Microbiome-immune interactions in autoimmune liver diseases

Table 1 Gut dysbiosis in experimental models of autoimmune hepatitis and in patients with this disease

Ref.	Model/patients	Sample	Sequencing method	Decreased gut microbiota taxa	Increased gut microbiota taxa	Correlations
Experimental models of autoimmune hepatitis
Wang et al[34]	MRL+/+ mice treated with 0.5 mg/mL trichloroethene	Feces	16S rRNA	Lactobacillus, Bifidobacterium, Rikenellaceae	Akkermansiaceae, Lachospiraceae	Dysbiosis associated with increased gut permeability
Centa et al[35]	Traf6ΔTEC mice	Feces	16S rRNA	Ruminococcaceae, Clostridiales	Sutterella, Parabacteroides distasonis, Bacteroides acidifaciens, Parabacteroides-like S24-7	Dysbiosis associated with increased Foxp3+ T cells and hepatic inflammation
Wang et al[36]	ConA-induced hepatitis in GSDMD-/- mice	Feces	16S rRNA	Lactobacillus, Roseburia	Allobaculum, Dubosiella	Lactobacillus negatively correlated with AST, hepatic expression of IL-17, serum IFN-γ, TNF-α, IL-17A and positive correlation with tight junction proteins expression; Allobaculum and Dubosiella positively correlated with ALT, AST, hepatic pathological score, serum IFN-γ, TNF-α, IL-17A and negatively correlated with tight junction protein expression
Kang et al[37]	S100/complete Freund’s adjuvant-induced AIH mouse model	Feces	16S rRNA	Ruminococcaceae, Clostridia UCG-014, Rikenella, Dubosiella, Alistipes, Bifidobacterium	Lactobacillaceae, Enterobacteriaceae, Escherichia-Shigella Alloprevotella, Proteobacteria, Bacteroides	Bacteroides vulgatus, Alloprevotella, Lactobacillus murinus, and Prevotellaceae UCG-001 positively correlated with bacterial translocation, inflammatory cytokine expression and negatively correlated with tight junction proteins expression
Lin et al[38]	S100-induced mice model in Pigr-/- mice	Feces	qRT-PCR	Akkermansia	Lactobacillus, Anaeromassilibacillus, Oscillospiraceae	Depletion of Pigr increased intestinal dysbiosis and permeability, but this effect was reduced after antibiotics treatment
Patients with autoimmune hepatitis
Lin et al[39]	Naive AIH, n = 24; HCs, n = 8	Feces	16S rDNA quantitative PCR	Bifidobacterium, Lactobacillus		Association of serum LPS, decreased expression of ZO-1 and occludin with advanced stages of the disease
Abe et al[40]	AIH, n = 17; PBC, n = 39; HCs, n = 15	Saliva	16S rRNA	Streptococcus, Fusobacterium	Veillonella, Neisseria	Veillonella positively correlated with the salivary levels of IL-1β, IL-6, IL-8, IL-12p70 and IgA
		Feces	16S rDNA	Clostridium cluster XIVa	Lactobacillales
Lou et al[41]	Naive AIH, n = 37; HCs, n = 78	Feces	16S rRNA	Pseudobutyrivibrio, Blautia, Lachnospira, Alistipes, Phascolarctobacterium, Erysipelotrichaceae incertae sedis, Ruminococcaceae incertae sedis	Veillonella, Faecalibacterium, Klebsiella, Gemella, Akkermansia, Lactobacillus	Veillonella, Lactobacillus, Megasphaera, Klebsiella, Faecalibacterium correlated with AST, ALT, GGT and total bilirubin; Akkermansia correlated with AST and ALT
Liwinski et al[33]	AIH, n = 72; HCs, n = 95; PBC, n = 99; UC, n = 81	Feces	16S rRNA	Faecalibacterium, Bifidobacterium	Streptococcus, Veillonella, Lactobacillus	Decreased Bifidobacterium associated with an increase of serum IgG; Veillonella abundance associated with ALT
Elsherbiny et al[42]	Naive AIH, n = 15; HCs, n = 10	Feces	16S rRNA	Prevotella, Parabacteroides, Dilaster	Faecalibacterium, Blautia, Streptococcus, Haemophilus, Bacteroides, Veillonella, Eubacterium, Lachnospiraceae, Butyricicoccus
Wei et al[10]	Naive AIH, n = 91; HCs, n = 98	Feces	16S rRNA	Clostridiales, RF39, Ruminococcaceae, Rikenellaceae, Oscillospira, Parabacteroides, Coprococcus	Veillonella, Klebsiella, Streptococcus, Lactobacillus	Veillonella positively correlated with AST and hepatic inflammation
Liang et al[43]	Naive AIH, n = 32; NAFLD, n = 20; HCs, n = 20	Feces	qRT-PCR, 16S rRNA	Bifidobacterium, Lactobacillus, Bacteroides, Clostridium leptum	Escherichia coli
Zhang et al[44]	Naive AIH, n = 68; HCs, n = 15	Feces	16S rRNA	Lactobacillus, Ruminiclostridium	Bacteroides, Prevotellaceae UCG-001

