Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
Department of Medical Sciences, Faculty of Health and Medicine, Örebro University, Örebro, Sweden.
Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
Vise andre og tillknytning
2018 (engelsk)Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, nr 6, s. 677-684Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Objective: Infliximab is important in the therapeutic arsenal of Crohn’s disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.

Materials and methods: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.

Results: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450–3000); controls 1163(225–1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8–1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.

Conclusion: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab’s clinical efficacy in colonic CD.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2018. Vol. 53, nr 6, s. 677-684
Emneord [en]
Inflammatory bowel disease, microbiology, large intestine, intestinal barrier function, adherent invasive E. coli
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-147615DOI: 10.1080/00365521.2018.1458146ISI: 000438146900008PubMedID: 29688802OAI: oai:DiVA.org:liu-147615DiVA, id: diva2:1202063
Merknad

Funding agencies: Swedish Research Council-Medicine [VR-MH 2014-02537]; ALF Grants Region Ostergotland

Tilgjengelig fra: 2018-04-27 Laget: 2018-04-27 Sist oppdatert: 2019-04-30bibliografisk kontrollert
Inngår i avhandling
1. Bacterial epithelial interaction in intestinal inflammation
Åpne denne publikasjonen i ny fane eller vindu >>Bacterial epithelial interaction in intestinal inflammation
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The intestine is constantly exposed to bacteria, invading viruses and ingested food. The intestinal barrier serves as a gate preventing passage of harmful components, and at the same time maintaining absorption of nutrients and water. There are over 300 different bacteria species in the human gastrointestinal tract (GI) comprising over 10 times as many cells as the human body. These bacteria are both of commensal and pathogenic strains in which commensal bacteria and antimicrobial peptides have an important role of controlling the intestinal colonization. The intestinal flora is sampled by the membranous cells (M cells) that are present in the follicle associated epithelium (FAE). Antigens encounter immune cells found in Peyer’s patches located in the distal ileum with FAE overlaying them. Due to environmental factors, genetic predisposition, immune dysregulation or dysbiosis the balance can be shifted which, in turn, will lead to the defect in the barrier function, leading to the development of disorders such as Crohn’s disease (CD). CD is a chronic inflammation in the GI tract, often originating in the distal ileum in FAE and associated with an increased number of adherent invasive strains of bacteria. Specifically adherent invasive E.coli (AIEC) that have been isolated from the ileum and colon of CD patients.

The aim of the present thesis was to study bacterial epithelial interaction during inflammation in in vivo, ex vivo and in vitro models.

In the first project we found that that Faecalibacterium prausnitzii (FP), possess anti-inflammatory properties in the ileum of an in vivo DSS induced colitis mouse model.

In the second project, we discovered that infliximab, known to have anti-inflammatory effects by binding soluble TNF and blocking TNF receptors, reduces bacterial transcytosis across colonic biopsies of CD patients and decreases transcytosis and internalization in cell monolayers in vitro. Moreover, we demonstrated that HM427 bacteria, isolated from colonic mucosa of CD patients, uses lipid raft formations to penetrate the barrier under the influence of TNF in an in vitro model.

In project three, we demonstrated that LF82 bacteria, which is an adherent invasive strain of E.coli that has been isolated from the ileum of CD patients, exploits FAE of CD patients and non-IBD control patients to penetrate the barrier via the CEACAM6 receptor and long polar fimbriae. We further demonstrated that there is an increased expression of CEACM6 receptor in the FAE of CD patients, which leads to increased transcytosis of LF82 compared to non-IBD control group.

In project four, our results suggested that human α-defensin 5 significantly decreases the passage of LF82 bacteria in an in vitro and ex vivo models. Moreover, we demonstrated that CD patients have a lower expression of human α-defensin 5 in the crypts compared to the non-IBD control patients.

Taken together, our findings have given a novel insight into the etiology of CD and into the mechanisms involved in bacterial-epithelial interaction in CD.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 65
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1627
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-147616 (URN)10.3384/diss.diva-147616 (DOI)9789176852781 (ISBN)
Disputas
2018-06-04, Berzeliussalen, entr 65, pl 9, Campus US, Linköping, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-04-27 Laget: 2018-04-27 Sist oppdatert: 2019-09-30bibliografisk kontrollert

Open Access i DiVA

Fulltekst mangler i DiVA

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Yakymenko, OlenaGullberg, ElisabetStröm, MagnusWallon, ConnyKeita, ÅsaSöderholm, Johan D
Av organisasjonen
I samme tidsskrift
Scandinavian Journal of Gastroenterology

Søk utenfor DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 164 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf