Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis

Table 1 Clinical studies of gut microbiota dysbiosis in cirrhotic patients with minimal hepatic encephalopathy

Ref.	Nationality	Number of patients	Etiology of cirrhosis	MHE diagnosis	Sample	Method	Microbiota alteration
Zhang et al[8]	China	51	AIH, HBV, PBC, alcohol	NCT-A DST	Stool	16S rRNA pyrosequencing	Enriched Streptococcus salivarius
Wang et al[14]	China	98	HBV, HCV, others	NCT-A DST	Stool	16S rRNA sequencing	Enriched Proteobacteria, especially Pasteurellaceae Haemophilus and Alcaligenaceae Parasutterella
Luo et al[29]	China	143	HBV	PHES	Stool	16S rRNA sequencing	Enriched Streptococcus salivarius and Veillonella
Liu et al[76]	China	55	HBV, HCV, alcohol, others	NCT-A BAEP	Stool	Stool bacterial culture	Overgrowth of E. coli and Staphylococcus spp.
Bajaj et al[27]	United States	97	HCV, alcohol, NASH, others	ICT PHES	Stool	Shotgun metagenomic sequencing	Alistipes ihumii, Prevotella copri, and Eubacterium spp. were higher, while Enterococcus spp. were uniquely lower in MHE diagnosed by ICT
Bajaj et al[28]	United States	247	HCV, alcohol, NASH, others	PHES ICT Stroop	Stool	Multi-tagged sequencing	Enriched Lactobacillaceae

AIH: Autoimmune hepatitis; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PBC: Primary biliary cirrhosis; NASH: Non-alcoholic steatohepatitis; NCT-A: Number connection test-A; DST: Digit symbol test; ICT: Inhibitory control test; PHES: Psychometric hepatic encephalopathy score; MHE: Minimal hepatic encephalopathy.

Table 2 Clinical Studies of gut microbiota modulation in cirrhotic patients with minimal hepatic encephalopathy

Ref.	Design	Patients	Duration	Sample	Method	Microbiota alteration	Therapeutic effect
Lactulose
Wang et al[14]	Multi-centre, open-label, randomized controlled trial	lactulose (n = 67), control (n = 31)	60 d	Stool	16S rRNA sequencing	Higher abundances of Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria were in non-responders for lactulose	Significantly ameliorated MHE
Rifaximin
Bajaj et al[56]	Controlled clinical trial	MHE patients before/after rifaximin (n = 20)	8 wk	Stool	Multi-tagged pyrosequencing, GC/LC-MS	Modest decrease in Veillonellaceae and increase in Eubacteriaceae, with significant changes in metabolite correlations	Significant improvement in endotoxemia and cognition
Probiotics
Lactobacillus GG
Bajaj et al[74]	Randomized phase I, placebo-controlled trial	Probiotic (n = 14), placebo (n = 16)	8 wk	Stool	Multi-tagged pyrosequencing, GC/LC-MS	Decreased Enterobacteriaceae and increased Lachnospiraceae and Clostridiales Incertae Sedis XIV, with significant alterations in metabolite correlations with amino acid and secondary bile acid metabolism	Attenuated endotoxemia and decreased TNF-α without change in cognition
Probiotics
Clostridium butyricum combined with Bifidobacterium infantis
Xia et al[73]	Randomized controlled trial	Probiotic (n = 30), placebo (n = 37)	3 mo	Stool	16S rRNA sequencing	Increased Clostridium cluster I and Bifidobacterium, decreased Enterobacteriaceae and Enterococcus	Reduced ammonia and improved cognition
Escherichia coli Nissle 1917 strain
Manzhalii et al[75]	Single-centre, open-label, randomized trial	Probiotic (n = 15), lactulose (n = 15), rifaximin (n = 15)	1 mo	Stool	16S rRNA sequencing	Normalized Bifidobacterium and Lactobacilli abundance	Reduced ammonia and pro-inflammatory cytokines and improved cognition
Rifaximin plus probiotic
Zuo et al[84]	Controlled clinical trial	Rifaximin (n = 7), rifaximin plus probiotic (n = 7)	4 wk	Stool	16S rRNA sequencing	Both treatments alone reduced the overall microbiome diversity, with decreased Streptococcus and Faecalibacterium, Clostridium and increased Lactobacillus	Rifaximin plus probiotics showed a more apparent effect
Rifaximin plus lactulose
Schulz et al[72]	Randomized controlled trial	Rifaximin (n = 1), rifaximin plus lactulose (n = 4)	3 mo	Stool	16S rRNA sequencing	Rifaximin with or without lactulose did not affect microbiota composition	MHE improvement with rifaximin lasted after the end of treatment
Synbiotics
Probiotics plus fermentable fiber
Liu et al[76]	Controlled clinical trial	Synbiotic (n = 20), fermentable fiber (n = 20), placebo (n = 15)	30 d	Stool	Stool quantitative bacteriological culture	Significant increase in non-urease-producing Lactobacillus species	Reduced ammonia and endotoxemia levels, reversal in 50% of MHE patients

GC/LC-MS: Gas chromatography/liquid chromatography-mass spectrometry; TNF-α: Tumor necrosis factor-alpha; MHE: Minimal hepatic encephalopathy.