The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study

Abstract

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.The bidirectional neural and hormonal communication system between the brain and the gastrointestinal (GI) tract is known as the 'brain-gut axis' 1 . It is part of an integrated interoceptive system which continuously conveys homeostatic information about the physiological state of the body to the brain.GI hormones are important mediators of these gut-brain interactions 1 . One of these hormones, motilin, is a 22-amino-acid gut peptide secreted by endocrine M cells in the small intestine 2 . Motilin is a physiological regulator of the migrating motor complex (MMC), a cyclical contraction pattern with different phases of activity (phase I-III) originating in the stomach or duodenum and migrating distally in the fasted state 3,4 . Phase III is characterized by strong contractile activity. In healthy humans, gastric but not duodenal phase IIIs are preceded by a motilin peak and exogenous administration of motilin induces a premature gastric phase III 5,6 , which has recently been associated with increases in hunger ratings and with the occurrence of hunger peaks during fasting 7 .Although motilin has thus been associated with the induction of these so-called hunger contractions 8 , the brain mechanisms underlying the putative role of motilin in regulating appetite and eating behavior have not

The gastrointestinal tract in hunger and satiety signalling

“…47 Intravenous administration of erythromycin activated brain regions involved in homeostatic and hedonic control of appetite and food intake, and these activations were correlated to hunger ratings. 49 Motilin-induced gastric phase III: Alterations in disease states and role as a target for therapy…”

Motilin: from gastric motility stimulation to hunger signalling

“…In the 1980s and 1990s, motilin was studied intensively for its effects on gastrointestinal motility [3][4][5]29,30,32,34,46,[97][98][99][100][101][102][103][104][105] . Since 2016, the implication of motilin in the control of hunger and food reward has generated a renewed interest in motilin and its receptor 11,106,107 . figure 1 provides an overview of the biological functions of motilin.…”

“…Contractions induced by either neostigmine (an acetylcholinesterase inhibitor) or ghrelin did not markedly increase hunger sensations during the fasted state, indicating that only motilin-induced gastric contractions or motilin itself increases hunger scores 11 . Erythromycin A has also been shown to modulate brain regions related to homeostatic and hedonic control of appetite and feeding 107 . Further support for a role of motilin in the control of food intake was provided by a study showing that a low dose of erythromycin A stimulated voluntary meal requests in healthy volunteers 106 .…”

Brain activation after nasal histamine provocation in house dust mite allergic rhinitis patients

“…7 For each PNIF measurement, we repeated the PNIF at 3 times with a short interval of 30 seconds and with less than 10% phMRI data were preprocessed and analyzed as described previously. 8,9 The effect of interest for the present study was the group (AR patients versus HC)-by-substance (histamine versus saline)- TA B L E 1 Overview of brain regions in which the response to histamine (versus saline as a control condition) differs between allergic rhinitis patients and healthy controls P < .05 was used combined with an extent threshold of k = 10 voxels (corresponding to p FWE < 0.001 at cluster level).…”