Table 1.
Summary of major randomized controlled trials using probiotics or synbiotics therapy for NAFLD/NASH.
| Study | Design/Population (N = Included in the Trial) |
Bacterial Species | Duration | Main Outcome Related to NAFLD | |
|---|---|---|---|---|---|
| Serology | Imaging or Biopsy | ||||
| Aller et al. [89], 2011 | Double-blind RCT/NAFLD (N = 28) |
Lactobacillus bulgaricus
Streptococcus thermophilus |
3 months | (↓) ALT, AST, GGT (-) Anthropometric parameters and cardiovascular risk factors | N/A |
| Vajro et al. [90], 2011 | Double-blind RCT/NAFLD obese children (N = 20) |
Lactobacillus rhamnosus | 8 weeks | (↓) ALT (-) BMI, TNF-α, peptidoglycanpolysaccharide antibody |
N/A |
| Malaguarnera et al. [91], 2012 | RCT/NASH (N = 66) |
Bifidobacterium longum + Prebiotics (Fructo-oligosaccharides) |
24 weeks | (↓) AST, LDL-C, CRP, TNF-α, endotoxin, HOMA-IR (-) ALT, bilirubin, HDL-C, TC, TG, glucose, insulin, C-peptide, BMI |
The liver biopsy indicated that steatosis and NASH activity improved |
| Shavakhi et al. [92], 2013 | Double-blind RCT/NASH on metformin (N = 64) |
Lactobacillus acidophilus
Lactobacillus casei Lactobacillus rhamnosus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus |
6 months | (↓) ALT, AST, TG, TC, BMI (-) FBS |
Grading of steatosis based on US measurement improved |
| Wong et al. [93], 2013 | RCT/NASH (N = 20) |
Lactobacillus plantarum, Lactobacillus deslbrueckii
Lactobacillus acidophilus Lactobacillus rhamnosus Bifidobacterium bifidum |
6 months | (↓) ALT (-) AST, BMI, waist circumference, glucose, and lipid levels |
Proton-magnetic resonance spectroscopy-measured that intrahepatic triglyceride content (IHTG) improved |
| Alisi et al. [94], 2014 | Double-blind RCT/NAFJD children (N = 44) |
Streptococcus thermophilus
Bifidobacterium breve Bifidobacterium longum Bifidobacterium infantis Lactobacillus acidophilus Lactobacillus plantarum Lactobacillus casei Lactobacillus bulgaricus |
4 months | (↓) BMI (↑) GLP-1, activated GLP-1 (-) ALT, triglycerides, HOMA |
Grading of steatosis based on US measurement improved |
| Eslamparast et al. [95], 2014 | Double-blind RCT/NAFLD with lifestyle modification (N = 52) |
Lactobacillus casei Lactobacillus rhamnosus Lactobacillus acidophilus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus + prebiotic (fructo-oligosaccharide) |
28 weeks | (↓) ALT, AST, CRP, TNF-ɑ, NF-κB p65 (-) BMI |
Transient elastography- measured fibrosis score improved |
| Nabvi et al. [96], 2014 | Double-blind RCT/NAFLD (N = 72) |
Lactobacillus acidophilus
Bifidobacterium lactis |
8 weeks | (↓) ALT, AST, TC, LDL-C (-) Glucose, TG, HDL-C |
N/A |
| Miccheli et al. [97], 2015 | Triple-blind RCT/NAFLD children (N = 31) |
Streptococcus thermophilus
Bifidobacterium breve Bifidobacterium longum Bifidobacterium infantis Lactobacillus acidophilus Lactobacillus plantarum Lactobacillus casei Lactobacillus bulgaricus |
4 months | (↓) AST, total and active GLP-1, BMI (-) ALT, TG, TC, HDL-C, LDL-C, glucose, insulin |
Grading of steatosis based on US measurement improved |
| Asgharian et al. [98], 2016 | Double-blind RCT/NAFLD (N = 80) |
