title: High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22.
abstract: Prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. We hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signaling and reducing synthesis/secretion of proteins that form the protective mucus barrier. In cultured intestinal cells non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. A prolonged HFD elevated the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity with a decrease in goblet cell differentiation and Muc2, a loss in the tight junction protein, claudin-1 and increased serum endotoxin levels. In Winnie mice, that develop spontaneous colitis, HFD-feeding increased ER stress, further compromised the mucosal barrier and increased the severity of colitis. In obese mice IL-22 reduced ER/oxidative stress and improved the integrity of the mucosal barrier, and reversed microbial changes associated with obesity with an increase in Akkermansia muciniphila. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free-fatty acids on intestinal cells, and this can be reversed by IL-22 therapy.
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Max
authors.initials: M
authors.lastname: Gulhane
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Lydia
authors.initials: L
authors.lastname: Murray
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Rohan
authors.initials: R
authors.lastname: Lourie
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Tong
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Yong H
authors.initials: YH
authors.lastname: Sheng
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: Alicia
authors.initials: A
authors.lastname: Kang
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Schreiber
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Kuan Yau
authors.initials: KY
authors.lastname: Wong
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Magor
authors.affiliation: The Commonwealth Scientific and Industrial Research Organization, St Lucia, Brisbane, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Denman
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Jakob
authors.initials: J
authors.lastname: Begun
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Florin
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Perkins
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: Páraic Ó
authors.initials: PÓ
authors.lastname: Cuív
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced*; D007378:Interleukins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000502:physiology; D008820:Mice, Obese; D009093:Mucus / Q000378:metabolism; D013312:Stress, Physiological; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D007378:Interleukins; D000097043:Interleukin-22