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Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
Department of Medical Sciences, Faculty of Health and Medicine, Örebro University, Örebro, Sweden.
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
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2018 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 6, p. 677-684Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Taylor & Francis, 2018. Vol. 53, no 6, p. 677-684
Keywords [en]
Inflammatory bowel disease, microbiology, large intestine, intestinal barrier function, adherent invasive E. coli
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-147615DOI: 10.1080/00365521.2018.1458146ISI: 000438146900008PubMedID: 29688802OAI: oai:DiVA.org:liu-147615DiVA, id: diva2:1202063
Note

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

Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2019-04-30Bibliographically approved
In thesis
1. Bacterial epithelial interaction in intestinal inflammation
Open this publication in new window or tab >>Bacterial epithelial interaction in intestinal inflammation
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 65
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1627
National Category
Microbiology in the medical area Immunology in the medical area Infectious Medicine Immunology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-147616 (URN)10.3384/diss.diva-147616 (DOI)9789176852781 (ISBN)
Public defence
2018-06-04, Berzeliussalen, entr 65, pl 9, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2019-09-30Bibliographically approved

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Yakymenko, OlenaGullberg, ElisabetStröm, MagnusWallon, ConnyKeita, ÅsaSöderholm, Johan D

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Yakymenko, OlenaGullberg, ElisabetStröm, MagnusWallon, ConnyKeita, ÅsaSöderholm, Johan D
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Surgery in LinköpingDepartment of Clinical and Experimental MedicineDivision of Neuro and Inflammation ScienceDepartment of Gastroentorology
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