Lactobacillus casei Lactobacillus acidophilus Lactobacillus rhamnosus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus + prebiotic (fructo-oligosaccharide) |
8 weeks | Prevent ASL and ALT elevation (-) CRP, BMI |
Grading of steatosis based on US measurement improved |
| Ferolla et al. [99], 2016 | RCT/NASH (N = 50) |
Lactobacillus reuteri + prebiotic (inulin) |
3 months | (↓) BMI (-) AST, ALT, ALP, GGT, TC, TG, HDL-C, VDL-C, LPS, and intestinal permeability measured by lactulose/mannitol urinary excretion |
MRI-PDFF- measured steatosis improved but liver fibrosis had no significant change |
| Sepideh et al. [100], 2016 | Double-blind RCT/NAFLD (N = 42) |
Lactobacillus casei
Lactobacillus acidophilus Lactobacillus rhamnosus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus |
8 weeks | (↓) IL-6, FBS, insulin, insulin resistance (-) TNF-alpha |
N/A |
| Abdel et al. [101], 2017 | RCT/NASH with obesity (N = 30) |
Lactobacillus acidophilus | 1 month | (↓) ALT, AST (-) TG, TC, FBS Bilirubin, HDL-C |
N/A |
| Behrouz et al. [102], 2017 | Double-blind RCT/NAFLD (N = 89) |
Lactobacillus casei
Lactobacillus rhamnosus Lactobacillus acidophilus Bifidobacterium longum Bifidobacterium breve |
12 weeks | (↓) Leptin, insulin, and HOMA-IR (-) Adiponectin, FBS |
N/A |
| Ekhlasi et al. [103], 2017 | Double-blind RCT/NAFLD with Vitamin E (N = 60) |
Lactobacillus casei Lactobacillus rhamnosus Stretococcus thermophilus Bifidobacterium breve Lactobacillus acidophilus Bifidobacterium longum Lactobacillus bulgaricus + prebiotic (fructo-oligosaccharide) |
8 weeks | (↓) ALT, AST, ALP, sytolic BP, malondialdehyde, TNF-alpha (-) Diastolic Blood Pressure, nitric oxide, BMI |
N/A |
| Famouri et al. [104], 2017 | Triple-Blind RCT/NAFLD obese children (N = 64) |
Lactobacillus acidophilus
Bifidobacterium lactis Bifidobacterium bifidum Lactobacillus rhamnosus |
12 weeks | (↓) ALT, AST, cholesterol, triglycerides, LDL-C, and waist circumference (-) BMI, weight |
Grading of steatosis based on US measurement improved |
| Manzhalii et al. [105], 2017 | RCT/NASH with low-fat/low-calorie diet (N = 75) |
Lactobacilli
Bifidobacteria Streptococcus thermophilus |
12 weeks | (↓) ALT, BMI and cholesterol (-) GGT |
Liver stiffness based on US measurement improved |
| Mofidi et al. [106], 2017 | Double-blind RCT/NAFLD (N = 50) |
Lactobacillus acidophilus Lactobacillus casei Lactobacillus rhamnosus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus + prebiotic (fructo-oligosaccharide) |
28 weeks | (↓) AST, ALT, GGT, glucose, triglyceride, Total cholesterol, CRP, NF-κB p65 (-) HDL-C, LDL-C, TNF-α |
Transient elastography-measured hepatic steatosis and fibrosis improved |
| Bakhshimoghaddam et al. [107], 2018 | RCT/NAFLD (N = 102) |
Bifidobacterium animalis + prebiotic (inulin) |
24 weeks | (↓) AST, ALT, GGT, ALP, TG, TC | Grading of steatosis based on US measurement improved |
| Javadi et al. [108], 2018 | Double-blind RCT/NAFLD (N = 75) |
Bifidobacterium longum Lactobacillus acidophilus + prebiotic (inulin) |
3 months | (↓) CRP, TNF-α, BMI (↑) TAC (-) IL-6, MDA |
N/A |
