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

Table 1 Summary of published studies on gut microbiota and hepatic diseases

Ref.	Population	Disease focus	Key findings	Implications
Chen et al[87], 2011	36 cirrhosis patients; 24 healthy controls	Cirrhosis	↑ Proteobacteria; ↑ Fusobacteria; ↑ Enterobacteriacea; ↑ Veillonellacea; ↑ Streptococcaceae; ↓ Bacteroidetes; ↓ Lachnospiraceae	Dysbiosis due to increased Enterobacteriaceae and Streptococcaceae may affect the prognosis of cirrhosis patients
Liu et al[88], 2012	Cirrhosis patients vs healthy controls	Cirrhosis	↓ Bifidobacterium; ↓ Bacteroidetes; ↑ Proteobacteria; ↑ Fusobacteria; ↑ Enterobacteriaceae; ↑ Enterococcus	On releasing endotoxin by enterobacteriaceae, intestinal permeability is increased
Bajaj et al[89], 2012	25 cirrhosis patients: 17 with HE and 8 without HE; 10 healthy controls	Cirrhosis	↑ Bacteroidetes; ↑ Veillonellaceae in HE; ↑ Enterobacteriacea; ↑ Alcaligeneceae; ↑ Porphyromonadacea; ↑ Fusobacteriaceae; ↓ Ruminococcaceae; ↓ Lachnospiraceae	Dysbiosis was found in patients with HE compared to healthy individuals; endotoxemia, impaired cognition, and inflammation in the liver were seen in patients with HE
Mutlu et al[26], 2012	ALD patients vs healthy control	ALD	↑ Proteobacteria; ↓ Bacteroidetes; ↓ Firmicutes; ↑ Enterobacteriaceae; ↓ Bacteroidetes; ↓ Lactobacillus	Decreased beneficial bacteria and increased intestinal permeability result in systemic endotoxemia
Zhang et al[90], 2013	26 cirrhosis patients with HE; 25 cirrhosis patients without HE; 26 healthy controls	Cirrhosis	↑ Streptococcus salivarius in HE; ↑ Streptococcaceae; ↑ Veillonellaceae	Streptococcus salivarius was found in patients with HE due to increased ammonia
Wong et al[91], 2013	NASH patients and healthy controls	NASH	↓ Firmicutes; ↓ Clostridiales (Faecalibacterium & Anaerosporobacte); ↑ Bacteroidetes (Parabacteroides & Allisonella)
Mouzaki et al[92], 2013	33 NAFLD patients; 11 steatosis patients; 22 NASH patients; 17 normal controls	NAFLD; NASH; steatosis	↑ C. Coccoides in NASH; ↓ Bacteroidetes in NASH	The relationship between Bacteroidetes and liver disease state was independent of increase in BMI
Zhu et al[51], 2013	22 NASH patients; 25 obese people; 16 healthy controls	NASH	↑ Bacteroides (Prevotella); ↑ Proteobacteria (Escherichia); ↓ Firmicutes; ↓ Actinobacteria	Increased population of ethanol producing bacteria in patients with NASH contributed to disease progression; increased ethanol-producing bacteria (Escherichia) was due to the use of antibiotics
Raman et al[30], 2013	30 NAFLD patients; 30 healthy controls	NAFLD	↑ Proteobacteria; ↑ Firmicutes; ↓ Bacteroidetes	Faecal ester volatile organic compounds could negatively influence the microbiome composition of patients with NAFLD
Kakiyama et al[93], 2013	47 cirrhosis patients; 14 healthy controls	Cirrhosis	↑ Staphylococcaeae; ↑ Enterobacteriaceae; ↑ Enterococcaceae; ↓ Lachnospiraceae; ↓ Ruminococcaceae; ↓ Clostridiales XIV; ↓ Blautia	Increased pathogenic bacteria as a result of gut dysbiosis in cirrhotic patients with altered bile acid composition
Qin et al[94], 2014	98 cirrhosis patients; 83 controls	Cirrhosis	↑ Proteobacteria; ↑ Veillonella; ↑ Streptococcus; ↓ Bacteroidetes; ↓ Lachnospiraceae; ↓ Ruminococcaceae; ↓ Blautia	Oral commensals were found in the gut of cirrhotic patients
Bajaj et al[4,95,96], 2014, 2016, and 2019	HE patients vs healthy control	HE due to cirrhosis	↑ Megasphaera; ↑ Enterococcus; ↑ Burkholderia; ↑ Veillonellaceae; ↓ Fecalibacterium; ↓ Blautia; ↓ Roseburia; ↓ Dorea	Increased pathogenic bacteria are linked with poor cognition and inflammation
