This review evaluated published data regarding the effects of ghrelin on GI motility using the PubMed database for English articles from 1999 to September 2009. Our strategy was to combine all available information from previous literature, in order to provide a complete structured review on the prokinetic properties of exogenous ghrelin and its potential use for treatment of various GI dysmotility ailments. We classified the literature into two major groups, depending on whether studies were done in health or in disease. We sub-classified the studies into stomach, small intestinal and colon studies, and broke them down further into studies done in vitro, in vivo (animals) and in humans. Further more, the reviewed studies were presented in a chronological order to guide the readers across the scientific advances in the field. The review shows evidences that ghrelin and its (receptor) agonists possess a strong prokinetic potential to serve in the treatment of diabetic, neurogenic or idiopathic gastroparesis and possibly, chemotherapy-associated dyspepsia, postoperative, septic or post-burn ileus, opiate-induced bowel dysfunction and chronic idiopathic constipation. Further research is necessary to close the gap in knowledge about the effect of ghrelin on the human intestines in health and disease.
Ghrelin is a 28-amino acid motilin-related peptide hormone mainly secreted by the X/A-like enteroendocrine cells of the oxyntic (parietal) mucosa of the gastric fundus. It is the endogenous ligand for the growth-hormone secretagogue receptor (GHS-R) 1a, recently discovered by two independent research groups [
This review evaluated published data regarding the prokinetic properties of exogenous ghrelin using the PubMed database for English articles from 1999 to September 2009. Our strategy was to combine and distil all currently available studies and reviews in order to provide an overview on exogenous ghrelin and its prokinetic abilities along the gut in health and disease. The search was performed by combining the terms “ghrelin” with “prokinetic” or with “gastrointestinal motility.” Clinical trials and review articles were specifically identified, and their reference citation lists were searched for additional publications not identified in the database searches. We classified the literature into two major groups, depending on whether studies were done in health or in disease. We sub-classified the studies into stomach, small intestinal and colon, and broke them down further into in vitro, in vivo (animals) and in humans. The reviewed studies were presented in a chronological order to guide the readers across the scientific advances in the field. We have combined all the available information from previous literature, in order to provide a complete review on the prokinetic properties of exogenous ghrelin and its potential applications for the treatment of various gastrointestinal (GI) dysmotility ailments.
in vitro studies demonstrated the prokinetic potential of ghrelin or its (receptor) agonists in enhancing gastric muscle contractility via activation of the growth hormone secretagogue receptor (GHS-R) and direct neural stimulation of the enteric nervous system (ENSs); an effect involving the cholinergic and tachykininergic pathways. Earliest studies were done in 2003 by Dass et al. on rodent gastric fundic circular muscle strips. Ghrelin concentration dependently increased the amplitude of cholinergic off-contractions at concentrations from 0.1 to 10
In vivo studies showed the role of ghrelin in the regulation of the migrating motor complex (MMC) in the fasting state and the involvement of the activation of GHS-R and neuropeptide Y (NPY) and possibly, vagal cholinergic neurons. In 2003, Fujino et al. reported that IV ghrelin induced MMC in the antrum of vagotomized fed rats via activation of the GHS-R and NPY neurons [
In vivo studies revealed opposite effects of ghrelin on the proximal and distal gastric tone in anaesthetized rats. Kobashi et al. reported that ICV ghrelin, or direct injection of ghrelin into the dorsal vagal complex (DVC), relaxed the proximal stomach, while ICV ghrelin at a higher dose contracted the distal stomach [
In vivo studies debated the effect of ghrelin on gastric myoelectrical activity (GMA). We have previously reported no effects of ghrelin on GMA in healthy dogs [
A number of in vivo studies preceded the in vitro studies and demonstrated prokinetic effects of ghrelin on gastric motility exerted via a vagally mediated mechanism. Masuda et al. were the first to report that IV ghrelin enhanced gastric contractions dose-dependently in anesthetized rats (from 0.8, 4, and 20
Studies on the prokinetic effects of exogenous ghrelin on the stomach of healthy human volunteers are summarized in Table
Prokinetic effects of exogenous ghrelin on gastric motility in healthy human volunteers (D-Lys). GHRP-6: GHRP receptor antagonist; GE: gastric emptying; GHRP-6: ghrelin secretagogue receptor 6 (non-synthetic ghrelin receptor agonist); GHS-R: growth hormone secretagogue receptor; IV: intravenous; MI; motility index; MMC: migrating motor complex; SPECT: single photon emission computed tomography; VAS: visual analogue scale.
