title: Age-associated modifications of intestinal permeability and innate immunity in human small intestine.
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.
authors.affiliation: Gut Health and Food Safety Program, Institute of Food Research, Norwich NR4 7UA, U.K.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Man
authors.affiliation: Department of Life Sciences, University of Siena, I-53100 Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Bertelli
authors.affiliation: C.O.U. Gastroenterology and Digestive Endoscopy, A.U.O.S. University Hospital, Siena I-53100, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rentini
authors.affiliation: Department of Life Sciences, University of Siena, I-53100 Italy.
authors.forename: Mari
authors.initials: M
authors.lastname: Regoli
authors.affiliation: Department of Paediatric Gastroenterology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, U.K.
authors.forename: Graham
authors.initials: G
authors.lastname: Briars
authors.affiliation: C.O.U. Gastroenterology and Digestive Endoscopy, A.U.O.S. University Hospital, Siena I-53100, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Marini
authors.affiliation: Gut Health and Food Safety Program, Institute of Food Research, Norwich NR4 7UA, U.K. Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, U.K.
authors.forename: Alastair J M
authors.initials: AJ
authors.lastname: Watson
authors.affiliation: Gut Health and Food Safety Program, Institute of Food Research, Norwich NR4 7UA, U.K. claudio.nicoletti@ifr.ac.uk.
authors.forename: Claudio
authors.initials: C
authors.lastname: Nicoletti
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001706:Biopsy; D018938:Caco-2 Cells; D002648:Child; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D017097:Electric Impedance; D004724:Endoscopy; D004848:Epithelium / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007113:Immunity, Innate; D009924:Organ Culture Techniques; D055815:Young Adult
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines
keywords: aging; infection; innate immunity; interleukin 6; intestinal permeability; intestine