ConA: Concanavalin A; GSDMD: Gasdermin D; Pigr: Polymeric immunoglobulin receptor; AIH: Autoimmune hepatitis; HC: Healthy controls; qRT-PCR: Quantitative real-time polymerase chain reaction; PBC: Primary biliary cholangitis; NAFLD: Non-alcoholic fatty liver disease; UC: Ulcerative colitis; IL: Interleukin; IFN: Interferon; TNF: Tumor necrosis factor; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; LPS: Lipopolysaccharide; ZO-1: Zonula occludens-1; IgA: Immunoglobulin A; IgG: Immunoglobulin G; GGT: Gamma-glutamyl transpeptidase.

Table 2 Gut microbiota-targeted therapy in the treatment of autoimmune hepatitis and its experimental models

Ref.	Model/patients	Sequencing method	Intervention	Taxa increased in gut microbiota after the treatment	Taxa decreased in gut microbiota after the treatment	Changes in gut after the treatment	Changes in immune system after the treatment	Changes in liver after the treatment	Other notes
Experimental models of autoimmune hepatitis
Sheng et al[47]	FXR knockout male mice on a western diet	16S rRNA, qPCR	Butyrate supplementation			Increased expression of tight junction proteins and SCFA receptor genes	Reduced hepatic TNF-α, TIMP1, IL-6, ACTA2, CCNA2	Reduced hepatic lymphocyte infiltration and steatosis
Wu et al[48]	S100/complete Freund’s adjuvant-induced AIH mouse model		Sodium butyrate			Decreased disruption of intestinal villi, increased expression of tight junction proteins	Decreased IL-6, TNF-α	Decreased serum AST, ALT, ameliorated lymphocyte infiltration; decreased Escherichia coli translocation to the liver	Decreased blood LPS
Hu et al[49]	S100-induced AIH mouse model		High fiber diet and sodium butyrate			Decreased intestinal lesions, normalization of villus height to crypt depth ratio, increased expression of ZO-1	Decreased Th17, IL-17A, IL-6, increased Treg/Th17 and Foxp3/RORγt ratios, IL-10, TGF-β	Improved liver histology, decreased serum transaminase	Elevated total fecal SCFAs
Zhang et al[50]	S100-induced AIH mouse model	16S rRNA	Bifidobacterium animalis ssp. lactis 420 for 4 weeks	Lactobacillus, Clostridia	Bacteroides, Ruminococcus	Normalized ratio of villus height to crypt depth, increased ZO-1 and occludin expression	Decreased hepatic macrophage/monocyte activation, TNF-α, IL-6, CCL2 expression, decreased hepatic Th17 cells	Decreased serum ALT, AST, attenuated portal inflammation and infiltration	Increased fecal SCFAs, decreased serum LPS
Liang et al[43]	S100/complete Freund’s adjuvant-induced AIH mouse model, treated with broad-spectrum antibiotics	qRT-PCR, 16S rRNA	Fecal microbiota transplantation	Bifidobacterium, Lactobacillus	Escherichia coli		Decreased serum IgG, hepatic IL-21, increased Tfr cells and Tfr/Tfh ratio, hepatic IL-10, TGF-β, Foxp3-mRNA	Decreased serum ALT, AST, improved histological score
Yamaguchi et al[51]	ConA-induced hepatitis mouse model	qRT-PCR, 16S rRNA	6.8% inulin	Akkermansia, Allobaculum		No difference	Decreased IFN-γ and TNF-α expression	Increased hepatic PPARγ and UCP2 expression	Increased fecal SCFAs
Liu et al[52]	S100/complete Freund’s adjuvant-induced AIH mouse model	16S rRNA	6 strains of Bifidobacterium, 8 strains of Lactobacillus, Streptococcus thermophilus St21	Bifidobacterium, Bacteroides, Clostridium, Ruminococcus, Anaerostipes, Blautia	Faecalibacterium, Helicobacter, Staphylococcus	Recovered ileum structure, elevated ZO-1 and occludin expression	Decreased Th1, Th17 and increased Tregs in the spleen; decreased hepatic IL-17A, IFN-γ and increased TGF-β	Alleviated liver injury and infiltration, decreased serum transaminases	Inhibited LPS translocation, increased fecal SCFAs