Author | Subjects | Study design | Ghrelin type | Effective dose | Methods | Results |
---|---|---|---|---|---|---|
Levin F., [ | Healthy volunteers (5M, 3F) | Randomized, double-blind, placebo-controlled, crossover | Ghrelin | 10 pmol/Kg/min for 180 min after meal | Assessment of solid GE by scintigraphy | Ghrelin accelerated the rate of GE |
Tack J., [ | Healthy fasting volunteers (4F, 5M) | Cross-sectional | Ghrelin (Clinalfa, Switzerland) | 40 | Assessment of antroduodenal motility and gastric tone by manometry | Ghrelin induced premature phase III contractions and increased the tone of the proximal stomach |
Cremonini F., [ | Healthy volunteers: obese (5M, 20F) and | Randomized, parallel-group, one dose, double-blind, placebo-controlled | Ghrelin (Clinalfa, Switzerland) | 0.33 | Assessment of gastric volume and emptying by SPECT | Ghrelin marginally decreased fasting gastric volumes, but not GE or symptoms |
normal weight (13F) | Assessment of symptoms by VAS | |||||
Bisschops R., [ | Healthy volunteers ( | No information | ( | 40 | Assessment of antroduodenal pressures by manometry and gastric tone by barostat | ( |
( | ( | |||||
Ang D., [ | Healthy volunteers (4M, 6F) | Randomized, placebo-controlled, double-blind, cross over | Ghrelin | 40 | Assessment of gastric accommodation by barostat | ( |
( |
In 2006, researchers debated the prokinetic effect of ghrelin on gastric emptying [
Ghrelin was reported to inhibit gastric accommodation in healthy volunteers [
Two recent studies by Qiu et al. reported that ghrelin or GHRP-6 increased the amplitude of carbachol-induced contractions of the gastric fundus of various diabetic rodent models [
Studies on the prokinetic effects of exogenous ghrelin on diseased stomach in vivo are summarized in Table
Prokinetic effects of exogenous ghrelin on diseased stomach in vivo. GE: gastric emptying; GHRP-6: ghrelin secretagogue receptor 6 (non-synthetic ghrelin receptor agonist); h: hour; iNOS: inducible nitric oxide synthase; IP: intraperitoneal; IV: intravenous; L-NAME: N
Author | Species | Ghrelin type | Effective dose | Methods | Results | Mechanism of action |
---|---|---|---|---|---|---|
Trudel L., | Conscious postop ileus model (SD male rats) | Human ghrelin-28 (IGBMC, France) | 20 | Assessment of GE by gastric retention of a phenol red-marked meal | Ghrelin reversed the postop delayed GE | |
Trudel L., [ | Conscious postop ileus model (female mongrel dogs) | Ghrelin (IGBMC, France) | ( | Assessment of GE by acetaminophen method | Ghrelin reversed the postop delayed GE | |
( | ||||||
( | ||||||
De Winter B., [ | Conscious LPS septic ileus model (Swiss OFI mice) | ( | ( | Assessment of GE by the gastric retention of an Evans blue-marked meal | Ghrelin and GHRP-6 accelerated GE in LPS septic ileus mice | |
( | ( | |||||
Poitras P., [ | Conscious postop ileus ± morphine-treated rat model (male SD rats) | Ghrelin receptor agonist RC-1139 (Rejuvenon Corp., USA) | 2.5–10 mg /Kg IV given immediately after meal | Assessment of GE by the retention of | ( | |
( | ||||||
Liu Y., | Conscious Cisplatin-treated adult male C57/6J black mice | Rat ghrelin (Bachem Ltd, UK) | 1 mg/Kg, IP b.i.d | Assessment of gastric emptying by the wet weight of gastric content | Ghrelin improved GE | |
Sallam H., | Conscious scald-burned model (SD male rats) | Ghrelin (Tocris, USA) | 2 nmol/rat given IP 20 min before meal | Assessment of GE by gastric retention of a phenol red-marked meal | Ghrelin accelerated GE; an effect blocked by pretreatment with atropine | Ghrelin’s effects on gastric motility involve the cholinergic pathway |
Venkova K., | Conscious postop ileus ± morphine-treated rat model (male SD rats) | Ghrelin receptor agonist TZP-101 (Tranzyme Pharma Canada) | 0.1–1 mg /Kg (1ml) IV given 1-2 min before meal | Assessment of GE by the retention of | TZP-101 accelerated GE dose-dependently in postop ileus rats ± morphine | |
