Gastrointestinal hormones and regulation of gastric emptying.

PURPOSE OF REVIEW: In this review, we evaluate recent findings related to the association between gastrointestinal hormones and regulation of gastric emptying. RECENT FINDINGS: Motilin and ghrelin, which act during fasting, promote gastric motility, whereas most of the hormones secreted after a meal inhibit gastric motility. Serotonin has different progastric or antigastric motility effects depending on the receptor subtype. Serotonin receptor agonists have been used clinically to treat dyspepsia symptoms but other hormone receptor agonists or antagonists are still under development. Glucagon-like peptide 1 agonists, which have gastric motility and appetite-suppressing effects are used as a treatment for obesity and diabetes. SUMMARY: Gastrointestinal hormones play an important role in the regulation of gastric motility. Various drugs have been developed to treat delayed gastric emptying by targeting gastrointestinal hormones or their receptors but few have been commercialized.

Motilin: a panoply of communications between the gut, brain, and pancreas.

Introduction: Motilin was first alluded to nearly a century ago. But it remains a rather abstruse peptide, in the shadow of its younger but more lucid 'cousin' ghrelin.Areas covered: The review aimed to bring to the fore multifarious aspects of motilin research with a view to aiding prioritization of future studies on this gastrointestinal peptide.Expert opinion: Growing evidence indicates that rodents (mice, rats, guinea pigs) do not have functional motilin system and, hence, studies in these species are likely to have a minimal translational impact. Both the active peptide and motilin receptor were initially localized to the upper gastrointestinal tract only but more recently - also to the brain (in both humans and other mammals with functional motilin system). Motilin is now indisputably implicated in interdigestive contractile activity of the gastrointestinal tract (in particular, gastric phase III of the migrating motor complex). Beyond this role, evidence is building that there is a cross-talk between motilin system and the brain-pancreas axis, suggesting that motilin exerts not only contractile but also orexigenic and insulin secretagogue actions.

Molecular cloning of motilin and mechanism of motilin-induced gastrointestinal motility in Japanese quail.

Motilin, a peptide hormone produced in the upper intestinal mucosa, plays an important role in the regulation of gastrointestinal (GI) motility. In the present study, we first determined the cDNA and amino acid sequences of motilin in the Japanese quail and studied the distribution of motilin-producing cells in the gastrointestinal tract. We also examined the motilin-induced contractile properties of quail GI tracts using an in vitro organ bath, and then elucidated the mechanisms of motilin-induced contraction in the proventriculus and duodenum of the quail. Mature quail motilin was composed of 22 amino acid residues, which showed high homology with chicken (95.4%), human (72.7%), and dog (72.7%) motilin. Immunohistochemical analysis showed that motilin-immunopositive cells were present in the mucosal layer of the duodenum (23.4±4.6cells/mm(2)), jejunum (15.2±0.8cells/mm(2)), and ileum (2.5±0.7cells/mm(2)), but were not observed in the crop, proventriculus, and colon. In the organ bath study, chicken motilin induced dose-dependent contraction in the proventriculus and small intestine. On the other hand, chicken ghrelin had no effect on contraction in the GI tract. Motilin-induced contraction in the duodenum was not inhibited by atropine, hexamethonium, ritanserin, ondansetron, or tetrodotoxin. However, motilin-induced contractions in the proventriculus were significantly inhibited by atropine and tetrodotoxin. These results suggest that motilin is the major stimulant of GI contraction in quail, as it is in mammals and the site of action of motilin is different between small intestine and proventriculus.

The proximal gastric corpus is the most responsive site of motilin-induced contractions in the stomach of the Asian house shrew.

The migrating motor complex (MMC) is responsible for emptying the stomach during the interdigestive period, in preparation for the next meal. It is known that gastric phase III of MMC starts from the proximal stomach and propagates the contraction downwards. We hypothesized that a certain region of the stomach must be more responsive to motilin than others, and that motilin-induced strong gastric contractions propagate from that site. Stomachs of the Suncus or Asian house shrew, a small insectivorous mammal, were dissected and the fundus, proximal corpus, distal corpus, and antrum were examined to study the effect of motilin using an organ bath experiment. Motilin-induced contractions differed in different parts of the stomach. Only the proximal corpus induced gastric contraction even at motilin 10(-10) M, and strong contraction was induced by motilin 10(-9) M in all parts of the stomach. The GPR38 mRNA expression was also higher in the proximal corpus than in the other sections, and the lowest expression was observed in the antrum. GPR38 mRNA expression varied with low expression in the mucosal layer and high expression in the muscle layer. Additionally, motilin-induced contractions in each dissected part of the stomach were inhibited by tetrodotoxin and atropine pretreatment. These results suggest that motilin reactivity is not consistent throughout the stomach, and an area of the proximal corpus including the cardia is the most sensitive to motilin.

