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Cited by 414Gut microbiota and healthLiver Diseases and ImmunityInflammatory Bowel Disease

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Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD

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Sabino, João, Vieira-Silva, Sara, Machiels, Kathleen, Joossens, Marie, Falony, Gwen, Ballet, Vera, Ferrante, Marc, Van Assche, Gert, Van der Merwe, Schalk, Vermeire, Severine, Raes, Jeroen·2016·Gut
DOI 10.1136/gutjnl-2015-311004PMC PMC5036217
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Abstract

Objective: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often leading to end-stage liver disease. Its pathogenesis remains largely unknown, although frequent concomitant IBD hints towards common factors underlying gut and bile duct inflammation. Considering the mounting evidence on the involvement of the intestinal microbiota in initiating and determining IBD phenotype, we investigated intestinal microbiota composition in patients with PSC. Design: Stool samples were collected from 147 individuals (52 patients with PSC, 52 age, gender and body mass index-matched healthy volunteers, 13 UC and 30 patients with Crohn's disease). An independent validation cohort of 14 PSC and 14 matched controls was recruited. 16S rDNA sequencing of faecal DNA was performed (Illumina MiSeq). Results: The microbiota of patients with PSC was characterised by decreased microbiota diversity, and a significant overrepresentation of Enterococcus (p=3.76e-05), Fusobacterium (p=3.76e-05) and Lactobacillus (p=0.0002) genera. This dysbiosis was present in patients with PSC with and without concomitant IBD and was distinct from IBD, and independent of treatment with ursodeoxycholic acid. A decision tree based on abundances of these three genera allowed reliable classification in the validation cohort. In particular, one operational taxonomic unit belonging to the Enterococcus genus was associated with increased levels of serum alkaline phosphatase (p=0.048), a marker of disease severity. Conclusions: We here present the first report of PSC-associated faecal dysbiosis, independent from IBD signatures, suggesting the intestinal microbiota could be a contributing factor in PSC pathogenesis. Further studies are needed to confirm these findings and assess causality.

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Crossref · 10.1136/gutjnl-2015-311004

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Figure 1 Faecal microbiota variation across healthy controls (HC) and patients with primary sclerosing cholangitis (PSC) and IBD (n=147). (A) Variation in microbial community composition represented in a principal coordinates analysis (PCoA) of the Bray–Curtis dissimilarity matrix, calculated from the operational taxonomic unit (OTU)-level abundance matrix. Patients with HC, PSC and IBD are significantly different (see online supplementary table S2), while PSC subgroups are not. (B) Box plots representation of microbiota richness (number of observed OTUs per sample) distribution across HC, PSC (PSC only, PSC-ulcerative colitis (UC) and PSC-Crohn's disease (CD)) and IBD (UC and CD). HC have significantly higher species richness than all patients with PSC combined, and than PSC-UC and CD individually. Horizontal bars represent false discovery rate (FDR)-corrected p value <0.05 (Kruskal–Wallis rank sum test). The body of the box plot represents the first and third quartiles of the distribution, and the median. The whiskers extend from the quartiles to the last datapoint within 1.5× IQR, with outliers beyond represented as dots.
Figure 1 Faecal microbiota variation across healthy controls (HC) and patients with primary sclerosing cholangitis (PSC) and IBD (n=147). (A) Variation in microbial community composition represented in a principal coordinates analysis (PCoA) of the Bray–Curtis dissimilarity matrix, calculated from the operational taxonomic unit (OTU)-level abundance matrix. Patients with HC, PSC and IBD are significantly different (see online supplementary table S2), while PSC subgroups are not. (B) Box plots representation of microbiota richness (number of observed OTUs per sample) distribution across HC, PSC (PSC only, PSC-ulcerative colitis (UC) and PSC-Crohn's disease (CD)) and IBD (UC and CD). HC have significantly higher species richness than all patients with PSC combined, and than PSC-UC and CD individually. Horizontal bars represent false discovery rate (FDR)-corrected p value <0.05 (Kruskal–Wallis rank sum test). The body of the box plot represents the first and third quartiles of the distribution, and the median. The whiskers extend from the quartiles to the last datapoint within 1.5× IQR, with outliers beyond represented as dots.CC BY-NC · PubMed Central
Figure 2 Faecal microbiota composition in healthy controls, patients with primary sclerosing cholangitis (PSC) (PSC-only, PSC-ulcerative colitis (UC) and PSC-Crohn's disease (CD)) and IBD (UC and CD) (n=147). (A) Phylum-level median relative abundances and (B) genus-level median relative abundances. The top 14 more abundant genera are represented and all others are summed into the category ‘others’.
Figure 2 Faecal microbiota composition in healthy controls, patients with primary sclerosing cholangitis (PSC) (PSC-only, PSC-ulcerative colitis (UC) and PSC-Crohn's disease (CD)) and IBD (UC and CD) (n=147). (A) Phylum-level median relative abundances and (B) genus-level median relative abundances. The top 14 more abundant genera are represented and all others are summed into the category ‘others’.CC BY-NC · PubMed Central
Figure 3 Genus-level microbiota signature of primary sclerosing cholangitis (PSC) (n=147). (A) Venn diagram summarising the overlap between the lists of genera with significantly different abundances in patient groups compared with healthy controls (HC). Genera overrepresented in patients as compared with controls are in red, and underrepresented ones in blue. The lists of genera included in each of the Venn diagram's sets (labelled from A to M) can be found in online supplementary table S3. (B) Box plots showing abundances of Fusobacterium, Enterococcus, Lactobacillus and Streptococcus in HC, patients with PSC and IBD. These compose the PSC signature (ie, genera significantly overrepresented or underrepresented in all PSC subgroups compared with HC), with the exception of Streptococcus, which association falls below significance after excluding patients under antibiotic treatment. Horizontal bar represents false discovery rate (FDR)-corrected p value <0.05 (Mann–Whitney test). Box plot definition is provided in the legend of figure 1.
Figure 3 Genus-level microbiota signature of primary sclerosing cholangitis (PSC) (n=147). (A) Venn diagram summarising the overlap between the lists of genera with significantly different abundances in patient groups compared with healthy controls (HC). Genera overrepresented in patients as compared with controls are in red, and underrepresented ones in blue. The lists of genera included in each of the Venn diagram's sets (labelled from A to M) can be found in online supplementary table S3. (B) Box plots showing abundances of Fusobacterium, Enterococcus, Lactobacillus and Streptococcus in HC, patients with PSC and IBD. These compose the PSC signature (ie, genera significantly overrepresented or underrepresented in all PSC subgroups compared with HC), with the exception of Streptococcus, which association falls below significance after excluding patients under antibiotic treatment. Horizontal bar represents false discovery rate (FDR)-corrected p value <0.05 (Mann–Whitney test). Box plot definition is provided in the legend of figure 1.CC BY-NC · PubMed Central
Figure 4 Positive correlation between Enterococcus abundance and alkaline phosphatase (ALP), a clinical marker for cholestasis and primary sclerosing cholangitis (PSC) progression (n=87, Spearman ρ=0.29, adjusted p value=0.012199). Black dots correspond to patients with PSC without cirrhosis or liver transplantation. Grey dots correspond to patients with PSC with either cirrhosis or liver transplantation.
Figure 4 Positive correlation between Enterococcus abundance and alkaline phosphatase (ALP), a clinical marker for cholestasis and primary sclerosing cholangitis (PSC) progression (n=87, Spearman ρ=0.29, adjusted p value=0.012199). Black dots correspond to patients with PSC without cirrhosis or liver transplantation. Grey dots correspond to patients with PSC with either cirrhosis or liver transplantation.CC BY-NC · PubMed Central