Ma et al[53]	S100-induced AIH mouse model	RT-qPCR, 16S rRNA	Prednisone + Lactobacillus treatment for 7 days	Bacteroides fragilis, Clostridium, Clostridium leptum, Bifidobacterium, Lactobacillus		Decreased intestinal damage	Reduced serum Tfh cells, IL-6, IL-21, TNF-α, reduced hepatic IL-21, Bcl-6, CXCR5, increased serum TGF-β, KGF-1, KGF-2, IL-10	Attenuated histological injury	Reduced serum endotoxin
Yang et al[54]	ConA-induced hepatitis mouse model		Methyl butyrate				Inhibited CXCL9, CXCL10, CXCL11, decreased hepatic T cells and neutrophils, hepatic IFN-γ, TNF-α and IL-6, decreased serum IFN-γ	Attenuated inflammatory infiltration and necrosis
Kang et al[37]	S100/complete Freund’s adjuvant-induced AIH mouse model	16S rRNA	Lactobacillus acidophilus, Bifidobacterium infantis and prebiotic KGMO for 42 days	Patescibacteria, Deferribacterota, Clostridia UCG-014, Oscillospiraceae, Enterobacteriaceae, Rikenella, Alistipes, Ruminococcaceae	Proteobacteria, Escherichia-Shigella, Akkermansia	Normalized ratio of villus height to crypt depth, increased ZO-1 and occludin	Decreased Tregs in spleen, hepatic IFN-γ, IL-6, IL-17A, IL-1β, reduced NF-κB and NLRP3 inflammasome expression	Alleviated liver inflammation, decreased liver weight, decreased AST, ALT	Decreased serum LPS
Liu et al[55]	ConA-induced hepatitis mouse model	16S rRNA	15 strains of probiotics, complex prebiotics and synbiotic groups treatment for 7 days	Muribaculaceae, Bifidobacterium, Akkermansia, Alloprevotella	Lachnospiraceae NK4A136, Alloprevotella, Escherichia-Shigella	Recovered ileum structure, increased expression of ZO-1 and occludin	Decreased hepatic injury, hepatic F4/80 + macrophage infiltration, decreased Th17 and increased Tregs in spleen, decreased IL-1β, IL-17A, IFN-γ, TNF-α expression	Decreased serum AST, ALT, total BAs	Decreased serum LPS
Ma et al[56]	S100/complete Freund’s adjuvant-induced AIH mouse model	RT-qPCR	Fecal microbiota transplantation	Lactobacillus, Bifidobacterium, Clostridium leptum	Escherichia coli		Elevated Tfh cells, IL-10, TGF-β, decreased IL-21	Attenuated liver injury, decreased serum AST, ALT, total bilirubin	Inhibited activation of TLR/MyD88 signaling
Song et al[57]	S100/complete Freund’s adjuvant-induced AIH mouse model	RT-qPCR	Bifidobacterium, Lactobacillus, Enterococcus capsules	Lactobacillus, Bifidobacterium, Clostridium leptum, Bacteroides fragilis	Escherichia coli		Decreased IgG, IgA, IgM, increased hepatic Tregs and reduced Th17, decreased hepatic IL-33	Attenuated liver injury and infiltration, decreased serum AST, ALT	Increased total SCFAs
Patients with autoimmune hepatitis
Ma et al[53]	Naive AIH, n = 25; naive AIH controls, n = 25	RT-qPCR, 16S rRNA	Prednisone + Lactobacillus for 7 days vs prednisone (RCT)	Bacteroides fragilis, Clostridium, Clostridium leptum, Bifidobacterium, Lactobacillus		Decreased diamine oxidase	Decreased serum SMA, ANA, IgG, IgA, IgM	Decreased serum AST, ALT, total bilirubin	Decreased LPS
Song et al[57]	AIH, n = 10; AIH controls, n = 10	RT-qPCR	Bifidobacterium, Lactobacillus, Enterococcus capsules + conventional treatment	Lactobacillus, Bifidobacterium, Clostridium leptum, Bacteroides fragilis	Escherichia coli		Decreased IgG, IgA, IgM, serum IL-33	Decreased serum AST, ALT	Increased total fecal SCFAs

