Neuron-associated macrophages in the gut as novel target for the treatment of enteric neuropathies: NEUMACS

Programme(s): H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)

Topic(s): ERC-2018-ADG - ERC Advanced Grant

Call for proposal: ERC-2018-ADG

Funding Scheme: ERC-ADG - Advanced Grant

Grant agreement ID: 833816

Project description:
A healthy enteric nervous system depends on resident macrophages
The gastrointestinal tract has its own enteric nervous system (ENS). Εnteric neuropathy (EN), the dysfunction of the neurons within the gut wall, results in stasis of luminal contents manifesting with malabsorption, chronic pain, vomiting, bloating and severe constipation. The EU-funded NEUMACS project is testing the provocative hypothesis that impaired support from a unique subpopulation of neuron-associated macrophages (NA-MF) to the ENS results in EN, leading to neural distress and apoptosis. Using innovative methods, the project will characterise the NA-MF populations and investigate the mechanisms that lead to their failure to support and protect the ENS. The project's insights will allow the identification of new therapeutic targets for EN treatment.

Objective

The gastrointestinal tract has the vital task to digest and absorb ingested food, a complex process requiring coordinated integration of motility, secretion, vascularization and absorption. Thereto the gastrointestinal tract is equipped with its own nervous system, the enteric nervous system (ENS), capable of controlling gut function independently of input from brain or spinal cord. Reduction in number or dysfunction of the neurons within the gut wall, also referred to as enteric neuropathy, significantly impacts on gut function, resulting in stasis of luminal contents and malabsorption, chronic pain, vomiting, bloating and severe constipation. Enteric neuropathies are common in prevalent disorders such as obesity, diabetes, and ageing, all major contributors to the health burden. Despite the continuous global increase in incidence of these disorders, the insight in the mechanisms leading to the reduction or dysfunction of enteric neurons is limited and most importantly, adequate treatment is lacking. Recently, we collected evidence that survival of enteric neurons is guaranteed by a unique subpopulation of resident macrophages closely associated to the ENS and expressing a typical neuroprotective / -supportive transcriptome. In line, depletion of these neuron-associated macrophages (NA-MF) results in apoptosis and a reduction in number of enteric neurons leading to severely impaired gastrointestinal motility. We pose the provocative hypothesis that enteric neuropathy results from impaired support to the ENS by NA-MF, leading to neural distress and apoptosis. Using state-of-the-art methods, we will first characterize in depth the NA-MF population to subsequently unravel the mechanisms leading to failure of NA-MF to support and protect the ENS in animal models and in patients. These ground-breaking insights will allow us to identify therapeutic targets for the treatment of enteric neuropathies, representing an exponentially growing health problem of the 21st century.