1. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis
- Author
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Michele Maria Luchetti, Simon Milling, Tommaso Stampone, Paola Di Benedetto, Alessio Fasano, Dirk Elewaut, Laura Saieva, Francesco Ciccia, Armando Gabrielli, H. Cypers, Giovanni Triolo, Aroldo Rizzo, Riccardo Alessandro, Giuliana Guggino, Ciccia, F., Guggino, G., Rizzo, A., Alessandro, R., Luchetti, M., Milling, S., Saieva, L., Cypers, H., Stampone, T., Di Benedetto, P., Gabrielli, A., Fasano, A., Elewaut, D., Triolo, G., Ciccia, Francesco, Guggino, Giuliana, Rizzo, Aroldo, Alessandro, Riccardo, Luchetti, Michele Maria, Milling, Simon, Saieva, Laura, Cypers, Heleen, Stampone, Tommaso, Di Benedetto, Paola, Gabrielli, Armando, Fasano, Alessio, Elewaut, Dirk, and Triolo, Giovanni
- Subjects
Genetics and Molecular Biology (all) ,Fatty Acid-Binding Protein ,Ankylosing Spondylitis ,Monocyte ,Biochemistry ,Monocytes ,Transgenic ,0302 clinical medicine ,Intestinal Mucosa ,Membrane Glycoproteins ,Zonulin ,Cadherins ,Adherens Junction ,Up-Regulation ,Antigen ,Acute Disease ,Membrane Glycoprotein ,Rats, Transgenic ,Infection ,Human ,Ankylosing ,Immunology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Permeability ,Tight Junctions ,03 medical and health sciences ,Rheumatology ,Antigens, CD ,Ileum ,Anti-Bacterial Agent ,Human Umbilical Vein Endothelial Cells ,Humans ,RNA, Messenger ,Endothelium ,Protein Precursors ,Ankylosing Spondyliti ,Biochemistry, Genetics and Molecular Biology (all) ,Bacteria ,Animal ,medicine.disease ,Dysbiosi ,Settore MED/16 - Reumatologia ,030104 developmental biology ,chemistry ,Case-Control Studies ,Rat ,Carrier Proteins ,Acute-Phase Proteins ,Spondylitis ,0301 basic medicine ,Lipopolysaccharides ,Lipopolysaccharide ,Messenger ,Acute-Phase Protein ,Gene Expression ,chemistry.chemical_compound ,Intestinal mucosa ,Immunology and Allergy ,Membrane Protein ,HLA-B27 Antigen ,Caco-2 Cell ,Tight junction ,Tight Junction ,Adherens Junctions ,Ileitis ,Ileiti ,Anti-Bacterial Agents ,CD ,medicine.anatomical_structure ,Infections ,Inflammation ,Animals ,Caco-2 Cells ,Cholera Toxin ,Chronic Disease ,Dysbiosis ,Fatty Acid-Binding Proteins ,Interleukin-8 ,Junctional Adhesion Molecule A ,Membrane Proteins ,Rats ,Spondylitis, Ankylosing ,medicine.symptom ,Case-Control Studie ,Human Umbilical Vein Endothelial Cell ,Adherens junction ,medicine ,Antigens ,Spondyliti ,030203 arthritis & rheumatology ,Haptoglobins ,business.industry ,Cadherin ,RNA ,Carrier Protein ,business - Abstract
BackgroundDysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS.MethodsIleal biopsies were obtained from 50 HLA-B27+ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed.ResultsAdherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats.ConclusionsBacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour.
- Published
- 2017