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.

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics

“…Numerous randomized controlled trials (RCTs) in humans across a range of populations, from healthy individuals to those with acute and chronic diseases, have been conducted to examine the health benefits of putative synbiotics. Many trials have been conducted in adults with metabolic diseases, including overweight and obesity 21 , 22 , type 2 diabetes mellitus 23 , 24 and non-alcoholic fatty liver disease 25 , 26 . Other outcomes, such as irritable bowel syndrome 27 , surgical infections 28 , 29 , chronic kidney disease 30 , 31 and atopic dermatitis 32 , have also been investigated.…”

Role of Probiotics in Non-alcoholic Fatty Liver Disease: Does Gut Microbiota Matter?

“…These mixed results also occurred with other serum markers including Gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting serum glucose (FBS) and inflammatory markers [69,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113]. Given the pattern of mixed results, Table 2 summarizes the most recently published meta-analyses of RCTs with probiotic/synbiotic treatment for NAFLD/NASH populations [114,115,116,117,118].…”

“…All of the meta-analyses listed indicated that microbial therapies are associated with a significant improvement in ALT and AST [114,115,116,117,118]. Regarding the other serum markers, Liu et al included 15 probiotics and synbiotics RCTs involving 782 patients with NAFLD up to April 2018.…”

“…Two large-scale meta-analyses conducted by Sharpton et al [118] and Liu et al [117] indicated that probiotics/synbiotics improved liver stiffness that was measured by elastography, and probiotics/synbiotics are associated with hepatic steatosis improvement as graded by the US though analyses showed heterogeneity. Another meta-analysis conducted by Khan et al indicated that probiotics/synbiotics are associated with a significant improvement in liver fibrosis score graded by fibroscan [115].…”

Diet induces hepatocyte protection in fatty liver disease via modulation of PTEN signaling (Review)

“…The proportion of Bacteroides has been described as markedly higher in patients with liver fibrosis compared with healthy controls, which influences NAFLD progression (94). Furthermore, probiotic administration has been associated with improved levels of liver markers of hepatic inflammation in patients with NAFLD (95). Accordingly, modulation of the gut microbiome presents a new therapeutic target in NAFLD treatment due to the distinct changes in the composition of gut microbiota.…”