Age-associated modifications of intestinal permeability and innate immunity in human small intestine

Man, Angela L., Bertelli, Eugenio, Rentini, Silvia, Regoli, Mari, Briars, Graham, Marini, Mario, Watson, Alastair J.M. and Nicoletti, Claudio (2015) Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clinical Science, 129 (7). pp. 515-527. ISSN 0143-5221

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    Abstract

    The physical and immunological properties of the human intestinal epithelial barrier in aging are largely unknown. Ileal biopsies from young (7–12 years), adult (20–40 years) and aging (67–77 years) individuals not showing symptoms of gastrointestinal (GI) pathologies were used to assess levels of inflammatory cytokines, barrier integrity and cytokine production in response to microbial challenges. Increased expression of interleukin (IL)-6, but not interferon (IFN)γ, tumour necrosis factor (TNF)-α and IL-1β was observed during aging; further analysis showed that cluster of differentiation (CD)11c+ dendritic cells (DCs) are one of the major sources of IL-6 in the aging gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of zonula occludens-1 (ZO-1), occludin and junctional-adhesion molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production in response to different microbial stimuli was assessed in a polarized in vitro organ culture (IVOC). IL-8 production in response to flagellin declined progressively with age although the expression and distribution of toll-like receptor (TLR)-5 on intestinal epithelial cells (IECs) remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in aging individuals. In contrast, TNF-α production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL-6 and expression of claudin-2. These data suggested that aging affects properties of the intestinal barrier likely to impact on age-associated disturbances, both locally and systemically.

    Item Type: Article
    Uncontrolled Keywords: aging,infection,innate immunity,interleukin 6,intestinal permeability,intestine
    Faculty \ School: Faculty of Science > School of Biological Sciences
    Faculty of Medicine and Health Sciences > Norwich Medical School
    University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
    Depositing User: Pure Connector
    Date Deposited: 12 Nov 2015 10:00
    Last Modified: 25 Jul 2018 10:51
    URI: https://ueaeprints.uea.ac.uk/id/eprint/55129
    DOI: 10.1042/CS20150046

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