Gut microbiome composition in patients with liver cirrhosis with and without hepatic encephalopathy: A systematic review and meta-analysis

Table 1 Agency for healthcare research and quality scoring table for studies

Ref.	Representativeness of the exposed cohort	Selection of the nonexposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at the start of the study	Comparability between exposed and nonexposed cohort	Assessment of outcome	Follow-up was long enough for outcomes to occur	Adequacy of follow-up of cohorts	Total score
Wang et al[9], 2023, China	1	1	1	1	2	1	1	1	9
Bajaj et al[12], 2012, United States	1	1	1	1	2	1	1	0	8
Bajaj et al[13], 2015, United States	1	1	1	1	1	1	1	1	8
Bajaj et al[14], 2019, United States	1	1	1	1	2	1	1	0	8
Bajaj et al[55], 2018, United States	1	1	1	1	1	1	1	1	8
Sung et al[15], 2019, China	1	1	1	1	2	1	1	1	9
Bloom et al[8], 2021, Japan	1	1	1	1	2	1	1	0	8
Saboo et al[56], 2022, United States	1	1	1	1	1	1	1	0	7
Yukawa-Muto et al[10], 2022, Japan	1	1	1	1	1	1	1	1	8
Li et al[57], 2022, China	1	1	1	1	2	1	1	0	8
Hua et al[58], 2022, China	1	1	1	1	1	1	1	0	7
Bajaj et al[59], 2022, United States	1	1	1	1	1	1	1	1	8
Yu et al[11], 2021, China	1	1	1	1	2	1	1	1	9
Baja et al[60], 2020, United States	1	1	1	1	2	1	1	1	9
Ahluwalia et al[16], 2016, United States	1	1	1	1	1	1	1	0	7
Zhang et al[17], 2013, China	1	1	1	1	1	1	1	1	8
Bajaj et al[61], 2012, United States	1	1	1	1	2	1	1	0	8

Table 2 Basic information included in the study

Ref.	Amplified region/reference databases	Characteristics of gut microbiota/alpha diversity indices
		Age	Gender (male/female)	MELD	Child-Pugh score/class	Etiology	PPI
Wang et al[9], 2023, China	N/A, N/A	Cirrhosis with HE (n = 30): (1) Higher of Burkholderiaceae, Ralstonia, Parabacteroides-distasonis; (2) Phylum: Firmicutes (58.08%), Proteobacteria (18.83%), Bacteroidetes (18.19%), and Actinobacteria (2.5%); (3) Genera: Bacteroides (10.59%), Enterococcus (22.98%), Prevotella (2.21%), Escherichia-Shigella (11.9%), Ruminococcus-gnavus (2.13%), and Streptococcus (5.9%); and (4) Shannon (3.84 ± 2.01), Simpson (0.78 ± 0.19), and Chao 1(231.26 ± 66.41)
		56.13 ± 13.20	19/11	19.67 ± 5.95	Child A: 0, Child B: 9, Child C: 21	HBV (9)/HCV (1)/alcohol (12)/HBV + alcoholic (1)/HCV + alcohol (1)/others (6)	N/A
		Cirrhosis without HE (n = 30): (1) Higher of Aegypius-monachus, Erysipelatoclostridiaceae, and Erysipelotrichales; (2) Phylum: Firmicutes (58.42%), Proteobacteria (15.08%), Bacteroidetes (20.14%), and Actinobacteria (1.6%); (3) Genera: Bacteroides (14.80%), Enterococcus (16.36%), Prevotella (2.55%), Escherichia-Shigella (2.55%), Ruminococcus-gnavus (5.35%), and Streptococcus (3.82%); and (4) Shannon (4.11 ± 1.61), Simpson (0.81 ± 0.18), and Chao 1 (211.16 ± 56.35)