Motilin-induced gastric contractions signal hunger in man.

RATIONALE: Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. OBJECTIVES: To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. FINDINGS: In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (ß=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. CONCLUSIONS: Motilin-induced gastric phase III is a hunger signal from GIT in man.

Ghrelin and motilin receptors as drug targets for gastrointestinal disorders.

The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.

Redefining the functional roles of the gastrointestinal migrating motor complex and motilin in small bacterial overgrowth and hunger signaling.

During the fasting state the upper gastrointestinal tract exhibits a specific periodic migrating contraction pattern that is known as the migrating motor complex (MMC). Three different phases can be distinguished during the MMC. Phase III of the MMC is the most active of the three and can start either in the stomach or small intestine. Historically this pattern was designated to be the housekeeper of the gut since disturbances in the pattern were associated with small intestinal bacterial overgrowth; however, its role in the involvement of hunger sensations was already hinted in the beginning of the 20th century by both Cannon (Cannon W, Washburn A. Am J Physiol 29: 441-454, 1912) and Carlson (Carlson A. The Control of Hunger in Health and Disease. Chicago, IL: Univ. of Chicago Press, 1916). The discovery of motilin in 1973 shed more light on the control mechanisms of the MMC. Motilin plasma levels fluctuate together with the phases of the MMC and induce phase III contractions with a gastric onset. Recent research suggests that these motilin-induced phase III contractions signal hunger in healthy subjects and that this system is disturbed in morbidly obese patients. This minireview describes the functions of the MMC in the gut and its regulatory role in controlling hunger sensations.

Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus.

Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 µg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 µg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 µg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 µg/kg BW) or ghrelin (1 µg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus.

Motilin stimulates pepsinogen secretion in Suncus murinus.

Motilin and ghrelin are gastrointestinal hormones that stimulate the migrating motor complex (MMC) of gastrointestinal motility during the fasting state. In this study, we examined the effect of motilin and ghrelin on pepsinogen secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. By using a gastric lumen-perfusion system, we found that the intravenous administration of carbachol and motilin stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was observed in the vagotomized suncus. This is the first report demonstrating that motilin stimulates pepsinogen secretion, and suggest that this effect occurs through a cholinergic pathway in suncus.

Ghrelin and the gut.

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) which was identified in the pituitary gland and is now named the ghrelin receptor. However, the peptide is most abundant in the stomach and ghrelin receptors are present in all major organ systems and tissues. Ghrelin forms with motilin, a new gut peptide family and the sequence similarities of peptides and receptors suggest they evolved by gene duplication. Nevertheless, no cross-reactivity exits between both peptides. Ghrelin shares with motilin motor effects in the gut, in particular gastric emptying and the induction of the migrating motor complex, but ghrelin also affects gastric acid secretion, offers gastroprotection and may modulate intestinal inflammation. The effects of ghrelin result from the activation of central, vagal and enteric neural receptors and receptors on immune cells. Ghrelin agonists have been developed for the treatment of hypomotility disorders and the peptidomimetic TZP-102 is in phase 2 clinical trials for diabetic gastroparesis.

Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (ß-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of ß-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.

Interdigestive migrating motor complex -its mechanism and clinical importance.

Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal (GI) contractions in the interdigestive state. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. MMC cycle is mediated via the interaction between motilin and 5-hydroxytryptamine (5-HT) by the positive feedback mechanism in conscious dogs. Luminal administration of 5-HT initiates duodenal phase II and phase III with a concomitant increase of plasma motilin release. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces phase III. 5-HT4 antagonists significantly inhibit both of gastric and intestinal phase III, while 5-HT3 antagonists inhibit only gastric phase III. These suggest that gastric MMC is regulated via vagus, 5-HT3/4 receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons (IPAN) and 5-HT4 receptors. We propose the possibility that maximally released motilin by a positive feedback depletes 5-HT granules in the duodenal EC cells, resulting in no more contractions. Stress is highly associated with the pathogenesis of functional dyspepsia (FD). Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity. Subset of FD patients shows reduced vagal activity and impaired gastric phase III. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Maintaining MMC cycle in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms.

