Insights of gut-liver axis in hepatic diseases: Mechanisms, clinical implications, and therapeutic potentials

Table 2 Potential therapeutic interventions targeting the gut-liver axis

Interventions	Mechanism of action	Targeted disease	Clinical outcomes	Ref.
Prebiotics (pectin)	Restore Bacteroides level	Alcoholic liver disease	Control dysbiosis	Ferrere et al[85], 2017
Prebiotics (Fructo-oligosaccharide)	Promote fatty acid oxidation	NAFLD	Reduced hepatocyte damage and inflammation	Matsumoto et al[116], 2017
Probiotics (E. coli Nissle strain)	↑ Lactobacillus species; ↑ Bifidobacterium species; ↓ Proteus hauseri; ↓ Citrobacter species; ↓ Morganella species	Cirrhosis (humans)	Significant improvement in gut microbiome with decreased endotoxemia, bilirubin, and ascites	Lata et al[117], 2007
Probiotics (Lactobacillus reuteri GMNL-263)	↑ Bifidobacteria; ↑ Lactobacilli; ↓ Clostridia	Hepatic steatosis (rats)	↓ Blood glucose levels, TNF-α and IL-6 production by adipose tissue	Hsieh et al[118], 2013
Probiotics	↑ Parabacteroide; ↑ Allisonella; ↓ Faecalibacterium; ↓ Anaerosporobacter	NASH (humans)	↑ Bacteroidetes ↓ Firmicutes	Wong et al[91], 2013
Probiotic: VSL#3 (8 probiotic mixture)	GLP-1	NAFLD	Decrease BMI and increase GLP-1 and activated GLP1	Alisi et al[119], 2014
Probiotics (VSL #3)	↑ Lactobacillus species	Cirrhosis (humans)	Reduced hospitalization due to HE with daily intake of probiotic for 6 mo	Dhiman et al[120], 2014
Probiotics (Lactobacillus GG)	↑ Firmicutes species; ↓ Enterobacteriaceae; ↓ Porphyromon adacea;	Cirrhosis (humans)	↓ Endotoxemia and TNF-α after 8 wk; ↓ dysbiosis due to decreased Enterobacteriaceae and increased Firmicutes species	Bajaj et al[95], 2014
Probiotics (cholesterol lowering probiotics and anthraquinone from Cassia obtusifolia L)	↑ Bacteroides; ↑ Lactobacillus P; ↑ Arabacteroides; ↓ Oscillospira	NAFLD (rats)	Improve intestinal barrier and decrease endotoxemia and inflammatory cytokines	Mei et al[121], 2015
Probiotics (Prohep: Lactobacillus rhamnosus GG (LGG), viable Escherichia coli Nissle 1917 (EcN), and heat-inactivated VSL#3)	↑ Alistipes; ↑ Butyricimonas; ↑ Mucispirillum; ↑ Oscillibacter; ↑ Parabacteroides; ↑ Paraprevotella; ↑ Prevotella; ↑ Bacteroidetes; ↓ Firmicutes; ↓ Proteobacteria	HCC (mice)	↑ Anti-inflammatory bacteria; ↓ Th17-inducing bacteria and segmented filamentous pro inflammatory bacteria	Li et al[77], 2016
Probiotics	↑ Ruminococcus; ↑ Saccharibacteria (TM7 phylum); ↓ Verrucomicrobia; ↓ Veillonella	NAFLD (rats)	↓ TC, TG, lipid deposition, and inflammation	Liang et al[122], 2019
Six probiotic mixtures	Gut microbiota	NAFLD	Reduce intrahepatic fat and body weight	Ahn et al[123], 2019
Probiotics (multispecies strain)	↑ Lactobacillus (brevis, salivarius, lactis); ↑ Faecalibacterium prausnitzii; ↑ Syntrophococcus sucromutans; ↑ Alistipes shahii; ↑ Bacteroides vulgatus; ↑ Prevotella	Cirrhosis (humans)	Gut microbiome enrichment in compensated cirrhosis patients and improved gut barrier function	Horvath et al[124], 2020
Probiotics (Bifidobacterium animalis spp. Lactis 420)	↑ Lactobacillus; ↑ Alistipes; ↑ Rikenella; ↑ Clostridia; ↓ Bacteroides; ↓ Ruminococcus	HCC (Mice)	Reduced liver injury and improved immune homeostasis via: Increment in tight junction proteins; ↓ Serum endotoxin levels; ↑ fecal SCFAs; ↑ α-diversity regulation of pro-inflammatory cytokines; (-) RIP3-MLKL signalling pathway of liver macrophages	Zhang et al[125], 2020
Probiotics (Bifidobacterium and Lactobacillus)	↑ Bacteroidetes; ↑ Bifidobacterium; ↑ Bacteroides; ↑ Clostridium; ↑ Ruminococcus; ↑ Anaerostipes; ↑ Blautia; ↓ Firmicutes; ↓ Faecalibacterium; ↓ Helicobacter; ↓ Staphylococcus	HCC (Mice)	↑ Treg cell differentiation; ↑ SCFAs; ↓ infiltration of inflammatory cells in the liver; ↓ ALT, AST; ↓ Th1, Th17 cells; (-) LPS translocation to the liver; (-) activation of the TLR/NF-kB pathway	Liu et al[126], 2021
Probiotic	Gut barrier	NAFLD		Mohamad et al[127], 2021
FMT	↑ Lactobacillaceae; ↑ Bifidobacteriaceae; ↑ Bacteroidetes; ↑ Firmicutes	HE	Improves dysbiosis and SCFAs	Bajaj et al[86], (2017)
FMT	Gut microbiota	Cirrhosis	Reduced systemic inflammation	Bajaj et al[128], 2019
FMT	Allogenic FMT: ↑ Ruminococcus ↑ Eubacterium hallii; ↑ Faecalibacterium; ↑ Prevotella copri; Autologous FMT: ↑ Lachnospiraceae	NAFLD	Decreased steatosis and liver inflammation and enhanced liver endothelial function	Witjes et al[129], 2020
FMT	Gut microbiota	NAFLD	Reduced intestinal permeability	Craven et al[130], 2020
FMT	↑ Bifidobacterium; ↑ Lactobacillus; ↓ Escherichia coli	HCC	Decreased AST, ALT, and serum IgG levels and prevented progression of alcohol induced hepatitis	Liang et al[131], 2021
FMT	Gut microbiota	NAFLD	Reduces gut dysbiosis and decreases fat accumulation	Xue et al[132], 2022
Synbiotics [Bifidobacterium longum and Fructo-oligosaccharide]	Gut microbiota	NASH	Reduced liver inflammation and hepatocyte damage	Malaguarnera et al[84], 2012
Synbiotics [Bifidobacterium animalis and inulin]	Gut microbiota	NAFLD	Improved steatosis and liver enzyme levels	Lambert et al[133], 2015
Synbiotics	Gut microbiota	NAFLD	Increased levels of Bifidobacterium and Faecalibacterium, and decreased Oscillibacter and Alistipes	Scorletti et al[134], 2020

NAFLD: Non-alcoholic fatty liver disease; NASH: Non alcoholic steatohepatitis; HCC: Hepatocellular carcinoma; FMT: Faecal microbial transplantation; HE: Hepatic encephalopathy; TC: Total cholesterol; TG: Triglycerides; SCFAs: Short chain fatty acids; LPS: Lipopolysaccharide; GLP: Glucagon like peptide.