ConA: Concanavalin A; AIH: Autoimmune hepatitis; FXR: Farnesoid X receptor; qRT-PCR: Quantitative real-time polymerase chain reaction; RT-qPCR: Reverse transcription quantitative polymerase chain reaction; RCT: Randomized controlled trial; ZO-1: Zonula occludens-1; SCFAs: Short-chain fatty acids; IL: Interleukin; TGF: Transforming growth factor; Th: T helper; IFN: Interferon; TNF: Tumor necrosis factor; Tregs: Regulatory T cells; Tfr: T follicular regulatory cell; Tfh: T follicular helper cell; IgG: Immunoglobulin G; KGF: Keratinocyte growth factor; NF-κB: Nuclear factor kappa-B; IgA: Immunoglobulin A; IgM: Immunoglobulin M; SMA: Smooth muscle antibodies; ANA: Antinuclear antibodies; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; LPS: Lipopolysaccharide; BAs: Bile acids; TLR: Toll like receptor; PPAR: Peroxisome proliferator-activated receptor; KGMO: Konjac glucomannan oligosaccharides.

Table 3 Gut dysbiosis in experimental models of primary biliary cholangitis and in patients with this disease

Ref.	Model/patients	Sample	Sequencing method	Decreased gut microbiota taxa	Increased gut microbiota taxa	Correlations
Experimental models of primary biliary cholangitis
Ma et al[89]	TLR2-deficient dnTGF-βR II mice	Feces	16S rRNA	S24-7, Ruminococcaceae, Rikenellaceae, Porphyromonadaceae	Lachnospiraceae, Bacteroidaceae	Treatment with antibiotics associated with significantly reduced hepatic mononuclear cells
Wang et al[90]	2-OA-OVA-induced murine cholangitis	Feces	16S rRNA		Clostridiaceae, Lachnospiraceae, Ruminococcaceae	TLR2 (receptor for microbial antigens) activation associated with cholangiocyte apoptosis
Liu et al[91]	DDC-diet mouse model	Liver	16S rRNA		Ligilactobacillus murinus, Lactococcus garvieae	Lactococcus garvieae aggravates DDC-induced cholangitis and was only found in PBC patients but not HCs
Patients with primary biliary cholangitis
Lv et al[92]	PBC, n = 42; HCs, n = 30	Feces	16S rRNA	Acidobacteria, Lachnobacterium, Bacteroides eggerthii, Ruminococcus bromii	γ-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara	Fusicatenibacter and Roseburia faecis negatively associated with IgG; Megamonas negatively associated with ALT; Enterobacteriaceae positively correlated with ALT and direct bilirubin; Catenibacterium positively correlated with IL-16; Parasutterella secunda positively associated with GGT; Prevotella positively associated with IL-8
Tang et al[11]	PBC, n = 60; HCs, n = 80	Feces	16S rRNA	Sutterella, Oscillospira, Faecalibacterium, Bacteroides	Haemophilus, Veillonella, Clostridium, Lactobacillus, Streptococcus, Pseudomonas, Klebsiella, an unknown genus in the family of Enterobacteriaceae	Faecalibacterium negatively correlated with gp210; Lactobacillus positive; correlated with conjugated bilirubin; Klebsiella positively correlated with GGT, total and conjugated bilirubin
Abe et al[40]	Naive AIH, n = 17; naive PBC, n = 39; HCs, n = 15	Saliva	16S rRNA	Fusobacterium	Veillonella, Eubacterium	Veillonella positively correlated with the levels of salivary IL-1β, IL-8 and IgA
		Feces		Clostridium cluster XIVa	Lactobacillales	Fecal Lactobacillales positively correlated with Veillonella in saliva
Furukawa et al[93]	PBC, n = 76; HCs, n = 23	Feces	16S rRNA	Clostridiales, Lachnospiraceae, Ruminococcaceae, Faecalibacterium	Bifidobacterium, Streptococcus, Lactobacillus, Enterococcus, Prevotella	Faecalibacterium abundance positively correlated with UDCA response
Lammert et al[94]	PBC with non-advanced fibrosis, n = 15; PBC with advanced fibrosis, n = 8	Feces	16S rRNA	Weissella, Ruminococcaceae UCG-005, Ruminococcaceae UCG-004, Ruminococcaceae NK4A214, Christensenellaceae R-7, Lachnospiraceae in advanced fibrosis group	Veillonella, Ruminococcaceae UCG-010 in advanced fibrosis group	Collinsella positively correlated with total SCFAs within non-advanced fibrosis; Lachnospiraceae and Collinsella positively correlated with fecal acetate within non-advanced fibrosis; fecal acetate and SCFAs were higher in advanced fibrosis
Kitahata et al[95]	PBC, n = 34; HCs, n = 21	Small intestinal mucosa	16S rRNA	Leptotrichiaceae, Burkholderiaceae, Comamonadaceae	Sphingomonadaceae, Pseudomonadaceae, Methylobacteriaceae, Moraxellaceae	Sphingomonadaceae associated with chronic nonsuppurative destructive cholangitis
Huang et al[96]	PBC FHRAC-positive, n = 25; PBC FHRAC-negative, n = 18	Feces	16S rRNA	Lachnospiraceae incertae sedis, Anaerostipes, Clostridium XlVb, Ruminococcus, Faecalibacterium, Fusicatenibacter in FHRAC-positive patients	Campylobacter, Lachnospira, Desulfovibrio, Klebsiella, Barnesiella, Lactobacillus, Romboutsia, Turicibacter, Acidaminococcus in FHRAC-positive patients	Lachnospiraceae incertae sedis and Veillonella associated with FHRAC
Zhou et al[8]	Naive PBC, n = 25, HCs, n = 25	Feces	16S rRNA	Faecalibacterium, Ruminococcaceae, Sutterellaceae, Oscillospiraceae, Parasutterella, Clostridia, Coprococcus, Christensenellaceae	Acidimicrobiia, Yersiniaceae, Serratia	Oscillospiraceae negatively correlated with anti-gp210; Serratia and Yersiniaceae positively related to the IgG level
Shi et al[97]	PBC ALBI grade 1, n = 36; PBC ALBI grade 2-3, n = 39	Feces	16S rRNA	Clostridia, Lachnospira in ALBI 2-3 patients	Bacilli, Lactobacillales, Streptococcus in ALBI 2-3 patients