		52.23 ± 9.00	20/10	13.90 ± 6.51	Child A: 9, Child B: 7, Child C: 14	HBV (14)/HCV (1)/alcohol (8)/HBV + alcoholic (3)/HCV + alcohol (1)/others (3)	N/A
Bajaj et al[12], 2012, United State	N/A, RDP	Cirrhosis with HE (n = 17): Leuconostocaceae (2.19 ± 1.08), Clostridiales-Incertae Sedis XIV (0.99 ± 0.21), Ruminococcaceae (5.68 ± 1.42), Lachnospiraceae (9.54 ± 3.72), Enterobacteriaceae (10.02 ± 4.13), Streptococcaceae (4.05 ± 1.98), Fusobacteriaceae (1.36 ± 0.95), Alcaligenaceae (2.61 ± 0.74); N/A
		56 ± 3	16/1	MELD17 ± 6	N/A	Alcohol (10)/others (7)	16
		Cirrhosis without HE (n = 8): Leuconostocacea (1.69 ± 0.95), Clostridiales_Incertae Sedis XIV (1.29 ± 0.35), Fusobacteriaceae (2.75 ± 2.75), Lachnospiraceae (12.08 ± 2.47), and Ruminococcaceae (9.04 ± 2.62); N/A
		55 ± 5	7/1	MELD 12 ± 5	N/A	Alcohol (3)/others (5)	7
Bajaj et al[13], 2015, United State	N/A	Cirrhosis with HE (n = 43): Clostridiales XIV (4.5%), Lachnospiraceae (16%), Ruminococcaceae (7.4%), Fusobacteriaceae (1.0%), Prevotellaceae (5.0%), Enterococcaceae (1.0%), Enterobacteriaceae (1.0%), Erysipelotrichaceae (0.6%), Bacteroidaceae (24.9%), and Streptococcacae (1.9%); N/A
		56 ± 16	34/9	17.2 ± 7.2	9.7 ± 4.4	HCV (20)/alcohol (6)/HCV + alcohol (9)/NASH (7)/others (1)	19
		Cirrhosis without HE (n = 59): ClostridialesXIV (6.6%), Lachnospiraceae (21.3%), Ruminococcaceae (8.7%), Fusobacteriaceae (0%), Prevotellaceae (5.3%), Enterococcaceae (0%), Enterobacteriaceae (3%), Erysipelotrichaceae (1.9%), Bacteroidaceae (24.5%), and Streptococcacae (4.4%); N/A
		54 ± 13	50/9	8.6 ± 2.5	6.2 ± 5.1	HCV (27)/alcohol (14)/HCV + alcohol (7)/NASH (7)/others (4)	21
Bajaj et al[14], 2019, United State	N/A, N/A	Cirrhosis with MHE (n = 122): (1) PHES: Higher of Lactobacillales, Bacilli, and Micrococcaceae; (2) ICT: Higher of Lactobacillales, Enterobacteriales, Bacilli, Enterobacteriaceae, Protebacteria, Gammaprotebacteria, Micrococcaceae, Eubacteriaceae, Streptococcaceae, Actinomycetales; (3) Stroop: Higher of Lactobacillales, Lactocillaceae, Actinobacteria; and (4) Shannon MHE on PHES (1.9 ± 0.7), MHE on ICT (2.0 ± 0.7), and MHE on Stroop 1.9 ± 0.6
		60.1 ± 7.0	122/0	11.3 ± 4.7	N/A	N/A	77
		Cirrhosis without HE (n = 145): (1) PHES: Higher of Clostridiales, Incertae Sedis XI and XIII, Pasteurellales, Pasteurellaceae, Lachnospiraceae, and Clostridia; (2) ICT: Higher of Bacteroidaceae, Bacteroidales, Bacteroidia, Bacteroidetes; (3) Stroop: Higher of Eubacteriaceae, GP1, Telmatobacter, Breoghania, Caulobacterales, Telmatobacter, Acidobacteria, proteobacteria-incertaesedis, Hyphomonadaceae, and Listeriaceae; and (4) Shannon non-MHE on PHES (2.2 ± 0.6), non-MHE on ICT (2.1 ± 0.6), and non-MHE on Stroop (2.1 ± 0.6)