Qui et al. | Diabetic mouse model (IP-alloxan-treated C57 mice) | Rat ghrelin | 50–200 | Assessment of GE by gastric retention of a phenol red-marked meal | Ghrelin and GHRP-6 at all doses accelerated GE; an effect blocked by atropine or L-NAME. | The effects of Ghrelin and GHRP-6 on GE in diabetic gastroparesis is mediated via the cholinergic pathways |
Qui et al. | Diabetic guinea pig model (IP-STZ-treated) | Ghrelin | 20, 50 and 100 | Assessment of GE by gastric retention of a phenol red-marked meal | Ghrelin and GHRP-6 at all doses accelerated GE; an effect blocked by atropine. | The effects of Ghrelin and GHRP-6 on GE in diabetic gastroparesis are mediated via the cholinergic pathways |
Chen Y., | LPS endotoxemia mouse model (male ICR mice) | Rat ghrelin (Global Peptide Services, UDA) | 20 | ( | ( | Ghrelin’s effect on LPS-delayed GE are mediated via the down regulation of NO |
( | ( | |||||
( | ( | |||||
Zheng Q., | Diabetic mouse model (IP-alloxan-treated C57 mice) | GHRP-6 (Tocris, UK) | 200 | Assessment of GE by gastric retention of a phenol red-marked meal | GHRP-6 accelerated diabetic-induced delayed GE; an effect blocked by pretreatment with atropine | GHRP-6 effects on gastric motility involve the cholinergic pathway |
Studies on the prokinetic effects of exogenous ghrelin in dyspeptic and/or gastroparetic patients are summarized in Table
Prokinetic effects of exogenous ghrelin in dyspeptic and/or gastroparetic patients. IDDM: insulin-dependent diabetes mellitus; GE: gastric emptying; GHRP-6: ghrelin secretagogue receptor 6 (non-synthetic ghrelin receptor agonist); GHS-R: growth hormone secretagogue receptor; h: hour; IV: intravenous; VAS: visual analogue scale.
Author | Subjects | Study design | Ghrelin type | Effective dose | Methods | Results |
---|---|---|---|---|---|---|
Tack J., [ | Six dyspeptic patients (5F, 1M) | Cross-sectional | Ghrelin (Clinalfa, Switzerland) | 40 | ( | Ghrelin accelerated GE for both liquids and solids, as well as meal-related symptom scores |
( | ||||||
Murray C., [ | Ten IDDM gastroparetic patients (5M, 5F) | Randomized, double blinded, cross-over | Synthetic human ghrelin (Bachem, UK) | 5 pmol/Kg/min IV over 2 h | ( | Ghrelin accelerated GE rate, but had no effect on patients’ symptoms, despite impaired cardiovagal tone |
( | ||||||
Binn M., [ | Six gastroparetic patients (all F; 1 with truncal vagotomy) | Cross-sectional | Synthetic human ghrelin (Merck Biosciences, Switzerland) | 20 | Assessment of GE by C13-octanoic acid breath test | Ghrelin accelerated gastroparetic-induced delayed GE, even despite vagotomy |
Bisschops R., [ | Dyspeptic patients with delayed GE ( | No information | ( | 40 | ( | ( |
( | ( | ( | ||||
Ejskjaer N., [ | Diabetic patients with gastroparesis (5M, 5F) | Randomized, double-blind, placebo-controlled, single dose, cross-over | TZP-101 (Tranzyme Pharma) | 80, 160, 320 and 600 | Assessment of GE by scintigraphy | TZP-101 accelerated GE of both liquid and solid components of the meal; no significant effect on symptoms |
Though the effect of ghrelin on patients’ symptoms remained debatable [
Despite the optimistic results of acute ghrelin administration on gastric motility in patients with gastroparesis, many researchers showed their concern regarding the side effects of the chronic use of ghrelin. Being the ligand of growth hormone secretagogue receptor, ghrelin has been shown to induce growth hormone secretion [
In the small intestine, studies reported a prokinetic effect of ghrelin on jejunal contractility in rodents, involving direct activation of the GHS-R on the myenteric neurons and the cholinergic pathway. In 2004, Fukuda et al. reported that ghrelin enhanced EFS-induced contractions in longitudinal jejunal muscles [
