From gut nutrient sensing to nutrient perception: a cooperative role involving CCK and 5-HT?

GUT-BRAIN AXIS INTERPLAY REMAINS a major question in physiology. The release of 5-HT by endocrine cells was previously demonstrated to respond to different stimuli including pressure sensors and sodium-glucose cotransporter, whereas CCK release responds to apolipoprotein A-IV and Pept1 activation. The paper from Savastano, Hayes, and Covasa in this issue of AJP-Regulatory, Integrative and Comparative Physiology (9) extends the release of 5-HT and 5-HT3 receptor activation to lipid and shows cooperation between CCK and 5-HT in luminal lipid-related informations. This concept could represent a key mechanism in the understanding of the interplay between gut mechanosensitivity, gut chemosensitivity, and specific nutrient sensing, transduction, central encoding, and perception. Whether apolipoprotein A-IV or another lipid-associated signal is involved in the transduction mechanism remains to be determined. The central encoding of the 5-HT3 and CCK1 receptors vagus-mediated mechanical and chemical-related sensory informations also represents an exciting area for future research. Understanding the mechanisms involved in gut-brain axis interplay remains a major question in physiology. It is established that intrinsic and extrinsic afferent fibers from nerves of the gastrointestinal tract continuously receive informations related to a number of mechanical and chemical stimuli applied to the mucosa of the small intestine. They transmit these informations to the enteric nervous system (ENS) and to the central nervous system (CNS), respectively. Altogether they exert feedback control of both gastrointestinal muscle contraction and intestinal secretion and also participate to the central feeling of satiation and satiety and to the control of food intake. Savastano et al. (9) show that cooperation between CCK and 5-HT in luminal lipid-related information represents an interesting contribution to the understanding of these complex mechanisms. The regulatory mechanisms involving mechanosensitivity and chemosensitivity of intrinsic and extrinsic gut afferent fibers are of particular importance since they participate, during meals, in the overall control and concomitant adaptation of food intake, meal digestion, and nutrient assimilation. They adapt food ingestion to stomach distension, regulate intestinal processes according to the entry of nutrients from the stomach, and participate in the regulation of the supply of nutrients and energy to the body. The extent of the gut mechanosensitivity and chemosensitivity has been inferred from in vivo physiological experiments in a variety of animal models and in humans. These experiments demonstrated that gastric and intestinal distension triggers the peristaltic reflex, affect gastric secretion, and induce satiation and meal termination. Similarly, luminal perfusion of the intestine with acid, carbohydrate, lipid, protein, amino acids, or high-osmolarity solutions is known to decrease gastric motility, delay gastric emptying, decrease gastric acid secretion, induce satiation or satiety, and produce an inhibition of food intake. Despite numerous studies conducted over the last decades, many controversies still remain on the transduction mechanisms in the nerve terminals responding to mechanical and chemical stimuli, the precise properties and responses of individual intrinsic and extrinsic afferent neurons, the cooperative processes by which these different and complex signaling pathways transmit specific mechanosensitive and chemosensitive informations to the ENS and CNS, the central encoding of these informations, and the precise mechanisms by which they participate in the regulation of gastrointestinal processes and control of food intake. Although afferent terminals may express specific receptors on the terminal membrane, the transduction mechanism that received considerable attention is the presence of “taste-like” cells in the intestinal mucosa. In response to mechanical or chemical luminal stimuli, these cells pass on the information to the ENS and CNS through the release of neuroactive modulators acting on neurons or neuron endings located in their close vicinity. The mucosal sensitive cell candidates are enteroendocrine cells releasing peptide hormones, such as 5-HT, cholecystokinin (CCK), secretin, corticotrophin-releasing factor, somatostatin, orexin, or peptide YY in response to luminal nutrients. When administered exogenously, several of these peptide hormones mimic the effects of intestinal nutrients on gut motor and secretory function and on food intake. This interaction involving taste-like cells and neuroactive modulators acting on terminal afferent extends the sensory repertoire of afferent neurons to luminal stimuli that could not be encoded by their direct action on terminals in the lamina propria. Previous studies showed the important role of intestinal 5-HT and CCK released from these intestinal enteroendocrine cells. They appear to be mediators in the signaling of many luminal mechanical and chemical stimuli to intrinsic and extrinsic afferent fibers. As for CCK receptors (CCK1), 5-HT receptors have been identified on vagal and spinal afferent neurons and are of the 5-HT3 receptor subtype. The specific transduction mechanisms in the nerve terminals responding to the different mechanical and chemical stimuli have been also subjected to different hypotheses. The gastrointestinal mechanosensitivity has been discussed for several decades and different results demonstrated enterochromaffin cells and 5-HT as pressure transducers and neuroactive modulator, respectively (4, 5). The results indicated that 5-HT released from enterochromaffin cells in response to pressure stimulated intrinsic afferent neurons within the enteric nervous system, leading to activation of the peristaltic reflex. Accordingly, Fos protein expression is increased in primary afferent neurons in the submucosal plexus in response to gut distension, and this effect was 5-HT dependant. It is also established that Address for reprint requests and other correspondence: Daniel Tomé, INRA, UMR914 Nutrition Physiology and Ingestive Behavior, AgroParisTech, 16 rue Claude Bernard, Paris, F-75005, France (e-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 292: R1061–R1062, 2007; doi:10.1152/ajpregu.00846.2006.