		59.4 ± 9.1	85/60	14.3 ± 7.1	N/A	N/A	54
Bajaj et al[55], 2018, United State	V1-2/RDP	Cirrhosis with prior HE (n = 10): Higher abundance of Erysipelothriceaea, Erysipelotrichia, and Erysipelotrichales; N/A
		N/A	N/A	13.2 ± 3.1	N/A	N/A	N/A
		Cirrhosis without prior HE (n = 14): Higher abundance of Selomonadales and Negativicutes; N/A
		N/A	N/A	7.8 ± 1.7	N/A	N/A	N/A
Sung et al[15], 2019, China	V3-4, N/A	Cirrhosis with HE (n = 62): (1) Firmicutes (41.4%), Bacteroidetes (36.5%), Proteobacteria (15.8%) and Actinobacteria (3.4%); (2) Schlegelella (1.172 ± 2.924), Megasphaera (1.105 ± 1.518), Veillonella (11.007 ± 12.473), Enterococcus (1.369 ± 5.038), Lactobacillus (1.086 ± 3.184), XI (1.603 ± 7.644), Prevotella (1.254 ± 4.101), Sedis (0.401 ± 0.923), Bacteroides (1.780 ± 4.062), and Parabacteroides (0.788 ± 2.946); and (3) Shannon (2.6 ± 0.59) and Chao 1 (146.83 ± 47.35)
		56.7 ± 12.2	49/13	18.5 ± 6	Child A: 0; Child B: 22; Child C: 40	HBV (18)/HCV (19)/alcoholic (36)/others (4)	22
		Cirrhosis without HE (n = 15): (1) Firmicutes (on average 332%), Bacteroidetes (47.2%), Proteobacteria (15.5%), and Actinobacteria (1.4%); (2) Schlegelella (0.029 ± 0.085), Megasphaera (1.031 ± 1.861), Veillonella (6.015 ± 7.01073), Enterococcus (0.02 ± 0.031), Lactobacillus (0.011 ± 0.017), XI (0.039 ± 0.081), Prevotella (0.022 ± 0.084), Sedis (1.788 ± 2.968), Bacteroides (1.607 ± 2.290), and Parabacteroides (1.334 ± 2.269); and (3) Shannon (2.64 ± 0.45) and Chao 1 (194.53 ± 52.93)
		58.1 ± 12.3	12/3	16.8 ± 5.58	Child A: 0; Child B: 8; Child C: 7	HBV (6)/HCV (2)/alcohol (8)/others (0)	4
Bloom et al[8], 2021, Japan	N/A, NCBI	Cirrhosis with HE (prior or current) (n = 33): (1) Higher of Bifidobacteriaceae, Enterococcaceae, Strptoccaceae, Lactobacteriaceae, and Enterobacteriaceae; and (2) Simpson (4.2 ± 2.64)
		57 ± 10	19/14	21 ± 8	N/A	Alcohol (16)/NASH (10)/viral and alcohol (4)/viral (1)/others (2)	28
		Cirrhosis without HE (n = 16): (1) Higher of Lachnospiraceae, Bacteroidaceae, Ruminococcaceae, Veillonellaceae, AKKermansiaceae, and Eubacteriaceae; and (2) Simpson (10.88 ± 9.46)
		59 ± 10	11/5	16 ± 10	N/A	Alcohol (6)/NASH (2)/viral and alcohol (3)/vral (4)/others (1)	11
Saboo et al[56], 2022, United State	V1-2/RDP	Cirrhosis with HE (n = 57): Lower of Lachnospriaceae, Bacteroidaceae, and Ruminococcaceae; N/A
		59.6 ± 6.4	46/11	15.1 ± 7.2	N/A	Alcohol (20)/HCV (22)/NASH (12)/others (3)	28
		Cirrhosis without HE (n = 125): Higher of Lachnospriaceae, Bacteroidaceae, and Ruminococcaceae; N/A
		60.8 ± 7	97/28	9.6 ± 3.8	N/A	Alcohol (54)/HCV (45)/NASH (21)/others (5)	50
