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Cited by 101Gut microbiota and healthSpondyloarthritis Studies and TreatmentsInflammatory Bowel Disease

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A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin

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Klingberg, Eva, Magnusson, Maria K., Strid, Hans, Deminger, Anna, Ståhl, Arne, Sundin, Johanna, Simrén, Magnus, Carlsten, Hans, Öhman, Lena, Forsblad-d’Elia, Helena·2019·Arthritis Research & Therapy
DOI 10.1186/s13075-019-2018-4PMC PMC6880506
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Abstract

BACKGROUND: Ankylosing spondylitis (AS) shares many characteristics with inflammatory bowel disease (IBD). Intestinal microbiota most likely plays an important role in the development of IBDs and may also be involved in the pathogenesis of AS. We aimed to define and compare the fecal microbiota composition in patients with AS, ulcerative colitis (UC), and healthy controls (HC) and to determine relationships between fecal microbiota, fecal calprotectin, and disease-related variables in AS. METHODS: Fecal microbiota composition was assessed with GA-map™ Dysbiosis Test (Genetic Analysis, Oslo, Norway), which also reports the degree of deviation of the microbiota composition compared with a healthy control population, a Dysbiosis Index (DI) score 1-5. The AS patients were assessed with questionnaires, back mobility tests, fecal calprotectin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: Totally, 150 patients with AS (55% men, median age 55.5 years, median BASDAI 3.2), 18 patients with UC (56% men, median age 30.5 years), and 17 HC (65% men, median age 22 years) were included. Principal component analysis showed highly separate clustering of fecal microbiota from the patients with AS, UC, and HC. Compared with HC, fecal microbiota in AS was characterized by a higher abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcus species, and Actinobacteria, but lower abundance of Bacteroides and Lachnospiraceae. Further, fecal microbiota composition differed between patients with normal (≤ 50 mg/kg, n = 57) and increased (≥ 200 mg/kg, n = 36) fecal calprotectin. Patients with increased fecal calprotectin had lower abundance of bacteria with anti-inflammatory properties such as Faecalibacterium prausnitzii and Clostridium and higher abundance of the genus Streptococcus. No association was found between the fecal microbiota composition and HLAB27 status, disease activity, function, or medication. Dysbiosis (defined as DI ≥ 3) was found in 87% of AS patients. CONCLUSIONS: Patients with AS have a distinct fecal microbiota signature, which is linked to fecal calprotectin levels, a marker of intestinal inflammation, but not to other clinical parameters. These findings suggest a local interplay between intestinal microbiota and gut inflammation in AS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00858819. Registered March 9, 2009.

