Probiotic supplementation for 24 weeks in patients with non-alcoholic steatohepatitis: the PROBILIVER randomized clinical trial.

Background and aim: Considering the increasing prevalence of non-alcoholic steatohepatitis (NASH) and treatment gaps, this study aimed to evaluate the effect of probiotic supplementation on liver function markers, nutritional status, and clinical parameters. Methods: This double-blind, randomized clinical trial (ClinicalTrials.gov ID: NCT0346782) included adult outpatients with biopsy-proven NASH. The intervention consisted of 24 weeks of supplementation with the probiotic mix Lactobacillus acidophilus (1 × 109 CFU) + Lactobacillus rhamnosus (1 × 109 CFU) + Lactobacillus paracasei (1 × 109 CFU) + Bifidobacterium lactis (1 × 109 CFU), or placebo, twice a day. The following parameters were evaluated: demographic and clinical data, transient elastography (FibroScan), liver enzymes, NAFLD fibrosis score, fatty liver index, laboratory assessment, serum concentration of toll-like receptor-4 (sTLR-4) and cytokeratin 18 (CK-18), anthropometric data, dietary intake, and physical activity. Regarding data analysis, the comparison between the groups was based on the delta of the difference of each variable analyzed (value at the end of treatment minus the baseline value) using the t-test for independent samples or the Mann-Whitney U-test. Results: Forty-four patients with NASH completed the trial (51.4 ± 11.6 years). At baseline, 87% of participants had a mild liver fibrosis degree on biopsy, normal values of liver enzymes, transient elastography values consistent with grade 1 fibrosis in both groups, increased waist circumference (WC), a BMI of 30.97 kg/m2, and 76% presented with metabolic syndrome (MetS). After the intervention, no differences were observed between the probiotic and placebo groups in terms of MetS, WC, BMI scores, or liver enzyme levels (p > 0.05 for all). The elastography values remained consistent with grade 1 fibrosis in both groups. Although CK-18 was reduced in both groups, a larger effect size was noted in the probiotic group (D = 1.336). sTLR-4 was also reduced in both groups, with no difference between groups (p = 0.885). Conclusion: Intervention with probiotics in the early stages of NASH demonstrated no significant change in hepatic and clinical parameters. Clinical trial registration: ClinicalTrials.gov, identifier NCT0346782.

Oral 24-week probiotics supplementation did not decrease cardiovascular risk markers in patients with biopsy proven NASH: A double-blind placebo-controlled randomized study.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease (CVD) is the major cause of death in non-alcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Probiotics are often indicated for the disease, but their results are controversial in part due to the poor quality of studies. Thus, we investigated the impact of 24-week probiotics supplementation on cardiovascular risk (CVR) in biopsy-proven non-alcoholic steatohepatitis (NASH) patients. PATIENTS AND METHODS: Double-blind, placebo-controlled, single-center study (NCT03467282), adult NASH, randomized for 24 weeks daily sachets of probiotic mix (109CFU of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei and Bifidobacterium lactis) or placebo. Clinical scores (atherogenic indexes, atherosclerotic cardiovascular disease-ASCVD and systematic coronary risk evaluation-SCORE), biochemistry, miR-122, miR-33a, plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), were determined before and after the intervention. RESULTS: Forty-six patients were enrolled (23 received probiotics and 23 placebo), with a mean age of 51.7 years, most of them females and whites. Clinical and demographic features were similar between the groups at the baseline. The Median NAFLD activity score was 4.13 in both groups. Fibrosis was mild in most patients (15.2% and 65.2% F0 and F1, respectively). Treatment did not promote any clinically significant changes in body mass index or laboratory, including lipid and glucose profile. High CVR patients through atherogenic indexes decreased from baseline in both groups, as well as PAI-1 and miR-122 levels, although there was no difference between probiotics and placebo. CONCLUSIONS: A 24-week probiotic mix administration was not superior to placebo in reducing CVR markers in patients with NASH.

Effect of probiotic supplementation in nonalcoholic steatohepatitis patients: PROBILIVER TRIAL protocol.

BACKGROUND: Recently factors in the relationship between gut microbiota, obesity, diabetes and the metabolic syndrome have been suggested in the development and progression of nonalcoholic steatohepatitis (NASH). In this sense, this work aims to evaluate the effects of probiotic supplementation on intestinal microbiota modulation, degree of hepatic steatosis and fibrosis, inflammation, gut permeability, and body composition. METHODS: This double-blind, randomized clinical trial will include adult outpatients with a diagnosis of NASH confirmed by biopsy with or without transient elastography. All patients will undergo a complete anamnesis to investigate their alcohol consumption, previous history, medications, nutritional assessment (dietary intake and body composition), sarcopenia, physical activity level and physical and functional capacity, cardiovascular risk, biochemical parameters for assessment of inflammatory status, lipid profile, hepatic function, gut permeability, and assessment of microbiota. These procedures will be performed at baseline and repeated after 24 weeks (at the end of the study). Through the process of randomization, patients will be allocated to receive treatment A or treatment B. Both patients and researchers involved will be blinded (double-blind study). The intervention consists of treatment with a probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1 x 109 CFU for each) and the placebo which is identical in all its characteristics and packaging. Patients will be instructed to consume two sachets/day during 24 weeks and to report any symptoms or side effects related to the use of the sachets. Adherence control will be carried out through the patient's notes on a form provided, and also by checking the number of sachets used. DISCUSSION: The final results of study will be analyzed and disseminated in 2020. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03467282 . Registered on 15 March 2018.