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United European Gastroenterology Journal Jul 2021Different peripheral pathways are implicated in the regulation of the food ingestion-digestion cycle. (Review)
Review
BACKGROUND
Different peripheral pathways are implicated in the regulation of the food ingestion-digestion cycle.
METHODS
Narrative review on gastrointestinal mechanisms involved in satiety and hunger signalling.
RESULTS
Combined mechano- and chemoreceptors, peripherally released peptide hormones and neural pathways provide feedback to the brain to determine sensations of hunger (increase energy intake) or satiation (cessation of energy intake) and regulate the human metabolism. The gastric accommodation reflex, which consists of a transient relaxation of the proximal stomach during food intake, has been identified as a major determinant of meal volume, through activation of tension-sensitive gastric mechanoreceptors. Motilin, whose release is the trigger of gastric Phase 3, has been identified as the major determinant of return of hunger after a meal. In addition, the release of several peptide hormones such as glucagon-like peptide 1 (GLP-1), cholecystokinin as well as motilin and ghrelin contributes to gut-brain signalling with relevance to control of hunger and satiety. A number of nutrients, such as bitter tastants, as well as pharmacological agents, such as endocannabinoid receptor antagonists and GLP-1 analogues act on these pathways to influence hunger, satiation and food intake.
CONCLUSION
Gastrointestinal mechanisms such as gastric accommodation and motilin release are key determinants of satiety and hunger.
Topics: Animals; Cholecystokinin; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Motilin; Myoelectric Complex, Migrating; Satiation; Taste
PubMed: 34153172
DOI: 10.1002/ueg2.12097 -
Frontiers in Endocrinology 2021Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of... (Review)
Review
Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs and house musk shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes to the maintenance of normal GI functions and transmits a hunger signal from the stomach to the brain. Motilin has been identified in various mammals, but the physiological roles of motilin in regulating GI motility in these mammals are well not understood due to inconsistencies between studies conducted on different species using a range of experimental conditions. Motilin orthologs have been identified in non-mammalian vertebrates, and the sequence of avian motilin is relatively close to that of mammals, but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R has also been identified in mammals and non-mammalian vertebrates, and can be divided into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50 years have passed since discovery of motilin, here we reviewed the structure, distribution, receptor and the GI motility regulatory function of motilin in vertebrates from fish to mammals.
Topics: Animals; Gastrointestinal Motility; Humans; Motilin; Muscle Contraction; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide
PubMed: 34497583
DOI: 10.3389/fendo.2021.700884 -
Science Advances Mar 2023Motilin is an endogenous peptide hormone almost exclusively expressed in the human gastrointestinal (GI) tract. It activates the motilin receptor (MTLR), a class A G...
Motilin is an endogenous peptide hormone almost exclusively expressed in the human gastrointestinal (GI) tract. It activates the motilin receptor (MTLR), a class A G protein-coupled receptor (GPCR), and stimulates GI motility. To our knowledge, MTLR is the first GPCR reported to be activated by macrolide antibiotics, such as erythromycin. It has attracted extensive attention as a potential drug target for GI disorders. We report two structures of G-coupled human MTLR bound to motilin and erythromycin. Our structures reveal the recognition mechanism of both ligands and explain the specificity of motilin and ghrelin, a related gut peptide hormone, for their respective receptors. These structures also provide the basis for understanding the different recognition modes of erythromycin by MTLR and ribosome. These findings provide a framework for understanding the physiological regulation of MTLR and guiding drug design targeting MTLR for the treatment of GI motility disorders.
Topics: Humans; Motilin; Erythromycin; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide
PubMed: 36921049
DOI: 10.1126/sciadv.ade9020 -
International Journal of Medical... 2022Grape seed is an important natural bioactive product with various health benefits. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal (GI)...
Grape seed is an important natural bioactive product with various health benefits. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal (GI) tract. The present study investigated the effects of grape seed powder (GSP) on ICC properties and GI motility. GSP depolarized the pacemaker potentials of ICCs in a dose‑dependent manner. Y25130 or SB269970 slightly inhibited GSP‑induced effects. However, Y25130 and SB269970 together completely blocked GSP-induced effects. In the presence of inhibitors of protein kinase C, protein kinase A, or mitogen-activated protein kinase, GSP‑induced ICC depolarization was inhibited. GSP increased the intestinal transit rate in normal mice and in mice with acetic acid-induced GI motility disorder. In addition, the levels of motilin and substance P were elevated after GSP dosing. These results demonstrate that GSP can regulate GI motility, and therefore, it is a potential therapeutic agent for treating GI motility disorders.
