The brain-gut axis in health and disease: from mucosal integrity to cortical processing.

Intense signalling occurs between the gastrointestinal tract and the brain. Under normal conditions, most of these signals are not perceived. We will test the hypothesis that this Gut-to-Brain signalling is in fact crucial for the control of food intake. We propose that the capacity for the stomach to relax during food intake, as well as the activation of anti-nociceptive pathways during meal ingestion are crucial determinants of the volume of ingested meals. We also hypothesize that maximal motor activity of the gastrointestinal tract between meals (so-called gastric phase 3), controlled by clock genes and ghrelin / motilin release, triggers hunger peaks and thereby determines meal frequency. We will study whether synaptic transmission and specific enteric nerve circuits are influenced by orexigenic and anorexigenic messengers, to synchronize central and peripheral pathways involved in food intake. Under pathological conditions, normally unperceived Gut-to-Brain signalling may reach perception levels. This phenomenon, referred to as visceral hypersensitivity, causes unexplained symptoms and may also interfere with the normal control of food intake. We propose that loss of mucosal barrier integrity in the gastrointestinal tract, associated increased mucosal permeability and low grade inflammation, is a peripheral mechanism of visceral hypersensitivity. We will investigate whether an interplay between acute infections, genetic susceptibility and stressful life events determine the persistence of low grade inflammation and visceral hypersensitivity after acute gastroenteritis. Impaired action of antinociceptive pathways in the central nervous system is another potential cause of visceral hypersensitivity. We propose that failure to activate descending antinociceptive pathways, which use endogenous opioids and endocannabinoids as key neurotransmitters, induces unexplained symptoms and impaired control of food intake. Cognitive-affective factors have a major impact on the (lack of) activation of these descending antinociceptive pathways. All research in this project will occur in a truly translational approach, where observations in isolated cells, in vitro tissues, experimental animals, healthy controls and patients mutually influence each other.

Keywords:Brain-gut axis

Disciplines:Gastro-enterology and hepatology