Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5.
GI-ARS
barrier function
defensins
intestine
irradiation
microbiome
tight junction
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
25
02
2023
accepted:
14
07
2023
medline:
29
8
2023
pubmed:
28
8
2023
entrez:
28
8
2023
Statut:
epublish
Résumé
The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5). Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels. Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation. These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.
Identifiants
pubmed: 37638013
doi: 10.3389/fimmu.2023.1174140
pmc: PMC10448521
doi:
Substances chimiques
alpha-Defensins
0
RNA, Ribosomal, 16S
0
Cytokines
0
Banques de données
figshare
['10.6084/m9.figshare.19758832']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1174140Subventions
Organisme : NIAID NIH HHS
ID : U01 AI170019
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK055532
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA012307
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125047
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI150574
Pays : United States
Informations de copyright
Copyright © 2023 Shukla, Rao, Meena, Giorgianni, Lee, Raju, Shashikanth, Shekhar, Beranova, Balazs, Tigyi, Gosain and Rao.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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