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Fig. 1 Fecal microbiota composition in patients with ankylosing spondylitis (AS, n=150), patients with ulcerative colitis (UC, n = 18), and healthy controls (HC, n = 17) analyzed by the GA-map™ Dysbiosis Test. Total variance of the analyzed 54 bacterial targets are shown in the principal component analysis (PCA)
Fig. 1 Fecal microbiota composition in patients with ankylosing spondylitis (AS, n=150), patients with ulcerative colitis (UC, n = 18), and healthy controls (HC, n = 17) analyzed by the GA-map™ Dysbiosis Test. Total variance of the analyzed 54 bacterial targets are shown in the principal component analysis (PCA)CC BY · PubMed Central
Fig. 2 Comparison of fecal microbiota composition in patients with ankylosing spondylitis (AS) and healthy controls (HC). Fecal samples were analyzed by the GA-map™ Dysbiosis Test and evaluated using orthogonal partial least squares discriminant analysis (OPLS-DA). AS (n = 150) and HC (n = 17). a Score scatter plot from the OPLS-DA showing the separation between patients with AS (red circles) and HC (white circles). R2 defines the goodness of fit, and Q2 the goodness of prediction. b Loading column plot from the OPLS-DA. White columns represent bacteria in higher abundance in HC, and red columns represent bacteria in higher abundance in AS patients. All bacteria were included in the analysis, but the loading column plot shows only bacteria which abundance differed between the groups. Error bars represent 95% confidence interval. All analyzed bacteria are listed in Additional file 1: Table S1
Fig. 2 Comparison of fecal microbiota composition in patients with ankylosing spondylitis (AS) and healthy controls (HC). Fecal samples were analyzed by the GA-map™ Dysbiosis Test and evaluated using orthogonal partial least squares discriminant analysis (OPLS-DA). AS (n = 150) and HC (n = 17). a Score scatter plot from the OPLS-DA showing the separation between patients with AS (red circles) and HC (white circles). R2 defines the goodness of fit, and Q2 the goodness of prediction. b Loading column plot from the OPLS-DA. White columns represent bacteria in higher abundance in HC, and red columns represent bacteria in higher abundance in AS patients. All bacteria were included in the analysis, but the loading column plot shows only bacteria which abundance differed between the groups. Error bars represent 95% confidence interval. All analyzed bacteria are listed in Additional file 1: Table S1CC BY · PubMed Central
Fig. 3 Fecal microbiota composition in relation to levels of fecal calprotectin. Comparison of the fecal microbiota composition in ankylosing spondylitis (AS) patients with normal (≤ 50 mg/kg, n = 57) vs. increased (≥ 200 mg/kg, n = 36) fecal calprotectin (Fcal). Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to define fecal microbial differences between the groups. a Score scatter plot from the OPLS-DA showing the separation between patients with normal Fcal (pink circles) and increased Fcal (red circles). R2 defines the goodness of fit, and Q2 the goodness of prediction. b Loading column plot from the OPLS-DA. Pink columns represent bacteria in higher abundance in AS patients with normal fecal, and red columns represent bacteria in higher abundance in AS patients with increased Fcal. All bacteria were included in the analysis, but the loading column plot shows only bacteria which abundance differed between the groups. Error bars represent 95% confidence interval. All analyzed bacteria are listed in Additional file 1: Table S2
Fig. 3 Fecal microbiota composition in relation to levels of fecal calprotectin. Comparison of the fecal microbiota composition in ankylosing spondylitis (AS) patients with normal (≤ 50 mg/kg, n = 57) vs. increased (≥ 200 mg/kg, n = 36) fecal calprotectin (Fcal). Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to define fecal microbial differences between the groups. a Score scatter plot from the OPLS-DA showing the separation between patients with normal Fcal (pink circles) and increased Fcal (red circles). R2 defines the goodness of fit, and Q2 the goodness of prediction. b Loading column plot from the OPLS-DA. Pink columns represent bacteria in higher abundance in AS patients with normal fecal, and red columns represent bacteria in higher abundance in AS patients with increased Fcal. All bacteria were included in the analysis, but the loading column plot shows only bacteria which abundance differed between the groups. Error bars represent 95% confidence interval. All analyzed bacteria are listed in Additional file 1: Table S2CC BY · PubMed Central
Fig. 4 The distribution of the Dysbiosis Index (DI) score among patients with ankylosing spondylitis (AS, n = 150), patients with ulcerative colitis (UC, n = 18), and healthy controls (HC, n = 17). Fecal samples were analyzed by the GA-map™ Dysbiosis Test. DI is scored between 1 and 5, where a score of 1 and 2 signifies normobiosis and 3–5 dysbiosis of increasing severity. Digits inside the columns represent the number of subjects within each column
Fig. 4 The distribution of the Dysbiosis Index (DI) score among patients with ankylosing spondylitis (AS, n = 150), patients with ulcerative colitis (UC, n = 18), and healthy controls (HC, n = 17). Fecal samples were analyzed by the GA-map™ Dysbiosis Test. DI is scored between 1 and 5, where a score of 1 and 2 signifies normobiosis and 3–5 dysbiosis of increasing severity. Digits inside the columns represent the number of subjects within each columnCC BY · PubMed Central
Fig. 5 Fecal calprotectin (Fcal) in relation to dysbiosis index (DI) in patients with ankylosing spondylitis (AS). Boxplots represent the Fcal concentration within each DI score. Values are the medians (horizontal line), interquartile range (box), and range (whiskers). Outliers: circles show cases with values between 1.5 and 3.0 box lengths and stars (extremes) values more than 3 box lengths from the upper or lower edge of the box. Fcal was compared between groups of patients with different DI score using the Mann-Whitney U test. AS patients with the most pronounced dysbiosis (DI = 5) had significantly higher Fcal than patients with a DI of 4 (p = 0.004) and patients with a DI 1–4 (p < 0.001)
Fig. 5 Fecal calprotectin (Fcal) in relation to dysbiosis index (DI) in patients with ankylosing spondylitis (AS). Boxplots represent the Fcal concentration within each DI score. Values are the medians (horizontal line), interquartile range (box), and range (whiskers). Outliers: circles show cases with values between 1.5 and 3.0 box lengths and stars (extremes) values more than 3 box lengths from the upper or lower edge of the box. Fcal was compared between groups of patients with different DI score using the Mann-Whitney U test. AS patients with the most pronounced dysbiosis (DI = 5) had significantly higher Fcal than patients with a DI of 4 (p = 0.004) and patients with a DI 1–4 (p < 0.001)CC BY · PubMed Central

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  1. Eriksson LK-WN, Trygg J, Wikström C. Multi- and megavariate data analysis: part I: basic principles and applications. Umeå: Umetrics Inc; 2006.

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Authors
Klingberg, E., Magnusson, M. K., Strid, H., Deminger, A., Ståhl, A., Sundin, J., Simrén, M., Carlsten, H., Öhman, L., & Forsblad-d’Elia, H.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • University of Gothenburg (SE)
  • Södra Älvsborg Hospital (SE)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Klingberg, Eva
ORCID
Venue
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-11-27
Volume
21
Issue
1
Pages
248-248
ISSN
  • 1478-6354 (ISSN-L)
  • 1478-6362
DOI
10.1186/s13075-019-2018-4
PMC
PMC6880506
OpenAlex
W2990319014
Cited by
101
References
52
Citations by year
2026: 12 · 2025: 15 · 2024: 13 · 2023: 16 · 2022: 22 · 2021: 16 · 2020: 6
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Arthritis Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement (ALFGBG-64220)
  • The Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement (ALFGBG-825511)
  • Västra Götalandsregionen (VGFOUREG-383071)
  • Rune och Ulla Amlövs Stiftelse för Neurologisk och Reumatologisk Forskning (.)
  • Reumatikerdistriktet i Göteborg (.)
  • Göteborgs Läkaresällskap (.)
  • COMBINE (.)
  • Stiftelsen Reuma Forskningsfond Margareta (.)
  • Svenska Läkaresällskapet (SLS-409021)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Rheumatology › Spondyloarthritis Studies and Treatments
  • Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Keywords
ankylosing spondylitis, gut microbiota, fecal calprotectin, dysbiosis, ulcerative colitis, inflammatory bowel disease, Proteobacteria, Enterobacteriaceae, Streptococcus, Faecalibacterium prausnitzii, Clostridium, Lachnospiraceae, Bacteroides, HLA-B27
MeSH terms
Gastrointestinal Microbiome, Adult, Bacteria, C-Reactive Protein, Colitis, Ulcerative, Feces, Female, Humans, Male, Middle Aged, Population Dynamics, Surveys and Questionnaires, Spondylitis, Ankylosing, Leukocyte L1 Antigen Complex, Young Adult, Dysbiosis

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