| Kobyliak et al. [109], 2018 | Double-blind RCT/NAFLD with type II DM (N = 48) |
Bifidobacterium Lactobacillus Lactococcus Propionibacterium Acetobacter + omega-3 fatty acids |
8 weeks | (↓) GGT, TG, TC, VLDL-C, TNF-α, IL-6 (-) AST, ALT, LDL-C, HDL-C, INF-γ, IL-1β, IL-8 |
Shear Wave Elastography-measured fatty liver index improvement but no significant change in liver stiffness |
| Kobyliak et al. [110], 2018 | Double-blind RCT/NAFLD with type II DM (N = 58) |
Bifidobacterium
Lactobacillus Lactococcus Propionibacterium Acetobacter |
8 weeks | (↓) AST, GTT, TNF-α, IL-6 (-) ALT, TC, TG, VLDL-C, HDL-C, IL-1β, IL-8, IFN- γ |
Shear Wave Elastography-measured fatty liver index improvement but no significant change in liver stiffness |
| Sayari et al. [111], 2018 | RCT/NAFLD with sitagliptin (N = 138) |
Lactobacillus casei Lactobacillus rhamnosus Lactobacillus acidophilus Lactobacillus bulgaricus Bifidobacterium breve Bifidobacterium longum Streptococcus thermophilus + prebiotic (fructo-oligosaccharide) |
16 weeks | (↓) AST, TC, LDL-C, FBS (-) ALT, HDL-C, TG, BMI |
N/A |
| Wang et al. [112], 2018 | Double-blind RCT/NAFLD (N = 200) |
Bifidobacterium Lactobacillus
Enterococcus Bacillus subtilis |
1 month | (↓) AST, ALT, TC, TG, glucose, VLDL-C, TNF-α (↑) High molecular weight adiponectin (-) HDL-C |
Grading of steatosis based on US measurement showed no significant difference |
| Ahn et al. [113], 2019 | Double-blind RCT/NAFLD with obesity (N = 68) |
Lactobacillus acidophilus
Lactobacillus rhamnosus Lactobacillus paracasei Pediococcus pentosaceus Bifidobacterium lactis Bifidobacterium breve |
12 weeks | (↓) TG (-) AST, ALT, TC, HDL-C, glucose, insulin, TNF-α, IL-6, LPS |
MRI-PDFF-measured intrahepatic fat fraction (IHF) and mean IHF reduced compared with control, but no significant change in liver stiffness |
| Duseja et al. [69], 2019 | Double-blind RCT/NAFLD (N = 30) |
Lactobacillus paracasei
Lactobacillus plantarum Lactobacillus acidophilus Lactobacillus delbrueckii subsp. bulgaricus Bifidobacterium longum Bifidobacterium infantis Bifidobacterium breve Streptococcus thermophilus |
1 year | (↓) ALT, ALP, leptin, TNF-α, and LPS (-) AST, Bilirubin, Adiponectin, IL-1β, IL-6 |
The biopsy indicated hepatocyte ballooning, NAS score and fibrosis improved, but not steatosis or lobular inflammation |
NAFLD: Non-alcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; ALT: alanine transaminase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; ALP: alkaline phosphatase; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride; FBS: fasting serum glucose; GLP-1: glucagon-like peptide 1; BMI: body mass index; LPS: Lipopolysaccharides; CRP: C reactive protein; TNF-α: tumor necrosis factor-alfa; NF-κB p65: nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65; IFN- γ: Interferon-gamma; IL-1β: interlukin 1beta; IL-6: interleukin 6; IL-8: interleukin 8; MDA: malondialdehyde; TAC: total antioxidant capacity; NAS: NAFLD activity score; HOMA-IR: homeostasis model assessment of insulin resistance; US: ultrasonography; MRI-PDFF: magnetic resonance imaging–derived proton density fat fraction; IHF: intrahepatic fat fraction.