Acetate, a metabolic product of Heligmosomoides polygyrus, facilitates intestinal epithelial barrier breakdown in a FFAR2-dependent manner

Elsevier

Available online 6 June 2022

International Journal for ParasitologyHighlights•

Heligmosmoides polygyrus secretes acetate during its L3 stage and as an adult worm.

Increased acetate is beneficial for Heligmosomoides polygyrus during infection.

Acetate increases permeability in murine intestinal organoids.

Acetate disorganizes tight junction protein Claudin 7 in murine intestinal organoids.

Permeability increasing effects of acetate are FFAR2-dependent.

Abstract

Approximately 2 billion people worldwide and a significant part of the domestic livestock are infected with soil-transmitted helminths, of which many establish chronic infections causing substantial economic and welfare burdens. Beside intensive research on helminth-triggered mucosal and systemic immune responses, the local mechanism that enables infective larvae to cross the intestinal epithelial barrier and invade mucosal tissue remains poorly addressed. Here, we show that Heligmosomoides polygyrus infective L3s secrete acetate and that acetate potentially facilitates paracellular epithelial tissue invasion by changed epithelial tight junction claudin expression. In vitro, impedance-based real-time epithelial cell line barrier measurements together with ex vivo functional permeability assays in intestinal organoid cultures revealed that acetate decreased intercellular barrier function via the G-protein coupled free fatty acid receptor 2 (FFAR2, GPR43). In vivo validation experiments in FFAR2-/- mice showed lower H. polygyrus burdens, whereas oral acetate-treated C57BL/6 wild type mice showed higher burdens. These data suggest that locally secreted acetate – as a metabolic product of the energy metabolism of H. polygyrus L3s – provides a significant advantage to the parasite in crossing the intestinal epithelial barrier and invading mucosal tissues. This is the first and a rate-limiting step for helminths to establish chronic infections in their hosts and if modulated could have profound consequences for their life cycle.

Keywords

Acetate

Microbiota

Barrier function

Intestinal permeability

Helminths

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© 2022 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

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