Topics: Animals; Gastrointestinal Motility; Intestine, Small; Membrane Potentials; Mice; Patch-Clamp Techniques; Powders; Seeds; Vitis
PubMed: 35693751
DOI: 10.7150/ijms.72529 -
Molecular Metabolism Dec 2021Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is...
OBJECTIVE
Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is stimulated by fats, bile, and duodenal acidification but the underlying molecular mechanisms of motilin secretion remain poorly understood. This study aimed to establish the key signaling pathways involved in the regulation of secretion from human motilin-expressing M-cells.
METHODS
Human duodenal organoids were CRISPR-Cas9 modified to express the fluorescent protein Venus or the Ca sensor GCaMP7s under control of the endogenous motilin promoter. This enabled the identification and purification of M-cells for bulk RNA sequencing, peptidomics, calcium imaging, and electrophysiology. Motilin secretion from 2D organoid-derived cultures was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), in parallel with other gut hormones.
RESULTS
Human duodenal M-cells synthesize active forms of motilin and acyl-ghrelin in organoid culture, and also co-express cholecystokinin (CCK). Activation of the bile acid receptor GPBAR1 stimulated a 3.4-fold increase in motilin secretion and increased action potential firing. Agonists of the long-chain fatty acid receptor FFA1 and monoacylglycerol receptor GPR119 stimulated secretion by 2.4-fold and 1.5-fold, respectively. Acidification (pH 5.0) was a potent stimulus of M-cell calcium elevation and electrical activity, an effect attributable to acid-sensing ion channels, and a modest inducer of motilin release.
CONCLUSIONS
This study presents the first in-depth transcriptomic and functional characterization of human duodenal motilin-expressing cells. We identify several receptors important for the postprandial and interdigestive regulation of motilin release.
Topics: Bile; Cells, Cultured; Duodenum; Fatty Acids, Nonesterified; Humans; Hydrogen-Ion Concentration; Motilin; Organoids
PubMed: 34662713
DOI: 10.1016/j.molmet.2021.101356 -
Pharmacology Research & Perspectives Apr 2022The gastrointestinal (GI) hormone motilin helps control human stomach movements during hunger and promotes hunger. Although widely present among mammals, it is generally... (Review)
Review
The gastrointestinal (GI) hormone motilin helps control human stomach movements during hunger and promotes hunger. Although widely present among mammals, it is generally accepted that in rodents the genes for motilin and/or its receptor have undergone pseudonymization, so exogenous motilin cannot function. However, several publications describe functions of low concentrations of motilin, usually within the GI tract and CNS of mice, rats, and guinea pigs. These animals were from institute-held stocks, simply described with stock names (e.g., "Sprague-Dawley") or were inbred strains. It is speculated that variation in source/type of animal introduces genetic variations to promote motilin-sensitive pathways. Perhaps, in some populations, motilin receptors exist, or a different functionally-active receptor has a good affinity for motilin (indicating evolutionary pressures to retain motilin functions). The ghrelin receptor has the closest sequence homology, yet in non-rodents the receptors have a poor affinity for each other's cognate ligand. In rodents, ghrelin may substitute for certain GI functions of motilin, but no good evidence suggests rodent ghrelin receptors are highly responsive to motilin. It remains unknown if motilin has functional relationships with additional bioactive molecules formed from the ghrelin and motilin genes, or if a 5-TM motilin receptor has influence in rodents (e.g., to dimerize with GPCRs and create different pharmacological profiles). Is the absence/presence of responses to motilin in rodents' characteristic for systems undergoing gene pseudonymization? What are the consequences of rodent supplier-dependent variations in motilin sensitivity (or other ligands for receptors undergoing pseudonymization) on gross physiological functions? These are important questions for understanding animal variation.
Topics: Animals; Gastrointestinal Tract; Genetic Variation; Ghrelin; Guinea Pigs; Humans; Mice; Motilin; Rats; Receptors, Gastrointestinal Hormone; Receptors, Ghrelin; Receptors, Neuropeptide; Rodentia; Species Specificity
PubMed: 35191209
DOI: 10.1002/prp2.900 -
Revista Da Associacao Medica Brasileira... 2023Functional constipation is the most common form of constipation, and its exact aetiology is still unclear. However, it is known that deficiencies in hormonal factors...
OBJECTIVE
Functional constipation is the most common form of constipation, and its exact aetiology is still unclear. However, it is known that deficiencies in hormonal factors cause constipation by changing physiological mechanisms. Motilin, ghrelin, serotonin acetylcholine, nitric oxide, and vasoactive intestinal polypeptide are factors that play a role in colon motility. There are a limited number of studies in the literature where hormone levels and gene polymorphisms of serotonin and motilin are examined. Our study aimed to investigate the role of motilin, ghrelin, and serotonin gene/receptor/transporter polymorphisms in constipation pathogenesis in patients diagnosed with functional constipation according to the Rome 4 criteria.
