Gut microbiota mediated molecular events and therapy in liver diseases

Table 1 Summary of metabolites associated with liver diseases

Liver disease	Sample sources	Metabolites	Gut microbiota	Functions in liver disease	Ref.
NAFLD	Serum	3-(4-hydroxyphenyl) lactate	Abundance in bacteria Firmicutes, Bacteroidetes, Proteobacteria	It is positively associated with liver fibrosis	[56]
NAFLD	Serum	Eight lipids (5α-androstan-3β monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5α-androstan-3β disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose)	Without special bacterial species	Glycocholate is positively associated with advanced liver fibrosis	[57]
FL	Stool	Tryptamine and I3A	Microbiota-dependent without exact bacterial species	They inhibited the pro-inflammatory cytokines in macrophages and hepatocytes. I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c	[58]
FL	Stool	Gly-MCA	Increases in the ratio of Bacteroidetes/Firmicutes	Gly-MCA is an intestinal FXR antagonist, which inhibits HFD-induced fatty liver	[59]
HCC	Stool	Secondary bile acids, such as deoxycholic acid	Increase of Bacteroides and Clostridium cluster XVIII. Low of Streptococcus, Bifidobacterium, and Prevotella	Bile acids derived from the increased microbiota promote the progression of HCC	[52]
HCC	Stool	Bile acids, such as primary bile acid CDCA	Increase in Clostridium species	Removing gram-positive bacteria by antibiotic treatment with vancomycin, which contains the bacteria mediating primary-to-secondary bile acid conversion, was sufficient to induce hepatic NKT cell accumulation and decrease liver tumor growth	[15]
Liver cirrhosis	Stool	Glutamic acid, fumaric acid, 4-aminobutyric acid, succinic acid, isoleucine, valine, lactic acid, mannitol, sorbitol, carbamide, 4-aminobutyric acid, 5-aminopylamine, glutamate, proline, hydroxyproline	High of Enterobacteriaceae and Veillonella. Low of Bacteroidetes	These metabolites are involved in the KEGG pathway in nitrogen metabolism alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine, pantothenate and CoA biosynthesis, glycolysis/ gluconeogenesis, fructose and mannose metabolism, arginine and proline metabolism	[60]
NAFL or NASH	Stool	1-pentanol and 2-butanone, and 4-methyl-2-pentanone	Abundance in Oscillospira, Dorea, and Ruminococcus	The results indicated that significantly lower levels of Oscillospira and higher levels of 1-pentanol and 2-butanone in NAFL patients compared to healthy ones. In NASH, lower levels of Oscillospira were associated with a higher abundance of Dorea and Ruminococcus and higher levels of 2-butanone and 4-methyl-2-pentanone compared to CTRLs	[4]
ALD	Stool, urine	e.g., SCFAs butyrate and propionate	The main harmful bacterial species included altered Bacteroides phylum as well as Bilophila, Alistipes, Butyricimonas, Clostridium, Proteus, and Escherichia coli. Faecalibacterium	Metabolites are affected by chronic ethanol feeding or consumption, including amino acids, steroids and their derivatives, fatty acids and conjugates	[61]

NAFLD: Nonalcoholic fatty liver disease; FL: Fatty liver; I3A: Indole-3-acetate; Gly-MCA: Glycine-β-muricholic acid; HFD: High-fat diet; HCC: Hepatocellular carcinoma; CDCA: Chenodeoxycholic acid; NAFL: Nonalcoholic fatty liver; NASH: Nonalcoholic steatohepatitis; ALD: Alcohol-induced liver disease; SCFAs: Short-chain fatty acids.