TLR: Toll like receptor; 2-OA-OVA: Ovalbumin conjugated with 2-octynoic acid; dnTGF-βR: Dominant negative form of transforming growth factor β receptor; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; PBC: Primary biliary cholangitis; AIH: Autoimmune hepatitis; HC: Healthy controls; FHRAC: Patients with a combination of five HLA-DRB1 high-risk alleles; ALBI: Albumin-bilirubin; IgG: Immunoglobulin G; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transpeptidase; SCFAs: Short-chain fatty acids; IL: Interleukin; UDCA: Ursodeoxycholic acid.

Table 4 Association of the gut microbiota composition and function with the effectiveness of therapy for primary biliary cholangitis

Ref.	Patients	Sequencing method	Treatment	Taxa increased in response group	Taxa decreased in response group	Taxa associated with poor response	Correlations	Other findings
Li et al[111]	PBC response, n = 14; PBC poor response, n = 14	Whole-genome shotgun	Cholestyramine	Lachnospiraceae	Roseburia intestinalis	Klebsiella pneumonia, Prevotella copri	Lachnospiraceae negatively correlated with total bilirubin, positively correlated with secondary BAs	Elevated fecal SCFAs in response group
Martinez-Gili et al[109]	PBC response, n = 212; PBC non response, n = 191	16S rRNA	UDCA	Desulfobacterota, Verrucomicrobiota, Actinobacteriota	Clostridia, Saccharimonadia, Veillonellaceae	Sellimonas, Coriobacteriia	Actinobacteriota positively correlated with a secondary BAs derived from cholic acid; Veillonellaceae correlated with urine levels of CDCA and UDCA	Responders had higher level of fecal secondary BAs and lower level of urinary BAs
Han et al[107]	PBC response, n = 14; PBC poor response, n = 11	Not specified	UDCA	Gemmiger qucibialis, Bariatricus comes, Faecalibacterium prausnitzii, Blautia obeum, and others	Ruminococcus, Clostridium	Ruminococcus gnavus	Gemmiger qucibialis negatively correlated with serum levels of ALT, total bilirubin and total BAs
Wang et al[108]	UDCA-naive patients with PBC, n = 51; HCs, n = 50		UDCA				Decreased fecal butyrate associated with poor response, ALT and total bilirubin	The suppressive function of circulating MDSCs was reduced in non-responders and restored by butyrate
Liu et al[115]	UDCA-naive patients with PBC, n = 132; HCs, n = 131	16S rRNA	UDCA	Bacteroides, Clostridia	Veillonella		Low abundance of fecal Clostridia was associated with poor response	Increased secondary BAs were associated with better response