In the colonic tissues, studies have shown that the prokinetic effects of ghrelin were species-specific. While it induced colonic contractions in fish or birds [
In vivo studies showed that ghrelin induced intestinal MMCs in fed rats involving the activation of the cholinergic pathway, and the NO, NPY or 5-hydroxytryptamine 4 (5-HT4) receptors. In 2003, Fujino et al. reported that ghrelin induced MMCs in fed and/or vagotomized rats; this effect was blocked by immunoneutralization of the NPY receptor [
Using a variety of techniques for the assessment of intestinal transit, researchers proved that ghrelin or its receptor agonist accelerated intestinal transit in rodents. In 2002, Trudel et al. showed that IV ghrelin 20
As for the colon, studies showed that to induce colon propulsion in conscious, not anesthetized, rats, central administration of ghrelin was needed. Although, ghrelin may exert an indirect effect on the colon merely by triggering upper GI MMCs, such possibility was not evidenced in the literature. The lack of direct effect of ghrelin on the colon may possibly be due to the lack of ghrelin immunoreactive cells and/or ghrelin receptors in the colon [
Tack et al. reported premature intestinal phase III contractions following IV ghrelin in healthy volunteers. These contractions were of gastric origin [
No studies were found on the effects of ghrelin on colon motility in healthy subjects.
No studies were found on the effects of ghrelin on small intestinal tissues obtained from diseased animal models.
However, ghrelin effects on colitis rodent model were reported. Recently, De Smet et al. showed that ghrelin decreased the colonic inhibitory responses in healthy mice and aggravated colitis in a dextran sodium sulfate (DDS)-induced colitis mice model [
Studies on the prokinetic effects of exogenous ghrelin on diseases intestines in vivo are summarized in Table
Prokinetic effects of exogenous ghrelin on intestinal motility in vivo in disease. CT: colon transit; GHRP-6: ghrelin secretagogue receptor 6 (non-synthetic ghrelin receptor agonist); h: hour; ICV: intracerebrovascular; iNOS: inducible nitric oxide synthase; IP: intraperitoneal; IT: intestinal transit; IV: intravenous; LPS: lipopolysaccharide; NO: nitric oxide; NPY: neuropeptide Y; Postop: postoperative; SC: subcutaneous; SD: Sprague Dawley.
Author | Species | Ghrelin type | Effective dose | Methods | Results | Mechanism of action |
---|---|---|---|---|---|---|
De Winter B., | Conscious healthy and LPS septic ileus model (Swiss OFI mice) | ( | ( | Assessment of IT by the transit of an Evans blue-marked meal | Ghrelin and GHRP-6, at either dose] had no prokinetic effect on IT in healthy or diseased mice. | |
( | ( | |||||
Sallam H., [ | Conscious scald-burned model (SD male rats) | Ghrelin (Tocris, USA) | 2 nmol/rat given IP 20 min before meal | ( | Ghrelin accelerated IT but had no effect on CT | Ghrelin’s effects on intestinal motility are mediated via the cholinergic pathway |
Venkova K., | Conscious postop ileus ± morphine-treated rat model (male SD rats) | Ghrelin receptor agonist TZP-101 (Tranzyme Pharma Canada) | 0.3–1 mg /Kg (1ml) IV given 1-2 min before meal | Assessment of IT by the transit of | TZP-101 accelerated IT dose-dependently in postop ileus rats ± morphine | |
Zheng Q., | Conscious diabetic mouse model (IP-alloxan-treated C57 mice) | GHRP-6 (Tocris, UK) | 200 | Assessment of IT and CT by the transit of a phenol red-marked meal | GHRP-6 accelerated IT, but not CT; an effect blocked by pretreatment with atropine | GHRP-6 effects on intestinal motility involve the cholinergic pathway |
Charoenthong-trakul S., | Conscious opiate-induced bowel disorder mice model (male lean C57BL/6 mice) | Ghrelin receptor agonist EX-1314 (Elixir Pharma-ceuticals) | 300 | Assessment of IT by percentage of distance of charcoal travelled/total length of small intestine | EX-1314 reversed opiate-induced delayed IT | |