Yukawa-Muto et al[10], 2022, Japan	N/A	Decompensated cirrhosis with HE (n = 26): (1) Higher of Streptococcus salivarius, Lactobacillus spp., Bifidobacterium dentium, Lactobacillus mucosae, Lactobacillus fermentum, Veillonella atypica, Veillonella parula, and Lactobacillus rhamnosus; and (2) Shannon (6.47 ± 0.38)
		68.4 (52-85)	15/11	11.7 (6-19)	N/A	HBV (3)/HCV (9)/NASH (7)/alcohol (3)/PBC (3)/AIH (1)	N/A
		Decompensated cirrhosis without HE (n = 27): (1) Lower of Streptococcus salivarius, Lactobacillus spp., Bifidobacterium dentium, Lactobacillus mucosae, Lactobacillus fermentum, Veillonella atypica, Veillonella parula, and Lactobacillus rhamnosus; and (2) Shannon (6.90 ± 0.5)
		67.6 (54-81)	16/11	8.2 (6-12)	N/A	HBV (0)/HCV (26)/NASH (1)/alcohol (0)/PBC (0)/AIH (0)	N/A
Li et al[57], 2022, China	V3-4/RDP	Cirrhosis with HE (n = 33): (1) Higher of Ruminococaceae, Lachnospiraceae, Ruminococcus, Rumi_uncultured, Roseburia, Dialister, Dialister, Coprococcus, Blautia, and Anaerostipes; and (2) Shannon (2.84 ± 0.45) and Chao 1 (221.39 ± 39.36)
		51 (44-58)	19/14	16.84 (13.6, 19.27)	8 (7-11); Child A: 3; Child B: 21; Child C: 9	HBV + HCV (25)/others (8)	N/A
		Cirrhosis without HE (n = 73): (1) Lower of Ruminococaceae, Lachnospiraceae, Ruminococcus, Rumi_uncultured, Roseburia, Dialister, Dialister, Coprococcus, Blautia, and Anaerostipes; and (2) Shannon (3.04 ± 0.39) and Chao 1 (244.24 ± 58.72)
		52 (45-58)	46/27	14.34 (12.15, 16.47)	7 (6-8); Child A: 34; Child B: 35; Child C: 4	HBV + HCV (50)/others (23)	N/A
Hua et al[58], 2022, China	N/A	Cirrhosis with HE (n = 5): (1) Higher of Pasteurellales, Pasteurellaceae, Haemophilus, and Selenomonas; (2) Higher of Veillonella (4.12 ± 6.09), Pasteurellales (2.39 ± 4.04), Pasteurellaceae (2.39 ± 4.04), Haemophilus (2.34 ± 3.96), Selenomonas (0.016 ± 0.04), Lachnospiraceae (11.48 ± 6.53), Coprococcus (0.311 ± 0.292), and Dorea (0.855 ± 0.716); and (3) N/A
		60.11 ± 9.54	4/1	N/A	N/A	HBV (5)	N/A
		Cirrhosis without HE (n = 15): (1) Higher of Veillonella; (2) Higher of Veillonella (4.40 ± 6.13), Blautia (1.36 ± 1.88), Turicibacterales (0.012 ± 0.039), Turicibacter (0.012 ± 0.039), Turicibacteraceae (0.012 ± 0.039), Adlercreutzia (0.053 ± 0.014), Holdemania (0.009 ± 0.016), and Coprococcus (0.305 ± 0.43); (3) Lachnospiraceae (9.08 ± 6.38); and (4) N/A
		61.73 ± 13.55	11/4	N/A	N/A	HBV (15)	N/A
Bajaj et al[59], 2022, United State	V1-2/RDP	Cirrhosis with MHE (n = 180): Higher of Pediococcus, Lacticaseibacillus, Pseudomonas, Doudenibacillus, Lactobacillus, Enterococcus, Escherichia-Shigella, Limosilactobacillus, Klebsiella, Sutterella, Megamonas, Veillonella, Absiella, and Prevotellamassila; N/A
