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Cholinergic modulation of immune homeostasis: new opportunities for treatment

Objective

In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial.
The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.

Field of science

  • /medical and health sciences/clinical medicine/allergology/food allergy
  • /medical and health sciences/clinical medicine/surgery
  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/allergology

Call for proposal

ERC-2013-ADG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

KATHOLIEKE UNIVERSITEIT LEUVEN
Address
Oude Markt 13
3000 Leuven
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 495 200
Principal investigator
Guy Eduard Elisabeth Boeckxstaens (Prof.)
Administrative Contact
Stijn Delaure (Dr.)

Beneficiaries (1)

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium
EU contribution
€ 2 495 200
Address
Oude Markt 13
3000 Leuven
Activity type
Higher or Secondary Education Establishments
Principal investigator
Guy Eduard Elisabeth Boeckxstaens (Prof.)
Administrative Contact
Stijn Delaure (Dr.)