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Authors
Sabino, J., Vieira-Silva, S., Machiels, K., Joossens, M., Falony, G., Ballet, V., Ferrante, M., Van Assche, G., Van der Merwe, S., Vermeire, S., & Raes, J.
Affiliations
  • KU Leuven (BE)
  • Department of Microbiology and Immunology, Laboratory of Molecular Bacteriology, KU Leuven—University of Leuven, Rega Institute for Medical Research, Leuven, Belgium
  • Vrije Universiteit Brussel (BE)
  • Rega Institute for Medical Research (BE)
  • Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
  • Department of Microbiology and Immunology, Center for the Biology of Disease, REGA institute, KU Leuven—VIB, Leuven, Belgium
Corresponding author
Raes, Jeroen
ORCID
Venue
Gut
Publisher
BMJ
Published
2016-05-20
Volume
65
Issue
10
Pages
1681-1689
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2015-311004
PMC
PMC5036217
OpenAlex
W2408052000
Cited by
413
References
40
Citations by year
2026: 28 · 2025: 28 · 2024: 46 · 2023: 46 · 2022: 42 · 2021: 52 · 2020: 44 · 2019: 45 · 2018: 33 · 2017: 34 · 2016: 13
FWCI
21.65
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Gut (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Socio-Environmental Systems Modeling (acceptedVersion, cc-by-nc)
  • Lirias (submittedVersion, cc-by-nc)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Digital Access to Libraries (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • KU Leuven
  • Vlaamse regering
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Keywords
primary sclerosing cholangitis, gut dysbiosis, gut microbiota, inflammatory bowel disease, Enterococcus, Fusobacterium, Lactobacillus, microbiome diversity, Crohn's disease, ulcerative colitis, ursodeoxycholic acid, alkaline phosphatase, disease severity
MeSH terms
Gastrointestinal Microbiome, Adult, Aged, Alkaline Phosphatase, Biopsy, Cholagogues and Choleretics, Colonoscopy, Feces, Female, Humans, Male, Middle Aged, Severity of Illness Index, Statistics as Topic, Ursodeoxycholic Acid, Cholangitis, Sclerosing, Inflammatory Bowel Diseases, Enterococcus, Dysbiosis

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