PMID- 28069576
OWN - NLM
STAT- MEDLINE
DCOM- 20170814
LR  - 20201209
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Print)
IS  - 0003-4967 (Linking)
VI  - 76
IP  - 6
DP  - 2017 Jun
TI  - Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in 
      patients with ankylosing spondylitis.
PG  - 1123-1132
LID - 10.1136/annrheumdis-2016-210000 [doi]
AB  - BACKGROUND: Dysbiosis 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. 
      METHODS: Ileal 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. RESULTS: Adherent 
      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. CONCLUSIONS: Bacterial 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.
CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not 
      already granted under a licence) please go to 
      http://www.bmj.com/company/products-services/rights-and-licensing/.
FAU - Ciccia, Francesco
AU  - Ciccia F
AD  - Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di 
      Reumatologia, University of Palermo, Palermo, Italy.
FAU - Guggino, Giuliana
AU  - Guggino G
AD  - Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di 
      Reumatologia, University of Palermo, Palermo, Italy.
FAU - Rizzo, Aroldo
AU  - Rizzo A
AD  - UOC di Anatomia Patologica, Ospedali riuniti villa Sofia-Cervello, Palermo, 
      Italy.
FAU - Alessandro, Riccardo
AU  - Alessandro R
AD  - Dipartimento di Biopatologia e Biotecnologie Mediche, Universita di Palermo, 
      Palermo, Italy.
FAU - Luchetti, Michele Maria
AU  - Luchetti MM
AUID- ORCID: 0000-0001-9132-7401
AD  - Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, 
      Universita Politecnica delle Marche, Ancona, Italy.
FAU - Milling, Simon
AU  - Milling S
AD  - Institute of Infection, Immunity and Inflammation, University of Glasgow, 
      Glasgow, UK.
FAU - Saieva, Laura
AU  - Saieva L
AD  - Dipartimento di Biopatologia e Biotecnologie Mediche, Universita di Palermo, 
      Palermo, Italy.
FAU - Cypers, Heleen
AU  - Cypers H
AD  - Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 
      Ghent University, Belgium.
AD  - Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, 
      Belgium.
FAU - Stampone, Tommaso
AU  - Stampone T
AD  - UOC di Anatomia Patologica, Ospedali riuniti villa Sofia-Cervello, Palermo, 
      Italy.
FAU - Di Benedetto, Paola
AU  - Di Benedetto P
AD  - Division of Rheumatology, Department of Biotechnological and Applied Clinical 
      Science, School of Medicine, University of L'Aquila, L'Aquila, Italy.
FAU - Gabrielli, Armando
AU  - Gabrielli A
AD  - Dipartimento di Biopatologia e Biotecnologie Mediche, Universita di Palermo, 
      Palermo, Italy.
FAU - Fasano, Alessio
AU  - Fasano A
AD  - Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for 
      Children, Center for Celiac Research and Treatment, Mucosal Immunology and 
      Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts, 
      USA.
FAU - Elewaut, Dirk
AU  - Elewaut D
AD  - Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 
      Ghent University, Belgium.
AD  - Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, 
      Belgium.
FAU - Triolo, Giovanni
AU  - Triolo G
AD  - Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di 
      Reumatologia, University of Palermo, Palermo, Italy.
LA  - eng
GR  - R01 DK048373/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20170109
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Acute-Phase Proteins)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Antigens, CD)
RN  - 0 (Cadherins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Fatty Acid-Binding Proteins)
RN  - 0 (HLA-B27 Antigen)
RN  - 0 (Haptoglobins)
RN  - 0 (Interleukin-8)
RN  - 0 (Junctional Adhesion Molecule A)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (PLVAP protein, human)
RN  - 0 (Protein Precursors)
RN  - 0 (RNA, Messenger)
RN  - 0 (cadherin 5)
RN  - 0 (lipopolysaccharide-binding protein)
RN  - 0 (zonulin)
RN  - 9012-63-9 (Cholera Toxin)
SB  - IM
MH  - Acute Disease
MH  - Acute-Phase Proteins
MH  - Adherens Junctions/genetics
MH  - Animals
MH  - Anti-Bacterial Agents/pharmacology
MH  - Antigens, CD/genetics
MH  - Bacteria/isolation & purification
MH  - Caco-2 Cells
MH  - Cadherins/genetics
MH  - Carrier Proteins/blood/genetics
MH  - Case-Control Studies
MH  - Cholera Toxin/*blood/genetics
MH  - Chronic Disease
MH  - Dysbiosis/*immunology/microbiology
MH  - Endothelium/*metabolism
MH  - Fatty Acid-Binding Proteins/blood
MH  - Gene Expression
MH  - HLA-B27 Antigen/genetics
MH  - Haptoglobins
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Ileitis/blood/*immunology
MH  - Ileum/immunology/microbiology
MH  - Interleukin-8
MH  - Intestinal Mucosa/*immunology/*metabolism/microbiology
MH  - Junctional Adhesion Molecule A/genetics
MH  - Lipopolysaccharides/blood
MH  - Membrane Glycoproteins/blood
MH  - Membrane Proteins/genetics
MH  - Monocytes/immunology
MH  - Permeability
MH  - Protein Precursors
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Transgenic
MH  - Spondylitis, Ankylosing/*immunology
MH  - Tight Junctions/drug effects/genetics
MH  - Up-Regulation
PMC - PMC6599509
MID - NIHMS863569
OTO - NOTNLM
OT  - Ankylosing Spondylitis
OT  - Infections
OT  - Inflammation
COIS- Competing interests: None declared.
EDAT- 2017/01/11 06:00
MHDA- 2017/08/15 06:00
PMCR- 2019/06/30
CRDT- 2017/01/11 06:00
PHST- 2016/06/01 00:00 [received]
PHST- 2016/12/19 00:00 [accepted]
PHST- 2017/01/11 06:00 [pubmed]
PHST- 2017/08/15 06:00 [medline]
PHST- 2017/01/11 06:00 [entrez]
PHST- 2019/06/30 00:00 [pmc-release]
AID - annrheumdis-2016-210000 [pii]
AID - 10.1136/annrheumdis-2016-210000 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2017 Jun;76(6):1123-1132. doi: 10.1136/annrheumdis-2016-210000. 
      Epub 2017 Jan 9.