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Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis.

ABSTRACT: BACKGROUND:The assessment and characterization of the gut microbiome has become a focus of research in the area of human autoimmune diseases. Ankylosing spondylitis is an inflammatory autoimmune disease and evidence showed that ankylosing spondylitis may be a microbiome-driven disease. RESULTS:To investigate the relationship between the gut microbiome and ankylosing spondylitis, a quantitative metagenomics study based on deep shotgun sequencing was performed, using gut microbial DNA from 211 Chinese individuals. A total of 23,709 genes and 12 metagenomic species were shown to be differentially abundant between ankylosing spondylitis patients and healthy controls. Patients were characterized by a form of gut microbial dysbiosis that is more prominent than previously reported cases with inflammatory bowel disease. Specifically, the ankylosing spondylitis patients demonstrated increases in the abundance of Prevotella melaninogenica, Prevotella copri, and Prevotella sp. C561 and decreases in Bacteroides spp. It is noteworthy that the Bifidobacterium genus, which is commonly used in probiotics, accumulated in the ankylosing spondylitis patients. Diagnostic algorithms were established using a subset of these gut microbial biomarkers. CONCLUSIONS:Alterations of the gut microbiome are associated with development of ankylosing spondylitis. Our data suggest biomarkers identified in this study might participate in the pathogenesis or development process of ankylosing spondylitis, providing new leads for the development of new diagnostic tools and potential treatments.

SUBMITTER: Wen C

PROVIDER: S-EPMC5530561 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis.

Wen Chengping C Zheng Zhijun Z Shao Tiejuan T Liu Lin L Xie Zhijun Z Le Chatelier Emmanuelle E He Zhixing Z Zhong Wendi W Fan Yongsheng Y Zhang Linshuang L Li Haichang H Wu Chunyan C Hu Changfeng C Xu Qian Q Zhou Jia J Cai Shunfeng S Wang Dawei D Huang Yun Y Breban Maxime M Qin Nan N Ehrlich Stanislav Dusko SD

Genome biology 20170727 1

<h4>Background</h4>The assessment and characterization of the gut microbiome has become a focus of research in the area of human autoimmune diseases. Ankylosing spondylitis is an inflammatory autoimmune disease and evidence showed that ankylosing spondylitis may be a microbiome-driven disease.<h4>Results</h4>To investigate the relationship between the gut microbiome and ankylosing spondylitis, a quantitative metagenomics study based on deep shotgun sequencing was performed, using gut microbial D ...[more]

PMID: 28750650

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Project description:BackgroundWe sought to discover serum biomarkers of ankylosing spondylitis (AS) for diagnosis and monitoring disease activity.MethodsWe studied biologic-treatment-naïve AS and healthy control (HC) patients' sera. Eighty samples matched by age, gender, and race (1:1:1 ratio) for AS patients with active disease, inactive disease, and HC were analyzed with SOMAscan™, an aptamer-based discovery platform. T-tests tests were performed for high/low-disease activity AS patients versus HCs (diagnosis) and high versus low disease activity (Monitoring) in a 2:1 and 1:1 ratio, respectively, to identify differentially expressed proteins (DEPs). We used the Cytoscape Molecular Complex Detection (MCODE) plugin to find clusters in protein-protein interaction networks and Ingenuity Pathway Analysis (IPA) for upstream regulators. Lasso regression analysis was performed for diagnosis.ResultsOf the 1317 proteins detected in our diagnosis and monitoring analyses, 367 and 167 (317 and 59, FDR-corrected q < .05) DEPs, respectively, were detected. MCODE identified complement, IL-10 signaling, and immune/interleukin signaling as the top 3 diagnosis PPI clusters. Complement, extracellular matrix organization/proteoglycans, and MAPK/RAS signaling were the top 3 monitoring PPI clusters. IPA showed interleukin 23/17 (interleukin 22, interleukin 23A), TNF (TNF receptor-associated factor 3), cGAS-STING (cyclic GMP-AMP synthase, Stimulator of Interferon Gene 1), and Jak/Stat (Signal transducer and activator of transcription 1), signaling in predicted upstream regulators. Lasso regression identified a Diagnostic 13-protein model predictive of AS. This model had a sensitivity of 0.75, specificity of 0.90, a kappa of 0.59, and overall accuracy of 0.80 (95% CI: 0.61-0.92). The AS vs HC ROC curve was 0.79 (95% CI: 0.61-0.96).ConclusionWe identified multiple candidate AS diagnostic and disease activity monitoring serum biomarkers using a comprehensive proteomic screen. Enrichment analysis identified key pathways in AS diagnosis and monitoring. Lasso regression identified a multi-protein panel with modest predictive ability.

Project description:[Background] Ankylosing spondylitis (AS), affecting 0.5% of the population, is a chronic inflammatory rheumatic disease affecting the axial skeleton and peripheral joints. The etiology of this disease is still poorly understood, but it may be involved with the interaction of genetic and environmental factors. Our aim was to identify differentially expressed protein mediators in synovial fluid (SF) of AS. [Methods] A Total of 40 SF samples from 10 AS and each 10 controls [Osteoarthritis (OA), Rheumatoid Arthritis (RA), gouty arthritis (Gout)] were collected. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) were used to identify differentially expressed proteins based on the label free quantification (MaxLFQ). Among the 9 proteins with fold changes of > 1.5, the 8 proteins were verified with the exception of the abundant protein Haptoglobin (HP). Matrix metalloproteinase-1(MMP1) and Matrix metalloproteinase-3(MMP3) were used as a positive control, and the remaining 6 proteins were subjected to western blot analysis. [Results] We identified 9 proteins that were found to be more than 1.5-fold differentially expressed in SF of AS patients compared to control groups. Proteins such as HP, MMP1, MMP3, Serum amyloid P-component(APCS), Complement factor H-related protein 5(CFHR5), Fumarylacetoacetase(FAH), Mannose-binding lectin 2(MBL2), Complement component C9(C9) and Complement C4-A(C4A) were found to be upregulated in the SF of AS patients. CFHR5 and C9 were reported in previous studies with AS serum. APCS was reported in SF as well as serum. However, FAH, C4A and MBL2 were newly discovered through this analysis. We were able to verify the unique expression level of C9 and CFHR5 in AS sample using western blot analysis compared to the other three diseases. [Conclusions] We performed quantitative proteomic analysis of the respective SF sample from 4 diseases,i.e., AS, OA, RA, and GOUT, by LC-MS/MS. The systematic comparative proteomic analysis of the four groups together was carried out for the first time, leading to several differentially expressed proteins in AS. Among them, we expect C9 and CFHR5, which expression level were confirmed by western blot analysis and will be further validated by ELISA, can be a potential biomarkers for AS.

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Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis.

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Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis.

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