Hepatoprotection of Probiotics Against Non-Alcoholic Fatty Liver Disease in vivo: A Systematic Review

Abstract

Probiotic supplements have been increasingly reported for their usefulness in delaying the development and progression of non-alcoholic fatty liver disease (NAFLD). Literature on the impact of probiotics on NAFLD covered various aspects of the disease. This study was undertaken to systematically review in vivo findings on hepatoprotection of probiotics against NAFLD. The literature search was performed through Cochrane, PubMed/MEDLINE, Embase, and Web of Science databases. Interventions of known probiotics in NAFLD-induced animal model with at least one measurable NAFLD-related parameter were included. The data were extracted by all authors independently. Quality assessment was conducted using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE's) Risk of Bias (RoB) tool. P-values of measures were compared inter- and intra-study for each parameter. Forty-four probiotic-based studies of NAFLD-induced rodents were shortlisted. The majority of the studies were presented with low/unclear risk of bias. Probiotics improved the histopathology of NAFLD rodents (primary outcome). Most of the probiotic-supplemented NAFLD rodents were presented with mixed effects on serum liver enzymes but with improved hepatic and serum lipid profiles (including increased serum high-density lipoprotein cholesterol). The findings were generally accompanied by downregulation of hepatic lipogenic, oxidative, and inflammatory signallings. Probiotics were found to modulate gut microbiota composition and its products, and intestinal permeability. Probiotics also resulted in better glycaemic control and reduced liver weight. Altogether, the present qualitative appraisals strongly implied the hepatoprotective potential of probiotics against NAFLD in vivo.

Keywords: dysbiosis; histopathology; non-alcoholic fatty liver disease; probiotics; rodents.

Figure 1

PRISMA flowchart of the literature selection process of the present systematic review.

Figure 2

Summary of outcomes derived from the SYRCLE's RoB risk of bias assessment tool (n = 44).

Figure 3

Summary of hepatoprotective effects of probiotic supplementations on NAFLD in vivo. (A) The infographic represents the commonly reported biochemical and molecular parameters (>2 studies) with the most reported trend of significant findings (>50% studies; p < 0.05) of NAFLD animal models supplemented with probiotics. Each horizontal stacked column represents the total number of findings which had reported the common parameters of the included studies. The number in each data series of each stacked column represents the most reported trend of significant findings (>50%; p < 0.05) out of the total number of findings reported in the included studies on each parameter. (B) The illustration represents the reported changes of gut microbiota and SCFA compositions at various sites along the gut of NAFLD animal models supplemented with probiotics. ACC, Acetyl-CoA carboxylase; ALP, alkaline phosphatase; A. municiphila, Akkermansia miniciphila; ChREBP, carbohydrate response-element binding protein; CPT1, carnitine palmitoyltransferase I; E. coli, Escherichia coli; F, fibrosis; FAS, fatty acid synthase; FBG, fasting blood glucose; GLP-1, glucagon-like peptide-1; GM, gut microbiota; GSH-Px, glutathione peroxidase; HOMA-IR, homeostasis model assessment for insulin resistance; I, inflammation; IL-1β, interleukin-1; IL-4, interleukin-4; IL-6, interleukin-6; IL-10, interleukin-10; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LPS, lipopolysaccharide; MDA, malanoyl dialdehyde; NF-κB, necrosis factor kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; pAMPK, phosphorylated AMP-activated protein kinase; PL, phospholipid; PPARɤ, peroxisome proliferator-activated receptor alpha; PGC-1ɑ, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; S, steatosis; SCFA, short chain fatty acid; SOD, superoxide dismutase; SREBP-1, sterol regulatory element-binding protein 1; TAG, triacylglycerol; TC, total cholesterol; TFA, total fatty acid; TGF-α, transforming growth factor beta; TJ, tight junction protein; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor alpha; ↑, increased; ↓, reduced; ↔, no changes.

Figure 4

Potential mechanisms underlying probiotic-mediated prevention of NAFLD in vivo. (A) Probiotic-based interventions could improve dysbiosis, and in turn modulate the gut microbiota-derived metabolites. (B) Concurrently, improved gut barrier function would limit the delivery of gut-derived insults. (C) In the liver, the increased butyrate would increase activation of hepatic AMPK. (D) This would downregulate the hepatic lipogenesis pathway through reduced transcription factors and lipogenic enzymes and/ or increased PPARα, improved fatty acid β-oxidation. (E) The reduced microbiota-derived insults to the liver, would reduce the activation of TLR-4, downregulating the oxidative and inflammatory responses. (F) The reduced hepatic MDA and increased antioxidants mechanisms, and/ or (G) reduced NF-κB would prevent further oxidative and inflammatory stresses to the liver. (H) Lesser liver injury would reduce the stellate cell activation, reducing the TGF-β and downregulate the fibrogenic pathway. (I) Improved hepatic lipid metabolism could be seen through improved dyslipidaemia, reduced adiposity, FFA supply and secretion of pro-inflammatory adipokines. (J) Increased butyrate would promote FIAF, reducing FFA source to the liver. ACC, Acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ChREBP, carbohydrate response-element binding protein; FAS, fatty acid synthase; FBG, fasting blood glucose; FFA, free fatty acid; FIAF, fasting-induced adipose factor; GLP-1, glucagon-like peptide-1; HOMA-IR, homeostasis model assessment for insulin resistance; IL-1β, interleukin-1; IL-4, interleukin-4; IL-6, interleukin-6; IL-10, interleukin-10; LDLR, low-density lipoprotein receptor; LPS, lipopolysaccharide; MDA, malanoyl dialdehyde; NF-κB, necrosis factor kappa B; PPARκ, peroxisome proliferator-activated receptor alpha; SCFA, short chain fatty acid; SREBP-1, sterol regulatory element-binding protein 1; TGF-β, transforming growth factor beta; TJ, tight junction protein; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor alpha; ↑, increased; ↓, reduced.