		N/A	N/A	N/A	N/A	N/A	N/A
		Cirrhosis without MHE (n = 141): Higher of Enterobacter, Weissella, Anaerobutyrium, Romboutsia, and Citrobacter; N/A
		N/A	N/A	N/A	N/A	N/A	N/A
Yu et al[11], 2021, China	N/A, NCBI	Cirrhosis with HE (n = 5): (1) Higher of Bacteroidetes and Proteobacteria; (2) Lower of Firmicutes, Candidatus Saccharibacteria, and the Verrucomicrobia phyla; and (3) Shannon (1.78 ± 0.52), Simpson (0.71 ± 0.15), and Chao 1 (48.42 ± 17.78)
		58.2 ± 7.04	3/2	N/A	N/A	N/A	N/A
		Cirrhosis without HE (n = 16): (1) Lower of Bacteroidetes and Proteobacteria; (2) Higher of Firmicutes, Candidatus Saccharibacteria, and the Verrucomicrobia phyla; and (3) Shannon (2.23 ± 0.4), Simpson (0.82 ± 0.07), and Chao 1 (68.14 ± 20.05)
		55.33 ± 5.86	10/6	N/A	N/A	N/A	N/A
Bajaj et al[60], 2020, United State	N/A, MYSQL	Cirrhosis with HE 16S rRNA (n = 29): (1) Bacteroidaceae (35%), Prevotellaceae (0%), Lactobacillaceae (1%), Lachnospiraceae (11.3%), Ruminococcaceae (4.4%), Streptococcaceae (1%), Veillonellaceae (0%), and Enterobacteriaceae (1%); and (2) Shannon (1.49 ± 0.37)
		58.8 ± 11.7	20/9	14.8 ± 7	N/A	N/A	28%
		Cirrhosis without HE (n = 51): (1) Bacteroidaceae (33%), Prevotellaceae (0%), Lactobacillaceae (1%), Lachnospiraceae (26%), Ruminococcaceae (10%), Streptococcaceae (0.1%), Veillonellaceae (0%), and Enterobacteriaceae (0%); and (2) Shannon (1.6 ± 0.4)
		57.9 ± 7.4	36/15	9.5 ± 3.4	N/A	N/A	18%
Ahluwalia et al[16], 2016, United State	N/A	Cirrhosis with prior HE (n = 85): (1) Phylum: Firmicutes (24 ± 20), Bacteroidetes (24 ± 26), Proteobacteria (7 ± 15); (2) Family: Bacteroidetes-Bacteroidaceae (18.2 ± 25.2), Bacteroidetes_Porphyromonadaceae (3.9 ± 7.7), Bacteroidetes-Prevotellaceae (2.9 ± 8), Bacteroidetes-Rikenelleaceae (0 ± 2.4), Firmicutes_Lactobacillaceae (4 ± 9.5), Firmicutes-Enterococcaceae (3.6 ± 10.9), Firmicutes-Clostridiales XIV (1.4 ± 3.5), Firmicutes-Lachnospiraceae (6.3 ± 11), Firmicutes-Ruminococcaceae (3.0 ± 5.4), Firmicutes-Veillonellaceae (2. 0 ± 4.8), and Proteobacteria_Enterobacteriaceae (5.5 ± 14.8); and (3) N/A
		56.2 ± 13.5	16/69	15.5 ± 5.2	N/A	HCV (27)/alcohol (16)/HCV + alcohol (20)/NASH (12)/others (10)	N/A
		Cirrhosis without prior HE (n = 62): (1) Phylum: Firmicutes (28 ± 19), Bacteroidetes (33 ± 30), and Proteobacteria (3 ± 6); (2) Family: Bacteroidetes-Bacteroidaceae (22.2 ± 24), Bacteroidetes-Porphyromonadaceae (2.1 ± 5.2), Bacteroidetes-Prevotellaceae (4.5 ± 13.5), Bacteroidetes-Rikenelleaceae (2.0 ± 5.5), Firmicutes-Lactobacillaceae (2.0 ± 8.5), Firmicutes-Enterococcaceae (1.1 ± 6.7), Firmicutes-Clostridiales XIV (3.2 ± 4.7), Firmicutes-Lachnospiraceae (10.5 ± 8.4), Firmicutes-Ruminococcaceae (5.5 ± 6.2), Firmicutes-Veillonellaceae (1.7 ± 2.9), and Proteobacteria-Enterobacteriaceae (2.4 ± 5.9); and (3) N/A
