Intestinal Metabolites Are Profoundly Altered in the Context of HLA-B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis

Mark Asquith, Sean Davin, Patrick Stauffer, Claire Michell, Cathleen Janowitz, Phoebe Lin, Joe Ensign-Lewis, Jason M. Kinchen, Dennis Koop, James (Jim) Rosenbaum

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

OBJECTIVE: HLA-B27-associated spondyloarthritides are associated with an altered intestinal microbiota and bowel inflammation. We undertook this study to identify HLA-B27-dependent changes in both host and microbial metabolites in the HLA-B27/β2 -microglobulin (β2 m)-transgenic rat and to determine whether microbiota-derived metabolites could impact disease in this major model of spondyloarthritis.

METHODS: Cecal contents were collected from Fischer 344 33-3 HLA-B27/β2 m-transgenic rats and wild-type controls at 6 weeks (before disease) and 16 weeks (with active bowel inflammation). Metabolomic profiling was performed by high-throughput gas and liquid chromatography-based mass spectrometry. HLA-B27/β2 m-transgenic rats were treated with the microbial metabolites propionate or butyrate in drinking water for 10 weeks, and disease activity was subsequently assessed.

RESULTS: Our screen identified 582 metabolites, of which more than half were significantly altered by HLA-B27 expression at 16 weeks. Both microbial and host metabolites were altered, with multiple pathways affected, including those for amino acid, carbohydrate, xenobiotic, and medium-chain fatty acid metabolism. Differences were even observed at 6 weeks, with up-regulation of histidine, tyrosine, spermidine, N-acetylmuramate, and glycerate in HLA-B27/β2 m-transgenic rats. Administration of the short-chain fatty acid propionate significantly attenuated HLA-B27-associated inflammatory disease, although this was not associated with increased FoxP3+ T cell induction or with altered expression of the immunomodulatory cytokines interleukin-10 (IL-10) or IL-33 or of the tight junction protein zonula occludens 1. HLA-B27 expression was also associated with altered host expression of messenger RNA for the microbial metabolite receptors free fatty acid receptor 2 (FFAR2), FFAR3, and niacin receptor 1.

CONCLUSION: HLA-B27 expression profoundly impacts the intestinal metabolome, with changes evident in rats even at age 6 weeks. Critically, we demonstrate that a microbial metabolite, propionate, attenuates development of HLA-B27-associated inflammatory disease. These and other microbiota-derived bioactive mediators may provide novel treatment modalities in HLA-B27-associated spondyloarthritides.

Original languageEnglish (US)
Pages (from-to)1984-1995
Number of pages12
JournalArthritis & rheumatology (Hoboken, N.J.)
Volume69
Issue number10
DOIs
StatePublished - Oct 1 2017

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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