Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression

Abstract

Background: Preclinical evidence suggests that modulation of the gut microbiome could represent a new therapeutic target in nonalcoholic fatty liver disease (NAFLD).

Objectives: The aim of this study was to evaluate the most current evidence for liver-specific and metabolic effects of microbiome-targeted therapies (MTTs) in persons with NAFLD.

Methods: We searched multiple electronic databases for randomized controlled trials (RCTs) published from January 1, 2005 to December 1, 2018 that enrolled persons with NAFLD who received MTT rather than placebo or usual care. MTT was defined as antibiotics, probiotics, synbiotics, or fecal microbiota transplantation (FMT). Clinical outcomes were pooled with the use of random-effects models and heterogeneity was assessed with the I2 statistic. A random-effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates between studies.

Results: Twenty-one RCTs (1252 participants) were included; 9 evaluated probiotics and 12 evaluated synbiotics, with treatment duration ranging from 8 to 28 wk. No RCTs examined the efficacy of antibiotics or FMT. Probiotics/synbiotics were associated with a significant reduction in alanine aminotransferase activity [ALT, weighted mean difference (WMD): -11.23 IU/L; 95% CI: -15.02, -7.44 IU/L] and liver stiffness measurement (LSM) by elastography (reflecting inflammation and fibrosis) (WMD: -0.70 kPa; 95% CI: -1.00, -0.40 kPa), although analyses showed heterogeneity (I2 = 90.6% and I2 = 93.4%, respectively). Probiotics/synbiotics were also associated with increased odds of improvement in hepatic steatosis, as graded by ultrasound (OR: 2.40; 95% CI: 1.50, 3.84; I2 = 22.4%). No RCTs examined sequential liver biopsy findings. Probiotics (WMD: -1.84; 95% CI: -3.30, -0.38; I2 = 23.6%), but not synbiotics (WMD: -0.85; 95% CI: -2.17, 0.47; I2 = 96.6%), were associated with a significant reduction in body mass index.

Conclusions: The use of probiotics/synbiotics was associated with improvement in liver-specific markers of hepatic inflammation, LSM, and steatosis in persons with NAFLD. Although promising, given the heterogeneity in pooled analyses, additional well-designed RCTs are needed to define the efficacy of probiotics/synbiotics for treatment of NAFLD. This study was registered with PROSPERO as CRD42018091455.

Keywords: fecal microbiota transplantation; microbiome; nonalcoholic fatty liver; probiotics; synbiotics.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram: flow of studies through the review process. MTT, microbiome-targeted therapy; NAFLD, nonalcoholic fatty liver disease.

FIGURE 2

Forest plot of the effect of MTT on serum ALT, stratified by probiotics and synbiotics, and measured by the WMD. Probiotics/synbiotics were associated with a significant reduction in ALT compared with control. ALT, alanine aminotransferase; MTT, microbiome-targeted therapy; WMD, weighted mean difference.

FIGURE 3

Forest plot of the effect of MTT on LSM, as measured by elastography, stratified by probiotics and synbiotics, and measured by the WMD. Probiotics/synbiotics were associated with a significant reduction in LSM compared with control. LSM, liver stiffness measurement; MTT, microbiome-targeted therapy; WMD, weighted mean difference.

FIGURE 4

Forest plot of the effect of MTT on improvement in hepatic steatosis, as graded by ultrasound, stratified by probiotics and synbiotics. Probiotics/synbiotics were associated with increased odds of having improvement from moderate/severe hepatic steatosis compared with control. MTT, microbiome-targeted therapy.

FIGURE 5

Forest plot of the effect of MTT on BMI, stratified by probiotics and synbiotics, and measured by the WMD. Probiotics/synbiotics were associated with a significant reduction in BMI compared with control. MTT, microbiome-targeted therapy; WMD, weighted mean difference.