangitis,and others),which can manifest as glomerulonephritis,arthritis,uveitis,vasculitis(cryoglobulinemic vasculitis,polyarteritis nodosa,Henoch-Schonlein purpura,isolated cutaneous necrotizing vasculitis),and other rheumatologic disorders,and be a trigger for the subsequent development of autoimmune hepatitis and primary biliary cholangitis.A further study of the association between autoimmune liver diseases and hepatotropic virus infection would be useful to assess the results of treatment of these associated diseases with antiviral drugs.The relationship of these immune disorders and their manifestations with hepatotropic viruses is best studied for chronic hepatitis B and C.Only isolated cases of these associations are described for hepatitis A.These links are least studied,and are often controversial for hepatitis E,possibly due to their relatively rare diagnoses.Patients with uveitis,glomerulonephritis,arthritis,vasculitis,autoimmune liver diseases should be tested for biomarkers of viral hepatitis,and if present,these patients should be treated with antiviral drugs.