Bajaj et al[97], 2014	Cirrhosis patients vs healthy controls	Cirrhosis	↑ Veillonella spp.; ↑ Streptococcus spp.; ↓ Bacteroidetes; ↓ Firmicutes
Grat et al[98], 2016	15 HCC patients; 5 patients without HCC; all participants with cirrhosis underwent liver transplantation	HCC	↑ E. coli; ↑ Enterobacteriaceae; ↑ Enterococcus; ↑ Lactobacillus; ↑ H2O2-producing Lactobacillus species	Increased faecal counts of E. coli were noted in the cirrhotic-HCC group, indicating its association with HCC development
Llopis et al[27], 2016	Severe AH patients vs healthy control	Alcoholic hepatitis	↑ Bifidobacteria; ↑ Streptococci; ↑ Enterobacteria; ↓ Clostridium leptum; ↓ Faecalibacterium prausnitziithan	Decreased anti-inflammatory bacteria and enhanced intestinal dysbiosis result in gut permeability which facilitates microbiota translocation
Chen et al[99], 2016	30 cirrhosis patients; 28 healthy controls	Cirrhosis	↑ Veillonella; ↑ Megasphaera; ↑ Dialister; ↑ Atopobium; ↑ Prevotella; ↑ Firmicutes	Raised oral commensal bacteria were found in duodenal mucosal microbiota of cirrhotic patients
Ahluwalia et al[100], 2016	87 patients with HE; 40 healthy controls	Cirrhosis	↑ Enterobacteriaceae; ↓ Lachnospiraceae; ↓ Ruminococcaceae	Specific bacterial families were associated with astrocytic and neuronal MRI changes; gut dysbiosis in cirrhosis was linked with systemic inflammation, elevated ammonia levels, and neuronal dysfunction
Yang et al[101], 2017	ALD patients vs healthy controls	ALD	↑ Candida; ↓ Epicoccum; ↓ Galactomyces
Dubinkina et al[102], 2017	ALD patients vs healthy controls	ALD	↑ Bifidobacterium; ↑ Streptococcus spp; ↑ Lactobacillus spp; ↓ Prevotella; ↓ Paraprevotella; ↓ Alistipes
Chierico et al[29], 2017	61 NASH/NAFLD patients; 54 healthy controls	NAFLD; NASH	↑ Actinobacteria; ↑ Bradyrhizobium; ↑ Anaerococcus; ↑ Peptoniphilus; ↑ P.acnes; ↑ Enterobacteriaceae (Escherichia coli); ↑ Dorea; ↑ Ruminococcus; ↓ Bacteroidetes; ↓ Oscillospira; ↓ Rikenellaceae	Increased microbial diversity in NASH/NAFLD; decreased Bacteroidaceae and Bacteroides were observed in NAFLD and NASH, while they were increased in obese patients compared to controls; increased ethanol-producing bacteria (Enterobacteriaceae) in NAFL/NASH compared to controls
Loomba et al[103], 2017	NAFLD patients and healthy controls	NAFLD	↑ Escherichia coli; ↑ Bacteriodes vulgatus; ↓ Ruminococcus spp.; ↓ Eubacterium rectale; ↓ Faecalibacterium prausnitzii
Liu et al[104], 2018	36 cirrhosis patients; 20 healthy controls	Cirrhosis	↑ Firmicutes; ↓ Bacteroidetes	Microbial dysbiosis in cirrhotic patients with Child-Pugh scores > 5 led to decreased gut motility
Ren et al[105], 2019	75 early HCC patients; 40 Liver cirrhosis patients; 75 healthy controls	HCC	↑ Actinobacteria; ↑ Gemmiger; ↑ Parabacteroides; ↑ Paraprevotella; ↑ Klebsiella; ↑ Haemophilus; ↓ Verrucomicrobia; ↓ Alistipes; ↓ Phascolarctobacterium; ↓ Ruminococcus; ↓ Oscillibacter; ↓ Faecalibacterium; ↓ Clostridium IV; ↓ Coprococcus	Decreased butyrate-producing bacteria and increased LPS-producing bacteria observed in early HCC
Ponziani et al[106], 2019	21 NAFLD-related cirrhosis patients with HCC; 20 NAFLD related cirrhosis patients without HCC; 20 healthy controls	HCC	↑ Bacteroides; ↓ Ruminococcaceae; ↑ Bifidobacterium	Increased faecal calprotectin in HCC patients is an indicator of inflammatory state
Piñero et al[107], 2019	407 cirrhosis patients: 25 with HCC; 25 without HCC; 25 healthy controls	HCC	↑ Erysipelotrichaceae; ↑ Odoribacter; ↑ Butyricimonas; ↓ Leuconostocaceae; ↓ Fusobacterium; ↓ Lachnospiraceae	Decreased Prevotella in cirrhotic patients with HCC, is associated with activation of several inflammatory pathways