		54.2 ± 11.6	46/16	11.0 ± 4.2	N/A	HCV (21)/alcohol (15)/HCV + alcohol (3)/NASH (15)/others (8)	N/A
Zhang et al[17], 2013, China	N/A	Cirrhosis with MHE (n = 26): Higher of S. salivarius; Chao 1 (276 ± 104)
		53 ± 12	13/13	N/A	Child A: 3; Child B: 16; Child C: 7	AIH (1)/HBV (13)/PBC (7)/PSC (0)/alcohol (5)	N/A
		Cirrhosis without MHE (n = 25): Lower of S. salivarius; Chao 1 (250 ± 139)
		59 ± 11	16/9	N/A	Child A: 12; Child B: 11; Child C: 2	AIH (2)/HBV (12)/PBC (3)/PSC (1)/alcohol (7)	N/A
Bajaj et al[61], 2012, United State	N/A	Cirrhosis with HE (n = 19): Incertae Sedis XIV_Blautia (1.6%), Incertae Sedis XIV_other (1.4%), and Fusobacteriaceae_other (1.1%); N/A
		N/A	N/A	N/A	N/A	N/A	N/A
		Cirrhosis without HE (n = 17): Leuconostocaceae_Leuconostoc (1.0%), Bacteroidales incertae sedis other (1.0%), and Alcaligenaceae other (0.8%); N/A
		N/A	N/A	N/A	N/A	N/A	N/A

MELD: Model for end-stage liver disease; RDP: Ribosomal database project; HE: Hepatic encephalopathy; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PPI: Proton pump inhibitor; AIH: Autoimmune hepatitis; NASH: Nonalcoholic steatohepatitis; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; ICT: Inhibitory control test, MHE: Minimal hepatic encephalopathy; NCBI; National Center for Biotechnology Information; PHES: Psychometric hepatic encephalopathy score; N/A: Not applicable.

Table 3 Differential microbiota between liver cirrhosis with and without hepatic encephalopathy

Bacterium	Ref.1	Ref.2
Ruminococcaceae	/	[8,12,13,16,56,60]
Lachnospiraceae	[57,58]	[8,12-14,16,60]
Clostridiales XIV	/	[13,16]
Prevotellaceae	/	[13,16,60]
Bacteroidaceae	[13,16,60]	[8,14,56]
Eubacteriaceae	[14]	[14,18]
Bacteroidetes	[11]	[9,14-16]
Lactobacillus	[15,59]	/
Enterococcus	[9,15,59]	/
Veillonella	[15,59]	[58]
Lactobacillaceae	[16,60]	/
Veillonella	[15,59]	[58]
Ruminococcus	[57]	[9]
Firmicutes	[11,15]	[9,16]
Proteobacteria	[9,11,15,16]	/
Coprococcus	[57,58]	/
Actinobacteria	[9,15]	/
Bacteroides	[15]	[9]
Prevotella	[15]	[9]
Escherichia-shigella	[9,59]	/
Erysipelotrichales	[55]	[8]
Enterococcaceae	[8,13,16]	/
Enterobacteriaceae	[8,14,16,60]	[13]
Streptococcaceae	[14,60]	/
Fusobacteriaceae	[13]	[12]
Pasteurellaceae	[58]	[14]
Pasteurellales	[58]	[14]
Veillonellaceae	[16]	[8]

¹Higher in cirrhosis with hepatic encephalopathy compared with cirrhosis without hepatic encephalopathy.

²Lower in cirrhosis with hepatic encephalopathy compared with cirrhosis without hepatic encephalopathy.

HE: Hepatic encephalopathy.