Chen Y., | LPS endotoxemia mouse model (male ICR mice) | Rat ghrelin (Global Peptide Services, UDA) | 20 | ( | ( | Ghrelin’s effect on LPS-delayed IT transit is mediated via the down regulation of NO |
( | ( | |||||
( | ||||||
Fraser G., | Conscious postop ileus rat model (male SD rats) | ( | 0.3–1 mg /Kg (t.i.d) IV given at 15 min, 2 and 4 h after surgery | Assessment of CT by monitoring the time of appearance and weight of fecal pellet output marked with trypan blue dye | TZP-101 accelerated CT dose-dependently at 12 and 24 h after surgery | |
Venkova K., | Conscious postop ileus rat model (male SD rats) | ( | ( | Assessment of CT by monitoring the time of appearance and weight of fecal pellet output marked with trypan blue dye | Ipamorelin and GHRP-6 accelerated CT 48 h after surgery | |
( | ( |
As for the colon, studies showed that IV administration of ghrelin agonists (TZP-101, ipamorelin, or GHRP-6) accelerated the colon transit in a postoperative ileus rat model [
No studies were found regarding the effects of ghrelin in patients with intestinal motility disorders.
In conscious animals, exogenous ghrelin was reported to (1) induce gastric and intestinal MMCs in fed rodents, but not in the canine; (2) exert controversial effects on gastric myoelectrical activity in rodents; (3) induce antral contractions in dogs; (4) accelerate gastric emptying in healthy, diabetic, postoperative, or morphine, or septic, or burn-induced ileus, and cisplatin-induced dyspepsia animal models; (5) accelerate intestinal transit in healthy, diabetic, postoperative, or morphine, or septic, or burn induced ileus, and opiate-induced bowel disorder rodent models; (6) accelerate colonic transit in healthy rodents, when centrally administrated.
Clinically, exogenous ghrelin was reported to (1) induce gastric and intestinal MMCs in fasted healthy subjects; (2) increase fundic tone in both fasted and fed healthy subjects; (3) exert controversial effects on gastric emptying and have no effect on postprandial symptoms in healthy subjects; (4) accelerate gastric emptying in dyspeptic and/or gastroparetic patients and have debatable effects on postprandial symptoms in these patients. Luckily, the prokinetic effects of ghrelin in gastroparesis and/or dyspepsia patients were independent of vagal involvement.
The prokinetic effects of ghrelin on GI motility involve the exclusive activation of the GHS-R 1a receptor, not the motilin receptor, the enteric nervous system (specifically the myenteric plexus), excitatory neurons involving 5-HT4 and NO, capsaicin-sensitive afferent neurons, tachykininergic motor neurons, as well as intact vagal cholinergic neurons.
Oral ghrelin use is limited due to its instant inhibition by the gastric acidic milieu; however, other routes for its administration are possible. The emergence of IV ghrelin agonists (e.g., synthetic peptide GHRP-6; synthetic non-peptide capromorelin or ipamorelin) or ghrelin receptor agonists (e.g., GSK894281, EX-1314, EX-1315, RC-1139, TZP-101) are paving the way for possible uses in patient treatment. Oral TZP-102 soon followed and has been tested in healthy volunteers [
In conclusion, the prokinetic face of ghrelin enables it to serve as a strong tool in the clinical practice for the treatment of various GI dysmotility ailments. The prokinetic properties of ghrelin or its (receptor) agonists have the potential to serve in the treatment of diabetic, neurogenic or idiopathic gastroparesis and possibly, chemotherapy-associated dyspepsia, postoperative, septic or post-burn ileus, opiate-induced bowel dysfunction and chronic idiopathic constipation. Further research is necessary to close the gap in knowledge about the effect of ghrelin on the human intestines in health and disease.