Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals.
Animals
Culture Media, Conditioned
Disease Models, Animal
Escherichia coli
/ metabolism
Escherichia coli Infections
/ metabolism
Gastrointestinal Microbiome
/ genetics
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Hypertension, Portal
/ metabolism
Intestine, Small
/ metabolism
Male
Mice
Mice, Transgenic
Neovascularization, Pathologic
/ metabolism
Organoids
/ metabolism
Paneth Cells
/ drug effects
Pore Forming Cytotoxic Proteins
/ metabolism
Proteome
Proteomics
/ methods
Tamoxifen
/ pharmacology
Antimicrobial peptides
Bacterial-derived products
Intestinal microflora
Intestinal organoids
Proteomics
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
26
09
2019
revised:
27
02
2020
accepted:
13
03
2020
pubmed:
25
3
2020
medline:
9
11
2021
entrez:
25
3
2020
Statut:
ppublish
Résumé
Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. We first treated Math1 Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.
Sections du résumé
BACKGROUND & AIMS
Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure.
METHODS
We first treated Math1
RESULTS
Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs.
CONCLUSIONS
These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension.
LAY SUMMARY
Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.
Identifiants
pubmed: 32205193
pii: S0168-8278(20)30178-1
doi: 10.1016/j.jhep.2020.03.019
pii:
doi:
Substances chimiques
Culture Media, Conditioned
0
Pore Forming Cytotoxic Proteins
0
Proteome
0
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
628-639Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK118904
Pays : United States
Informations de copyright
Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.