Neuron-associated macrophages in the gut as novel target for the treatment of enteric neuropathies (NEUMACS)
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.
Page 3 of 8
Associated with document Ref. Ares(2019)3077582 - 08/05/2019