Host responses to intestinal microbial antigens in gluten-sensitive mice.
OBJECTIVE
Excessive uptake of commensal bacterial antigens through a permeable intestinal barrier may influence host responses to specific antigen in a genetically predisposed host. The aim of this study was to investigate whether intestinal barrier dysfunction induced by indomethacin treatment affects the host response to intestinal microbiota in gluten-sensitized HLA-DQ8/HCD4 mice.


RESULTS
HLA-DQ8/HCD4 mice were sensitized with gluten, and gavaged with indomethacin plus gluten. Intestinal permeability was assessed by Ussing chamber; epithelial cell (EC) ultra-structure by electron microscopy; RNA expression of genes coding for junctional proteins by Q-real-time PCR; immune response by in-vitro antigen-specific T-cell proliferation and cytokine analysis by cytometric bead array; intestinal microbiota by fluorescence in situ hybridization and analysis of systemic antibodies against intestinal microbiota by surface staining of live bacteria with serum followed by FACS analysis. Indomethacin led to a more pronounced increase in intestinal permeability in gluten-sensitized mice. These changes were accompanied by severe EC damage, decreased E-cadherin RNA level, elevated IFN-gamma in splenocyte culture supernatant, and production of significant IgM antibody against intestinal microbiota.


CONCLUSIONS
Indomethacin potentiates barrier dysfunction and EC injury induced by gluten, affects systemic IFN-gamma production and the host response to intestinal microbiota antigens in HLA-DQ8/HCD4 mice. The results suggest that environmental factors that alter the intestinal barrier may predispose individuals to an increased susceptibility to gluten through a bystander immune activation to intestinal microbiota.
Natividad
Jane M
JM
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada.
Huang
Xianxi
X
Slack
Emma
E
Jury
Jennifer
J
Sanz
Yolanda
Y
David
Chella
C
Denou
Emmanuel
E
Yang
Pinchang
P
Murray
Joseph
J
McCoy
Kathy D
KD
Verdú
Elena F
EF
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D015820:Cadherins / Q000235:genetics; D005983:Glutens / Q000009:adverse effects*; D006683:HLA-DQ Antigens / Q000276:immunology; D007213:Indomethacin / Q000008:administration & dosage; D007422:Intestines / Q000382:microbiology* / Q000648:ultrastructure; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics
D000942:Antigens, Bacterial; D015820:Cadherins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D012333:RNA, Messenger; D005983:Glutens; D007213:Indomethacin