Ni et al[108], 2019	68 primary HCC patients: (23 Stage I, 13 Stage II, 30 Stage III, 2 Stage IV); 18 healthy controls	HCC	↑ Dysbiosis index Proteobacteria (Enterobacter, Haemophilus); ↑ Desulfococcus; ↑ Prevotella; ↑ Veillonella; ↓ Cetobacterium	Dysbiosis is seen in patients with primary HCC when compared to healthy controls
Liu et al[69], 2019	57 HCC patients (35 with HBV related HCC, 22 with non-HBV non-HCV related HCC); 33 healthy controls	HCC	↑ Bifidobacterium; ↑ Lactobacillus; ↓ Proteobacteria; ↓ Firmicutes	Decreased anti-inflammatory and increased pro-inflammatory bacteria in non-HBC non-HCV related HCC patients are positively correlated with alcohol consumption
Schwimmer et al[109], 2019	87 NAFLD patients; 37 healthy controls	NAFLD	↑ Bacteroidetes; ↑ Proteobacteria; ↓ Firmicutes	Decreased α-diversity in NAFLD was associated with differences in bacterial abundance rather than an increase in specific phyla or genus; increased bacterial pro-inflammatory products (LPS) were seen in patients with NAFLD
Duarte et al[110], 2019	NASH patients; healthy controls	NASH	↑ Bacteroides; ↑ Proteobacteria; ↑ Enterobacteriaceae; ↑ Escherichia; ↓ Firmicutes; ↓ Actinobacteria; ↑ Klebsiella pneumoniae	Increased alcohol-producing bacteria supply a constant source of ROS which results in liver inflammation
Kravetz et al[111], 2020	44 NAFLD patients; 29 healthy controls	NAFLD	↓ Bacteroidetes; ↓ Prevotella; ↓ Gemmiger; ↓ Oscillospira	Decreased bacterial diversity in patients with NAFLD is associated with an increase in the rate of inflammation in NAFLD
Lang et al[65], 2020	NAFLD patients and healthy controls	NAFLD	↓ Virus and bacteriophage diversity; ↑ Escherichia; ↑ Enterobacteria; ↑ Lactobacillus phage
Lang et al[112], 2021	NAFLD patients and healthy controls	NAFLD	↑ Gemmiger; ↓ Faecalibacterium; ↓ Bacteroides; ↓ Prevotella
Behary et al[113], 2021	32 NAFLD-HCC patients; 28 NAFLD-cirrhosis patients; 30 non-NAFLD controls	HCC	↑ Proteobacteria; ↑ Enterobacteriaceae; ↑ Bacteroides xylanisolvens; ↑ B. caecimuris; ↑ Ruminococcus gnavus; ↑ Clostridium bolteae; ↑ Veillonella parvula; ↑ Bacteroides caecimuris; ↑ Veillonella parvula; ↑ Clostridium bolteae; ↑ Ruminococcus gnavus; ↓ Oscillospiraceae; ↓ Erysipelotrichaceae; ↓ Eubacteriaceae	Increased B. caecimuris and Veillonella parvula distinguish NAFLD-HCC from NAFLD-cirrhosis and non-NAFLD controls; decreased gut microbial α-diversity and increased SCFAs serum levels in NAFLD-HCC result in immunosuppression
Trebicka et al[114], 2021	Cirrhosis patients vs healthy controls	Cirrhosis	↑ Enterobacteriaceae; ↑ Alcaligenaceae; ↑ Streptococcaceae; ↑ Veillonellaceae; ↑ Fusobacteriaceae; ↓ Bacteroidetes; ↓ Ruminococcaceae; ↓ Lachnospiraceae	Pathogenic organisms' overgrowth results in accelerated disease progression and endotoxemia which results in reduction of organisms that can produce SCFAs and anti-bacterial peptides
Solé et al[115], 2021	182 cirrhosis patients	Cirrhosis	↑ Enterococcus; ↑ Streptococcus in ACLF; ↑ Faecalibacterium; ↑ Ruminococcus; ↑ Eubacterium in decompensated patients	As cirrhosis progressed from compensated to uncompensated to ACLF, there was a marked reduction in metagenomic richness

ACLF: Acute-on-chronic liver failure; ALD: Alcohol-related liver diseases; SCFAs: Short chain fatty acids; NAFLD: Non-alcoholic fatty liver disease; HCC: Hepatocellular carcinoma; ROS: Reactive oxygen species; LPS: Lipopolysaccharide; HCV: Hepatitis C virus; HBV: Hepatitis B virus; NASH: Non alcoholic steatohepatitis; HE: Hepatic encephalopathy; BMI: Body mass index.

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.