METHODS
Sociodemographic data, symptom duration, accompanying findings, the presence of constipation in the family, Rome 4 criteria, and clinical findings according to Bristol scale of 200 cases (100 constipated patients and 100 healthy control) who applied to Istanbul Haseki Training and Research Hospital, Pediatric Gastroenterology Outpatient Clinic, between March and September 2019 (6-month period) were recorded. Polymorphisms of motilin-MLN (rs2281820), serotonin receptor-HTR3A (rs1062613), serotonin transporter-5-HTT (rs1042173), ghrelin-GHRL (rs27647), and ghrelin receptor-GHSR (rs572169) were detected by real-time PCR.
RESULTS
There was no difference between the two groups in terms of sociodemographic characteristics. Notably, 40% of the constipated group had a family history of constipation. The number of patients who started to have constipation under 24 months was 78, and the number of patients who started to have constipation after 24 months was 22. There was no significant difference between constipation and control groups in terms of genotype and allele frequencies in MLN, HTR3A, 5-HTT, GHRL, and GHSR polymorphisms (p<0.05). Considering only the constipated group, the rates of gene polymorphism were similar among those with/without a positive family history of constipation, constipation onset age, those with/without fissures, those with/without skin tag, and those with type 1/type 2 stool types according to the Bristol stool scale.
CONCLUSION
Our study results showed that gene polymorphisms of these three hormones may not be related to constipation in children.
Topics: Child; Humans; Motilin; Ghrelin; Serotonin; Constipation; Polymorphism, Genetic
PubMed: 36888769
DOI: 10.1590/1806-9282.20220986 -
Frontiers in Pharmacology 2021Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (HS) receive a bad connotation; in low concentrations these play a major governing... (Review)
Review
Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (HS) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and HS on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.
PubMed: 34354597
DOI: 10.3389/fphar.2021.720703 -
World Journal of Gastroenterology Sep 2023Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA)... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA) plays an important role in septic AGI (S-AGI), but its specific mechanism is not completely understood, and few clinical reports are available.
AIM
To explore the effect and mechanism of HPA inhibition in S-AGI patients.
METHODS
In our prospective clinical trial, 48 patients with S-AGI were randomly assigned to a control group to receive conventional treatment, whereas 47 patients were randomly assigned to an intervention group to receive conventional treatment combined with low molecular weight heparin. AGI grade, sequential organ failure assessment score, acute physiology and chronic health evaluation II score, D-dimer, activated partial thromboplastin time (APTT), anti-Xa factor, interleukin-6, tumour necrosis factor-α, HPA, syndecan-1 (SDC-1), LC3B (autophagy marker), intestinal fatty acid binding protein, D-lactate, motilin, gastrin, CD4/CD8, length of intensive care unit (ICU) stay, length of hospital stay and 28-d survival on the 1, 3 and 7 d after treatment were compared. Correlations between HPA and AGI grading as well as LC3B were compared. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic value of HPA, intestinal fatty acid binding protein and D-lactate in S-AGI.
RESULTS
Serum HPA and SCD-1 levels were significantly reduced in the intervention group compared with the control group ( < 0.05). In addition, intestinal fatty acid-binding protein, D-lactate, AGI grade, motilin, and gastrin levels and sequential organ failure assessment score were significantly decreased ( < 0.05) in the intervention group. However, LC3B, APTT, anti-Xa factor, and CD4/CD8 were significantly increased ( < 0.05) in the intervention group. No significant differences in interleukin-6, tumour necrosis factor-α, d-dimer, acute physiology and chronic health evaluation II score, length of ICU stay, length of hospital stay, or 28-d survival were noted between the two groups ( > 0.05). Correlation analysis revealed a significant negative correlation between HPA and LC3B and a significant positive correlation between HPA and AGI grade. ROC curve analysis showed that HPA had higher specificity and sensitivity in diagnosis of S-AGI.
CONCLUSION
HPA has great potential as a diagnostic marker for S-AGI. Inhibition of HPA activity reduces SDC-1 shedding and alleviates S-AGI symptoms. The inhibitory effect of HPA in gastrointestinal protection may be achieved by enhanced autophagy.
Topics: Humans; Gastrins; Interleukin-6; Motilin; Tumor Necrosis Factor-alpha; Sepsis; Lactic Acid; Abdominal Injuries; Fatty Acid-Binding Proteins; Heparin, Low-Molecular-Weight
PubMed: 37744293
DOI: 10.3748/wjg.v29.i35.5154