Motilin stimulates preadipocyte proliferation and differentiation and adipocyte lipid storage.

Motilin is a circulating gastrointestinal peptide secreted primarily by duodenal mucosal M cells and recognized for its prokinetic effects on gastrointestinal tissues. Little information is available regarding effects on insulin/glucose homeostasis or adipocyte function. Our aim was to evaluate the effects of motilin on adipocyte proliferation, differentiation, lipolysis, and macronutrient uptake in adipocytes. 3T3-L1 cells and primary rat adipocytes were treated acutely and chronically with varying motilin concentrations, and effects were compared with vehicle alone (control), set as 100% for all assays. In preadipocytes, motilin stimulated proliferation ([(3)H]thymidine incorporation) and mitochondrial activity (141 ± 10%, P < 0.001 and 158 ± 10%, respectively, P < 0.001), in a concentration-dependent manner. Chronic supplementation with motilin during differentiation further increased lipogenesis (Oil red O staining 191 ± 27%, P < 0.05) and was associated with an upregulation of PPARγ (148 ± 8%, P < 0.01), C/EBPα (142 ± 17%, P < 0.05), and Cav3 (166 ± 20%, P < 0.05) expression. In mature 3T3-L1 adipocytes motilin increased fatty acid uptake/incorporation (≤ 202 ± 12%; P < 0.01) and glucose uptake (146 ± 9% P < 0.05) and decreased net fatty acid release (maximal -31%, P < 0.05) without influencing total lipolysis (glycerol release). Similar effects were obtained in primary rat adipocytes. Motilin acutely increased expression of PPARγ, CEBPß, DGAT1, and CD36 while decreasing adiponectin mRNA and secretion. In human adipose tissue, motilin receptor GPR38 correlated with HOMA-IR and GHSR1 (r = 0.876, P < 0.0001). Motilin binding and fatty acid incorporation into adipocytes were inhibited by antagonists MB10 and [D-lys3]-GRP6 and PI 3-kinase inhibitor wortmannin. Taken together, these results suggest that motilin may directly influence adipocyte functions by stimulating energy storage.

The translational value of rodent gastrointestinal functions: a cautionary tale.

Understanding relationships between gene complements and physiology is important, especially where major species-dependent differences are apparent. Molecular and functional differences between rodents (rats, mice, guinea pigs) and humans are increasingly reported. Recently, the motilin gene, which encodes a gastrointestinal hormone widely detected in mammals, was found to be absent in rodents where the receptors are pseudogenes; however, actions of motilin in rodents are sometimes observed. Although ghrelin shares common ancestry with motilin, major species-dependent abberations are not reported. The apparently specific absence of functional motilin in rodents is associated with specialised digestive physiology, including loss of ability to vomit; motilin is functional in mammals capable of vomiting. The exception is rabbit, the only other mammal unable to vomit, in which motilin might be conserved to regulate caecotrophy, another specialised digestive process. Motilin illustrates a need for caution when translating animal functions to humans. Nevertheless, motilin receptor agonists are under development as gastroprokinetic drugs.

Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together?

The gastrointestinal system can be considered the gateway for food entry in our body. Rather than being a passive player, it is now clear that gut strongly influence the feeding behavior and contribute to maintain energy balance with different signals. The aim of this review is to summarize the current knowledge about the role of gastrointestinal tract in the control of food intake, by focusing on the interplay existing between the enteric nervous system and gastrointestinal hormones and their ability to modulate digestive motility and sensitivity. Also the latest advances about the contribution of gut microbiota and gastrointestinal taste receptors are described. From the reported data it clearly emerges that gut hormones together with nervous signals likely contribute to the regulation of energy balance and modulate food intake through the control of digestive motility and sensations. The close linkage among gastrointestinal hormones, the gut and the central nervous systems appears very intriguing and has induced the development of a new field of research: the gastroendocrinology.

Colitis affects the smooth muscle and neural response to motilin in the rabbit antrum.

