Vagal and hormonal gut-brain communication: from satiation to satisfaction

Abstract

Studying communication between the gut and the brain is as relevant and exciting as it has been since Pavlov's discoveries a century ago. Although the efferent limb of this communication has witnessed significant advances, it is the afferent, or sensory, limb that has recently made for exciting news. It is now clear that signals from the gut are crucial for the control of appetite and the regulation of energy balance, glucose homeostasis, and more. Ghrelin, discovered just a few years ago, is the first gut hormone that increases appetite, and it may be involved in eating disorders. The stable analogue of glucagon-like peptide-1 has rapidly advanced to one of the most promising treatment options for type-2 diabetes. Changes in the signalling patterns of these and other gut hormones best explain the remarkable capacity of gastric bypass surgery to lower food intake and excess body weight. Given the enormous societal implications of the obesity epidemic, these are no small feats. Together with the older gut hormone cholecystokinin and abundant vagal mechanosensors, the gut continuously sends information to the brain regarding the quality and quantity of ingested nutrients, not only important for satiation and meal termination, but also for the appetitive phase of ingestive behaviour and the patterning of meals within given environmental constraints. By acting not only on brainstem and hypothalamus, this stream of sensory information from the gut to the brain is in a position to generate a feeling of satisfaction and happiness as observed after a satiating meal and exploited in vagal afferent stimulation for depression.

Figure 1

The sensory limb of gut–brain communication. Simplified schematic diagram shows the major transduction sites and mechanisms for the detection of ingested food and its macronutrient components. Ordinary enterocytes are shown in light grey and enteroendocrine cells in darker grey. Note that the molecular machinery given for a particular epithelial cell is not completely known and does, therefore, not define specific fixed configurations. In particular, it is not completely clear to what extent ordinary enterocytes and certain enteroendocrine cells express the different types of G-protein-coupled receptors of the T1R and T2R families, the amino acid-sensing calcium receptor and GPCR6, and the fatty acid transporters FATP4, CD36 and GPR120. After release of nutrients and hormones into the lamina propria, they are either taken up by capillaries and sent to the brain and other organs through the general circulation and/or the lymphatic system. Circulating nutrients and hormones have access to the brain at all levels. Hormones and transmitters in the lamina propria can also interact with relevant receptors on mucosal endings of vagal afferent neurons and enteric neurons as well as dorsal root afferents (not shown). Vagal afferent information reaches the brain through the nucleus tractus solitarius and area postrema in the caudal brainstem and is then disseminated to hypothalamus and forebrain as indicated by grey arrows. Note that intestinal epithelial cells can also communicate with each other through paracrine or humoral mechanisms, and with other organs involved in energy balance regulation such as the pancreas, liver, adipose tissue and muscle, through humoral mechanisms.

Figure 2

Vagal afferent mechano- and nutrient-sensors in the rat gastrointestinal tract. Vagal afferent fibres and terminal structures were anterogradely traced with the fluorescent dye DiI (bright white) injected into nodose ganglia. A: Intramuscular array (IMA) in longitudinal muscle layer of gastric fundus. Arrow indicates parent axon entering the muscle layer from myenteric plexus. The inset shows vagal afferent fibres in intimate anatomical contact with interstitial cell of Cajal. B: Intraganglionic laminar endings (IGLE) in myenteric plexus of gastric fundus. Two different parent axons are indicated by arrows. Myenteric ganglion is indicated by arrowheads. C: Mucosal endings close to epithelium (e) in villus of proximal duodenum.