PBC: Primary biliary cholangitis; HC: Healthy controls; UDCA: Ursodeoxycholic acid; BAs: Bile acids; CDCA: Chenodeoxycholic acid; ALT: Alanine aminotransferase; SCFAs: Short-chain fatty acids; MDSCs: Myeloid-derived suppressor cells.

Table 5 Changes in the microbiota in primary sclerosing cholangitis patients

Ref.	Patients	Sample	Sequencing method	IBD	Decreased gut microbiota taxa	Increased gut microbiota taxa	Correlations
Sabino et al[126]	PSC, n = 13; PSC + IBD, n = 39; HCs, n = 52	Feces	16S rRNA	-	Anaerostipes	Enterococcus, Fusobacterium, Lactobacillus, Morganella, Streptococcus, Veillonella	Enterococcus and Lactobacillus positively correlated with GGT; Enterococcus positively correlated with serum ALP
				+		Enterococcus, Fusobacterium, Lactobacillus, Streptococcus, Veillonella
Torres et al[127]	PSC + IBD, n = 19; PSC, n = 1; IBD, n = 15; HCs, n = 9	Ileocolonic biopsies	16S rRNA	+/-	Clostridiales	Barnesiellaceae, Blautia
Kummen et al[128]	PSC, n = 85 (PSC + IBD, n = 55); UC, n = 36; HCs, n = 348	Feces	16S rRNA	+/-		Veillonella, Akkermansia, Clostridium	Veillonella associated with PSC
Bajer et al[129]	PSC, n = 43 (PSC + IBD, n = 32); UC, n = 32; HCs, n = 31	Feces	16S rRNA	-	Faecalibacterium prausnitzi, Coprococcus catus, Ruminococcus gnavus, Adlercreutzia equolifaciens, Prevotella copri	Rothia, Enterococcus, Streptococcus, Clostridium, Veillonella, Haemophilus, Lactobacillus, Staphylococcus, Escherichia	The abundance of Prevotella copri was negatively associated with PSC
				+	Faecalibacterium prausnitzi, Prevotella copri, Coprococcus catus, Ruminococcus gnavus, Phascolarctobacterium	Coprobacillus, Escherichia, Corynebacterium, Rothia, Enterococcus, Streptococcus, Clostridium, Veillonella, Haemophilus, Lactobacillus salivarius	Phascolarctobacterium negatively associated with the IBD; Coprobacillus, Escherichia, Corynebacterium, Lactobacillus associated with PSC-IBD
Pereira et al[130]	PSC, n = 80; HCs, n = 46	Bile	16S rRNA	-		Prevotella, Streptococcus, Veillonella, Fusobacterium, Haemophilus, Enterobacteriaceae	Streptococcus abundance positively correlated with an increase in disease severity
Torres et al[131]	PSC + IBD, n = 15; IBD, n = 15	Feces	16S rRNA	+	Dorea, Veillonella, Lachnospira, Blautia, Roseburia	Ruminococcus, Fusobacterium
Iwasawa et al[132]	Pediatric PSC + IBD, n = 24: UC, n = 16; HCs, n = 24	Saliva	16S rRNA	+	Pasteurellaceae, Rothia, Haemophilus	Lachnospiraceae, Bacteroidetes, Oribacterium
Rühlemann et al[117]	PSC, n = 137 (PSC + UC, n = 75); UC, n = 118; HCs, n = 133	Feces	16S rRNA		Holdemanella, Desulfovibrio, Faecalibacterium, Clostridium IV, Coprococcus	Veillonella, Streptococcus, Lactobacillus, Enterococcus, Bacteroides, Parabacteroides	Patients with PSC-IBD had decreased Bilophila
Rühlemann et al[133]	PSC, n = 65 (PSC + IBD, n = 32); UC, n = 38; HCs, n = 66	Feces	PCR, spacer 2		Saccharomyces	Candida, Humicola
Lemoinne et al[134]	PSC, n = 22; PSC + IBD, n = 27; IBD, n = 33; HCs, n = 30	Feces	16S rRNA	-	Saccharomyces	Exophiala, Sordariomycetes, Ruminococcaceae, Rikenellaceae, Filobasidium	PSC associated with increases in Exophiala and Sordariomycetes
				+		Lachnospiraceae, Veillonellaceae, Enterococcaceae, Fusarium, Enterobacteriaceae, Sordariomycetes, Monographella	No strong associations were found