BACKGROUND AND PURPOSE: The underlying mechanisms of gastric dysfunction during or after an episode of intestinal inflammation are poorly understood. This study investigated the effects of colitis on the contractile effects of motilin, an important endocrine regulator of gastric motility, in the antrum. EXPERIMENTAL APPROACH: Myeloperoxidase (MPO) activity, NF-kappaB activity and motilin receptor density were determined in the antrum of rabbits 5 days after the induction of 2,4,6-trinitrobenzenesulphonic acid colitis. Smooth muscle and neural responses to motilin were studied in antral smooth muscle strips in vitro. KEY RESULTS: Colitis did not affect MPO activity, but increased NF-kappaB activity in the antrum. Motilin receptor density in the antrum was not affected. Under control conditions, motilin induced a slowly developing tonic smooth muscle contraction. Five days post-inflammation, tonic contractions to motilin were reduced and preceded by a rapid initial contraction. Other kinases were recruited for the phosphorylation of myosin light chain (MLC) (a multi-functional MLC kinase), and for the inhibition of MLC phosphatase (Rho kinase in addition to protein kinase C) to mediate the motilin-induced contractions during inflammation. Colitis potentiated the cholinergic neural on-contractions in the antrum. This was associated with a hyper-reactivity to motilin and an increased muscle response to ACh. CONCLUSIONS AND IMPLICATIONS: Colitis altered the course of the motilin-induced smooth muscle contraction in the antrum. This involved changes in the kinases phosphorylating MLC. Increased cholinergic excitability to motilin in the antrum may play a role in the pathogenesis of inflammation-associated gastric motility disorders.

Mechanism of interdigestive migrating motor complex in conscious dogs.

BACKGROUND: The migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This study was designed to clarify the mechanisms of gastric MMC (G-MMC) and intestinal MMC (I-MMC) in conscious dogs. METHODS: Five strain gauge transducers were implanted on the stomach and intestine. To investigate the correlation between luminal 5-HT and phase III contractions, gastric and duodenal juices were collected during the MMC cycle. The 5-HT concentrations in gastric and duodenal juice were measured by HPLC. To investigate whether luminal 5-HT initiates MMC, 5-HT (10(-8)-10(-6) M, 10 ml) was administered into the duodenum 20 min after gastric phase III. To investigate the involvement of 5-HT(3) or 5-HT(4) receptors in mediating G-MMC and I-MMC, 5-HT(3) antagonists (ondansetron) or 5-HT(4) antagonists (GR 125,487) were infused for 120 min. RESULTS: Luminal administration of 5-HT (10(-6) M) initiated duodenal phase II followed by G-MMC and I-MMC with a concomitant increased release of plasma motilin. The duodenal 5-HT concentration was significantly increased during phase II (59 +/- 9 ng/ml) and phase III (251 +/- 21 ng/ml) compared to that of phase I (29 +/- 5 ng/ml). On the other hand, the 5-HT content in the stomach was not significantly changed throughout the MMC cycle. Intravenous infusion of motilin (0.3 microg/kg/h) increased the luminal 5-HT content and induced G-MMC and I-MMC. 5-HT(4) antagonists significantly inhibited both G-MMC and I-MMC, while 5-HT(3) antagonists inhibited only G-MMC. CONCLUSION: It is suggested that the MMC cycle is mediated by a positive feedback mechanism via the interaction between motilin and 5-HT.

Motilin and ghrelin as prokinetic drug targets.

Motilin is a hormone released by the endocrine cells of the duodenal mucosa during fasting to stimulate gastrointestinal motility. Ghrelin, the closest family member of motilin, was discovered 10 years ago from the rat stomach as the long-awaited endogenous ligand of the growth hormone secretagogue receptor. Ghrelin has now emerged as a multifunctional hormone with important effects on energy homeostasis but also on gastrointestinal motility. Like motilin, it induces hunger contractions in the fasting state and acts postprandially to accelerate gastric emptying. While the development of motilin agonists for the treatment of hypomotility disorders has been going on for more than 15 years, the development of ghrelin agonists is still in its infancy. The failure of the first generation of motilin agonists in clinical trials has been largely due to problems of desensitization and worsening of symptoms due to effects on gastric accommodation. These issues are being taken care of with the second generation of motilin agonists that are currently under evaluation. Ghrelin agonists have the same potential as motilin agonists to treat hypomotility disorders but their effects on appetite may even be a bonus to treat disorders such as functional dyspepsia while ghrelin's anti-inflammatory effects may make it superior to motilin to treat post-operative ileus. Nevertheless the important endocrine activities of ghrelin may result in side effects which are not encountered with motilin. Future studies will need to point out whether the motilin-ghrelin receptor family will make it as a new class of gastroprokinetics.