Role of intestinal flora in primary sclerosing cholangitis and its potential therapeutic value

Table 1 Changes in the intestinal flora of patients with primary sclerosing cholangitis

Methods	Increased	Decreased	Ref.
16S RNA gene sequencing: ileum, colon, and rectal samples	Actinobacillus, Bifidobacterium, Fusobacterium, Haemophilus, Roseburia	Bacteroides	[135]
qPCR: fecal samples	Enterobacteriaceae	Bifidobacterium, Lactobacillus	[136]
16S RNA gene sequencing: fecal samples	Clostridium, Lactobacillus, Ruminococcus gnavus, Veillonella	Coprococcus, Faecalibacterium, Phascolarctobacterium, Ruminococcus	[137]
16S RNA gene sequencing: duodenal fluid, saliva, duodenal mucosa, and bile samples	Duodenal mucosa biopsy: Escherichia coli, Veillonella dispar; Bile fluid: Enterococcus, Neisseria, Proteobacteria, Staphylococcus, Veillonella dispar		[42]
Metagenomic shotgun sequencing	Clostridiales	Eubacterium, Ruminococcus obeum	[45]
16S RNA gene sequencing: fecal and saliva samples	Bacteroides fragilis, Blautia, Clostridium spp. Enterococcus, Enterobacteriaceae, Lactobacillus, Ruminococcus gnavus, Streptococcus salivarius Veillonella dispar	Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii	[43]
Sigmoid mucosal biopsies and 16S RNA gene sequencing	Haemophilus parainfluenzae, Pseudomonas, Streptococcus	Lachnospiraceae	[40]
16S RNA gene sequencing: fecal samples	Veillonella	Blautia, Faecalibacterium, Lachnoclostridium, Ruminococcus	[44]
16S RNA gene sequencing: fecal samples	Enterococcus, Lactobacillus, Streptococcus, Veillonella	Clostridium cluster IV, Coprococcus, Desulfovibrio, Faecalibacterium, Holdemanella	[38]
16S RNA gene sequencing: fecal samples	Veillonella	Coprococcus, Desulfovibrio, Phascolarctobacterium, Succinivibrio	[36]
16S RNA gene sequencing: fecal samples	Clostridium, Enterococcus, Haemophilus, Rothia, Streptococcus, Veillonella	Adlercreutzia equolifaciens, Coprococcus catus, Faecalibacterium prausnitzii, Prevotella copri, Ruminococcus gnavus	[47]
Colonic mucosal biopsies and 16S RNA gene sequencing	Escherichia, Lachnospiraceae, Megasphaera	Bacteroides, Prevotella, Roseburia	[37]
16S RNA gene sequencing: fecal samples	Veillonella		[39]
16S RNA gene sequencing: fecal samples	Enterococcus, Streptococcus, Veillonella		[7]
16S RNA gene sequencing: fecal samples	Bacteroidetes, Enterococcus, Fusobacterium, Lactobacillus, Morganella, Streptococcus, Veillonella	Anaerostipes	[35]
Colonic mucosal biopsies and 16S RNA gene sequencing: ileal samples	Barnesiellaceae, Blautia		[8]
Mucosal biopsy of the ileocecal region and 16S RNA gene sequencing	Clostridium clusters IVand XIVa, Akkermansia sp. (Verrucomicrobia), Uncultured Clostridiales II		[34]