Visseren et al[135]	PSC, n = 97 (rPSC, n = 14)	Colonic biopsies	16S rRNA	-	Gammaproteobacteria, Shigella in rPSC patients	Deinococcus Thermus, Fusobacteraceae, Listeriaceae, Desulfosarcina, Fastidiosipila in rPSC patients	Shigella was significantly higher in patients without rPSC
				+	Bacteroidetes, Rhodobacteraceae	Moraxellaceae, Acinetobacter
Quraishi et al[120]	PSC + IBD, n = 20; UC, n = 10; HCs, n = 10	Colonic biopsies	16S rRNA	+	Lachnospiraceae, Lentisphaerae, Gammaproteobacteria, Enterobacteriacea, Prevotellacae, Paraprevotellacae, Myxococcales	Bacilli, Pseudomonas, Streptoccocus, Haemophilus parainfluenzae, Staphylococcus, Parvimonas, Bacteroides fragilis
Cortez et al[136]	Pediatric PSC, n = 11; PSC + UC, n = 7; UC, n = 12; HCs, n = 23	Feces	16S rRNA	-		Veillonella, Megasphaera, Streptococcus	A higher abundance of Ruminoclostridium 5 and Ruminococcaceae UCG 002 associated with remission/controlled disease; a higher abundance of Veillonella associated with active disease
				UC	Lactobacillus	Prevotella, Veillonella
Denoth et al[137]	PSC + IBD, n = 7; IBD, n = 42; HCs, n = 28	Ileocolonic biopsy	16S rRNA	+	Bacteroides	Roseburia, Haemophilus, Fusobacterium, Bifidobacterium, Actinobacillus, Brachyspira
Lapidot et al[138]	PSC, n = 17; PSC + IBD, n = 18; HCs, n = 30	Feces	16S rRNA	-	Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii, Bilophila, Clostridium, Ruminococcus, Lachnospiraceae	Clostridium XlVa, Clostridium symbiosum, Clostridium perfringens, Streptococcus salivarius, Veillonella dispar, Ruminococcus gnavus, Bacteroides fragilis, Enterococcus, Lactobacillus, Blautia, Butyricicoccus, Megasphaera	Salivary and fecal Veillonella, Scardovia and Streptococcus associated with PSC
				+	Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii	Clostridium XlVa, Clostridium symbiosum, Clostridium perfringens, Streptococcus salivarius, Veillonella dispar, Ruminococcus gnavus, Bacteroides fragilis, Enterococcus, Lactobacillus, Blautia
		Saliva		+/-		Streptococcus salivarius, Prevotella histicola, Rothia mucilaginosa, Veillonella parvula, Actinomyces, Campylobacter concisus, Bifidobacterium stellenboschense, Phocaeicola
Hole et al[139]	PSC, n = 84; PSC-LT, n = 51; HCs, n = 40	Ileocolonic biopsies	16S rRNA	-	Faecalibacterium, Odoribacter, Lachnospiraceae, Bilophila, Akkermansia	Haemophilus, Veillonella, Roseburia, Streptococcus, Hungatella, Klebsiella	Klebsiella associated with reduced LT-free survival; reduced Akkermansia associated with concomitant IBD
Leibovitzh et al[140]	PSC + IBD, n = 54; IBD, n = 62	Feces	Not specified	+	Blautia obeum	Veillonella atypica, Veillonella dispar, Clostridium scindens	Decreased serum sulphated bile acids and increased serum conjugated secondary bile acids were associated with PSC-IBD and increased liver fibrosis
Del Chierico et al[141]	Pediatric PSC + UC, n = 26; UC, n = 27; HCs, n = 26	Feces	16S rRNA	+/-	Akkermansia, Bacteroides, Dialister, Parabacteroides, Oscillospira, Meyerozyma, Malassezia	Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, Debaryomyces	The abundance of Streptococcus associated with PSC-UC

IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis; UC: Ulcerative colitis; LT: Liver transplantation; rPSC: Recurrent primary sclerosing cholangitis after liver transplantation; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 6 Gut microbiota-targeted therapy in the treatment of primary sclerosing cholangitis and its experimental models

