Microbiome-immune interactions in autoimmune liver diseases

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.