Highlights
- •Paneth cells synthesize and secret anti-bacterial peptides to prevent dysbiosis.
- •In response to microbial stimuli, Paneth cells also secrete pro-angiogenic signalling molecules.
- •Secretory pro-angiogenic signaling molecules promote intestinal and mesenteric angiogenesis, regulating portal hypertension.
- •In the absence of Paneth cells, portal hypertension, intestinal and mesenteric angiogenesis are significantly decreased.
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 Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently,
we performed partial portal vein or bile duct ligation. We then studied the effects
of these interventions on hemodynamic parameters, proliferation of blood vessels and
the expression of genes regulating angiogenesis. Intestinal organoids were cultured
and exposed to different microbial products to study the composition of their secreted
products (by proteomics) and their effects on the proliferation and tube formation
of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 20, 2020
Accepted:
March 13,
2020
Received in revised form:
February 27,
2020
Received:
September 26,
2019
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