Table 2 Gut microbiota-based clinical trials

Study	Mechanism	Trial phase	Patients (n)	ClinicalTrials.gov identifier	Estimated study completion date
Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People with Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer from Colorectal or Pancreatic Cancers	Immunotherapy + Antibiotic	Phase II	27	NCT03785210	2022
Administration of Rifaximin to Improve Liver Regeneration and Outcome Following Major Liver Resection (ARROW)	Antibiotic	Phase II	96	NCT02555293	2020
Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients with Decompensated Cirrhosis to Prevent ACLF Development (2018-001698-25)	Antibiotic	Phase III	240	NCT03780673	2021
Comparative Study of Rifaximin Versus Norfloxacin in the Secondary Prophylaxis of Spontaneous Bacterial Peritonitis (SBP)	Antibiotic	Phase III	100	NCT02120196	2023
Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated with Prednisolone (AntibioCor)	Antibiotic	Phase III	280	NCT02281929	2019
Rifaximin Reduces the Complications of Decompensated Cirrhosis: A Randomized Controlled Trial	Antibiotic	Phase IV	200	NCT02190357	2019
Steady-State Pharmacokinetics of Rifaximin 550 mg Tablets in Healthy and Hepatically Impaired Subjects	Antibiotic	Phase IV	18	NCT03818672	2019
Efficacy, Safety, And Pharmacokinetics of Rifaximin In Subjects with Severe Hepatic Impairment and Hepatic Encephalopathy	Antibiotic	Phase IV	100	NCT01846663	2021
Rifaximin Soluble Solid Dispersion (SSD) Tablets Plus Lactulose for the Treatment of Overt Hepatic Encephalopathy (OHE) (OHE)	Antibiotic	Phase II	325	NCT03515044	2019
Mastiha Treatment for Obese with NAFLD Diagnosis (MAST4HEALTH)	Prebiotic	Early Phase I	52	NCT03135873	2019
Study on the Optimal Strategy for Acute-on-chronic Liver Failure with Integrative Treatment	Prebiotic	N/A	510	NCT03577938	2020
Efficacy of Albumin Therapy with Standard Medical Treatment (SMT) as Compared to Standard Medical Treatment (SMT) in Improving Patient Survival and Immune Modulation in Patients with Acute on Chronic Liver Failure (ASIA Trial).	Prebiotic	N/A	200	NCT03754400	2020
Impact of a Specific Micronutrient-probiotic-supplement on Fatty Liver of Patients After Mini-Gastric Bypass Surgery (FMG-01)	Probiotic	Phase III	60	NCT03585413	2019
Probiotics in the Treatment of NAFLD	Probiotic	N/A	58	NCT02764047	2018
Probiotics in NASH Patients - PROBILIVER TRIAL (NASH)	Probiotic	N/A	46	NCT03467282	2021
Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota (SYN-ALD)	Probiotic	N/A	40	NCT03863730	2031
Novel Therapies in Moderately Severe Acute Alcoholic Hepatitis (NTAH-Mod)	Probiotic	N/A	130	NCT01922895	2019
Probiotics in the Prevention of Hepatocellular Carcinoma in Cirrhosis	Probiotic	N/A	280	NCT03853928	2023
Dietary Modulation of Intestinal Microbiota as Trigger of Liver Health: Role of Bile Acids - "A Diet for Liver Health" (ADLH)	Synbiotic	N/A	84	NCT03897218	2020
Investigation of Synbiotic Treatment in NAFLD (INSYTE)	Synbiotic	N/A	100	NCT01680640	2019
Fecal Microbiota Transplantation (FMT) in Nonalcoholic Steatohepatitis (NASH). A Pilot Study	FMT	Phase I	5	NCT02469272	2018
Fecal Microbiota Transplantation for the Treatment of Non-Alcoholic Steatohepatitis (FMT-NASH)	FMT	Phase I	15	NCT03803540	2021
Fecal Microbial Transplant for Alcohol Misuse in Cirrhosis	FMT	Phase I	20	NCT03416751	2019
FMT in Cirrhosis and Hepatic Encephalopathy	FMT	Phase II	100	NCT03796598	2023
Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy	FMT	Phase II	30	NCT03420482	2021
Fecal Microbiota Transplantation (FMT) in the Management of Hepatic Encephalopathy (HE): A Pilot Study	FMT	Phase II	10	NCT02255617	2019
Fecal Transplant for Hepatic Encephalopathy	FMT	Phase II	30	NCT03439982	2021
Trial of Faecal Microbiota Transplantation in Cirrhosis (PROFIT)	FMT	Phase III	32	NCT02862249	2019
To Assess the Role of Fecal Microbiota Transplant in Acute Liver Failure	FMT	N/A	40	NCT03363022	2018