Ref.	Model/patients	Sequencing method	Intervention	Taxa increased in gut microbiota after the treatment	Taxa decreased in gut microbiota after the treatment	Changes in gut after the treatment	Changes in immune system after the treatment	Changes in liver after the treatment	Other notes
Experimental models of primary sclerosing cholangitis
D’Onofrio et al[162]	DDC-diet induced mouse model	16S rRNA	Indole-3-carboxaldehyde-loaded enteric microparticles	Lactobacillus reuteri	Escherichia coli, Klebsiella pneumonia	Increased ZO-1 expression and improved intestinal permeability	Reduced serum IL-6, IL-17A, INF-γ, TNF-α, decreased hepatic CD11b+, F4/80+ cells	Decreased serum ALT, total bilirubin
Jiang et al[164]	DDC-diet induced mouse model	16S rRNA	Prevotella copri treatment	Prevotella copri, Muribaculaceae, Lactobacillus, Turicibacter, Bifidobacterium, Clostridium sensu stricto, Odoribacter, Alistipes	Staphylococcus, Akkermansia			Decreased serum ALT, AST, ALP, total bilirubin, reduced collagen-1a and TIMP1 hepatic expression	Activated FXR signalling pathway
Han et al[161]	DDC-diet induced mouse model	16S rRNA	Pediococcus pentosaceus Li05 treatment	Bacteroidaceae, Ruminococcaceae, Sutterellaceae, Rhodocyclaceae, Bacteroides, Ruminococcus, Pediococcus, Tuzzerella	Erysipelotrichaceae, Eggerthellaceae, Anaeromyxobacteraceae, Comamonadaceae, Faecalibaculums, Turicibacter, Enterorhabdus, Lactobacillus	Restored expression of ZO-1, occludin, claudin1, and MUC2	Decreased hepatic expression of IL-1β, IL-6, TNF-α, decreased serum IL-1β, IL-2, IL-6, INF-γ	Decreased serum ALT, AST, ALP, total and direct bilirubin, total BAs; reduced hepatic necrosis and infiltration	Increased FXR and FGF15 ileal expression, increased fecal BAs and SCFAs
Xiao et al[163]	C57BL/6J mice	16S rRNA	Oral vancomycin for 3 weeks + Clostridium scindens for 3 days					Decreased serum ALT, AST, decreased hepatic collagen synthesis and deposition, ACTA2, Col1a1 and TGF-β expression	Decreased primary/secondary bile acid ratio
Patients with primary sclerosing cholangitis
Philips et al[170]	38 years old male patient with PSC	16S rRNA	FMT	Bacteroides, Megamonas, Bifidobacterium	Proteobacteria, Clostridium, Veillonella, Fecalibacterium, Oscillopsira, Lachnospira			Decreased serum ALT, AST, ALP, GGT, total bilirubin	Decreased total BAs
Allegretti et al[171]	PSC + IBD, n = 10	16S rRNA	FMT	Odoribacter, Alistipes, Erysipelotrichaceae incertae sedis, Clostridia	Negativicutes, Verrucomicrobiae			Decreased ALP	BAs profile did not change
Quraishi et al[169]	PSC-IBD, n = 15	16S rRNA	Oral vancomycin for 4 weeks	Fusobacteria, Verrucomicrobia, Fusobacterium nucleatum, Enterobacter hormaechei, Escherichia coli, Veillonella, Klebsiella, Akkermansia muciniphila, Roseburia hominis, Prevotella buccae, Lachnospiraceae bacterium, Blautia hansenii, Bacteroides thetaiotaomicron	Faecalibacterium prausnitzii, Anaerostipes hadrus, Bifidobacterium longum, Clostridium, Ruminococcus, Lachnospira, Roseburia	Reduction in fecal calprotectin and mucosal inflammation		Decreased serum ALT, ALP, total bilirubin	Decreased secondary BAs, increased primary BAs, reduced fecal SCFAs

DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis; FMT: Fecal microbiota transplantation; ZO-1: Zonula occludens-1; IL: Interleukin; TGF: Transforming growth factor; IFN: Interferon; TNF: Tumor necrosis factor; CD: Cluster of differentiation; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase; FXR: Farnesoid X receptor; FGF: Fibroblast growth factor; SCFAs: Short-chain fatty acids; BAs: Bile acids.