Table 2 Intestinal flora regulation in primary sclerosing cholangitis treatment

Treatment			Results	Ref.
Oral Antibiotics	Vancomycin	125 mg four times daily for 90 d	Fecal calprotectin and serum GGT levels returned to normal	[94]
		125 mg four times daily for 12 wk	Significantly decreased ALP, MRS, ESR, and GGT levels. Fatigue, pruritus, diarrhea, and anorexia significantly improved	[91]
		50 mg/kg/d for 30 to 118 mo	Decreased ALT, AST, GGT, and ESR levels. Jaundice improved. The overall rate of positive serum autoantibodies decreased after 3.5 mo	[138]
	Vancomycin and metronidazole	Vancomycin: 125 mg or 250 mg four times daily for 12 wk; Metronidazole: 250 mg or 500 mg three times daily for 12 wk	Decreased ALP and MRS levels. The decrease in ALP level was more pronounced following vancomycin administration	[90]
	Metronidazole with ursodeoxycholic acid	Taken together for 36 mo	Significantly decreased ALP and MRS levels	[98]
	Azithromycin	500 mg three days per week for 6 wk	Decreased ALP and TBIL levels and cholestasis-related symptoms. The urine was turned dark in color again	[139]
	Rifaximin	550 mg twice daily for 12 wk	Decreased GGT and CRP levels; Improved pruritus symptoms	[95]
	Minocycline	100 mg twice daily for one year	Significantly decreased ALP and MRS levels	[100]
Fecal microbiota transplantation at 24 wk			Significantly decreased ALP levels; Reduced AST levels (by at least 30%)	[107]
Probiotics	Lactobacilli and Bifidobacteria	Three months of: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius, and Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium	Reduced ALP levels (by 15%)	[113]
	Combined	Prednisolone (30 mg/d), salazosulfapyridine (3000 mg/d), and Lactobacillus casei Shirota (3 g/d) for 2 wk	Decreased ALP, ALT, AST, and GGT levels	[114]

ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; MRS: Mayo primary sclerosing cholangitis risk score; ESR: Erythrocyte sedimentation rate; GGT: Gamma-glutamyl transpeptidase; CRP: C-reactive protein; TBIL: Total bilirubin.

Table 3 Clinical trials related to primary sclerosing cholangitis treatment

Study Phase	Study title	ClinicalTrials.gov identifier	Actual enrollment	Status	Interventions
Phase 1	A Pilot Study of Vancomycin or Metronidazole in Patients with Primary Sclerosing Cholangitis (PSC)	NCT01085760	35 participants	Completed	Drug: vancomycin; Drug: metronidazole
	Minocycline in Primary Sclerosing Cholangitis (PSC)	NCT00630942	16 participants	Completed	Drug: minocycline
	Treating Primary Sclerosing Cholangitis and Biliary Atresia with Vancomycin	NCT02137668	200 participants	Recruiting	Drug: oral vancomycin
	A Pilot Study to Characterize Bile Acid Metabolism and Dysbiosis in Primary Sclerosing Cholangitis	NCT02464020	8 participants	Completed	Drug: vancomycin
	Gastrointestinal Microbiota in Primary Sclerosing Cholangitis and Biliary Atresia with Vancomycin (PSC)	NCT01322386	32 participants	Completed	Drug: vancomycin
	Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.	NCT02424175	10 participants	Completed	Biological: Fecal microbiota transplantation
Phase 2	Norursodeoxycholic Acid in the Treatment of Primary Sclerosing Cholangitis (NUC-3)	NCT01755507	159 participants	Completed	Drug: norursodeoxycholic acid; Drug: placebo
	Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC) (AESOP)	NCT02177136	77 participants	Completed	Drug: OCA; Drug: placebo
	Vancomycin for Primary Sclerosing Cholangitis	NCT03710122	102 participants	Recruiting	Drug: vancomycin; Other: placebo
	Trial of High-dose Urso in Primary Sclerosing Cholangitis	NCT00059202	150 participants	Completed	Drug: ursodeoxycholic acid; Drug: placebo
	Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.	NCT02424175	10 participants	Completed	Biological: fecal microbiota transplantation
Phase 3	Primary Sclerosing Cholangitis with Oral Vancomycin by the Study of Its Antimicrobial and Immunomodulating Effects (PSC)	NCT01802073	34 participants	Completed	Drug: oral vancomycin
	Probiotics in Patients with Primary Sclerosing Cholangitis	NCT00161148	12 participants	Unknown1	Drug: probiotics
	Norursodeoxycholic Acid vs Placebo in PSC	NCT03872921	300 participants	Recruiting	Drug: norursodeoxycholic acid
	Vancomycin for Primary Sclerosing Cholangitis	NCT03710122	102 participants	Recruiting	Drug: vancomycin; Other: placebo
	Trial of High-dose Urso in Primary Sclerosing Cholangitis	NCT00059202	150 participants	Completed	Drug: ursodeoxycholic acid; Drug: placebo
Phase 4	Effect and Safety of Oral Vancomycin in Primary Sclerosing Cholangitis Patients	NCT02605213	30 participants	Unknown1	Drug: vancomycin; Drug: placebo

¹Study has passed its completion date and status has not been verified in more than two years.

PSC: Primary sclerosing cholangitis; OCA: Obeticholic Acid; AESOP: Aetiology and Ethnicity in Schizophrenia and Other Psychoses.