Regulation Of Intestinal Motility Research Articles

Progress of Research on the Function of Enteric Glial Cells in the Gastrointestinal Tract

EGCs can affect the axonal maintenance of enteric neurons, enteric neuronal survival and genesis, and the regulation of intestinal motility; affect the integrity and permeability of the intestinal mucosal barrier; respond to intestinal inflammation; and influence the function of intestinal neuroimmunological regulation

Does ghrelin regulate intestinal motility in rabbits? An in vitro study using isolated duodenal strips

Rabbit duodenum has been used for examining the ability of motilin to cause muscle contraction in vitro. A motilin-related peptide, ghrelin, is known to be involved in the regulation of gastrointestinal (GI) motility in various animals, but its ability to cause rabbit GI contraction have not been well examined. The aim of this study is to clarify the action of rat ghrelin and its interaction with motilin in the rabbit duodenum. The mRNA expression of ghrelin and motilin receptors was also examined using RT-PCR. Rat ghrelin (10−9–10−6 M) did not change the contractile activity of the duodenum measured by the mean muscle tonus and area under the curve of contraction waves. In agreement with this result, the distribution of ghrelin receptor mRNA in the rabbit GI tract varied depending on the GI region from which the samples were taken; the expression level in the duodenum was negligible, but that in the esophagus or stomach was significant. On the other hand, motilin (10−10–10−6 M) caused a concentration-dependent contraction by means of increased mean muscle tonus, and consistently, motilin receptor mRNA was expressed heterogeneously depending on the GI region (esophagus = stomach = colon = rectum < duodenum = jejunum = ileum < cecum). Expression level of motilin receptor was comparable to that of ghrelin receptor in the esophagus and stomach. Pretreatment with ghrelin (10−6 M) prior to motilin did not affect the contractile activity of motilin in the duodenum. In conclusion, ghrelin does not affect muscle contractility or motilin-induced contraction in the rabbit duodenum, which is due to the lack of ghrelin receptors. The present in vitro results suggest that ghrelin might not be a regulator of intestinal motility in rabbits.

Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain

Enteric glial cells are emerging as critical players in the regulation of intestinal motility, secretion, epithelial barrier function, and gut homeostasis in health and disease. Enteric glia react to intestinal inflammation by converting to a ‘reactive glial phenotype’ and enteric gliosis, contributing to neuroinflammation, enteric neuropathy, bowel motor dysfunction and dysmotility, diarrhea or constipation, ‘leaky gut’, and visceral pain. The focus of the minireview is on the impact of inflammation on enteric glia reactivity in response to diverse insults such as intestinal surgery, ischemia, infections (C. difficile infection, HIV-Tat-induced diarrhea, endotoxemia and paralytic ileus), GI diseases (inflammatory bowel diseases, diverticular disease, necrotizing enterocolitis, colorectal cancer) and functional GI disorders (postoperative ileus, chronic intestinal pseudo-obstruction, constipation, irritable bowel syndrome). Significant progress has been made in recent years on molecular pathogenic mechanisms of glial reactivity and enteric gliosis, resulting in enteric neuropathy, disruption of motility, diarrhea, visceral hypersensitivity and abdominal pain. There is a growing number of glial molecular targets with therapeutic implications that includes receptors for interleukin-1 (IL-1R), purines (P2X2R, A2BR), PPARα, lysophosphatidic acid (LPAR1), Toll-like receptor 4 (TLR4R), estrogen-β receptor (ERβ) adrenergic α-2 (α-2R) and endothelin B (ETBR), connexin-43 / Colony-stimulating factor 1 signaling (Cx43/CSF1) and the S100β/RAGE signaling pathway. These exciting new developments are the subject of the minireview. Some of the findings in pre-clinical models may be translatable to humans, raising the possibility of designing future clinical trials to test therapeutic application(s). Overall, research on enteric glia has resulted in significant advances in our understanding of GI pathophysiology.

Brain-derived neurotrophic factor - a key player in the gastrointestinal system.

Brain-derived neurotrophic factor (BDNF) is highly expressed throughout the gastrointestinal (GI) tract and plays a critical role in the regulation of intestinal motility, secretion, sensation, immunity, and mucosal integrity. Dysregulation of BDNF signalling has been implicated in the pathophysiology of various GI disorders including inflammatory bowel disease, irritable bowel syndrome, functional dyspepsia, and diabetic gastroenteropathy. This review provides a comprehensive overview of BDNF localization, synthesis, receptors, and signalling mechanisms in the gut. In addition, current evidence on the diverse physiologic and pathophysiologic roles of BDNF in the control of intestinal peristalsis, mucosal transport processes, visceral sensation, neuroimmune interactions, gastrointestinal mucosal healing, and enteric nervous system homeostasis are discussed. Finally, the therapeutic potential of targeting BDNF for the treatment of functional GI diseases is explored. Advancing knowledge of BDNF biology and mechanisms of action may lead to new therapies based on harnessing the gut trophic effects of this neurotrophin.

Proteolipid protein 1 is involved in the regulation of intestinal motility and barrier function in the mouse.

Proteolipid protein 1 (Plp1) is highly expressed in enteric glia, labeling cells throughout the mucosa, muscularis, and the extrinsic innervation. Plp1 is a major constituent of myelin in the central and peripheral nervous systems, but the absence of myelin in the enteric nervous system (ENS) suggests another role for Plp1 in the gut. Although the functions of enteric glia are still being established, there is strong evidence that they regulate intestinal motility and permeability. To interrogate the role of Plp1 in enteric glia, we investigated gut motility, secretomotor function and permeability, and evaluated the ENS in mice lacking Plp1. We studied two time points: ∼3 mo (young) and >1 yr (old). Old Plp1 null mice exhibited increased fecal output, decreased fecal water content, faster whole gut transit times, reduced intestinal permeability, and faster colonic migrating motor complexes. Interestingly, in both young and old mice, the ENS exhibited normal glial and neuronal numbers as well as glial arborization density in the absence of Plp1. As Plp1-associated functions involve mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mapk/Erk1/2) signaling and Mapk/Erk1/2 are reported to have a regulatory role in intestinal motility, we measured protein expression of Erk1/2 and its active form in the small intestine. Old Plp1 null mice had reduced levels of phosphorylated-Erk1/2. Although Plp1 is not required for the normal appearance of enteric glial cells, it has a regulatory role in intestinal motility and barrier function. Our results suggest that functional changes mediated by Plp1-expressing enteric glia may involve Erk1/2 activation.NEW & NOTEWORTHY Here, we describe that Plp1 regulates gut motility and barrier function. The functional effects of Plp1 eradication are only seen in old mice, not young. The effects of Plp1 appear to be mediated through the Erk1/2 pathway.

The effect of Raphanus sativus L. seeds on regulation of intestinal motility in rats consuming a high-calorie diet

PurposeThe purpose of this study was to explore the effects of a short-term high-calorie diet and the regulation mechanism of Raphanus sativus L. seeds (RSL seeds) on the intestinal motility of young rats. MethodsWe fed 20 Specific Pathogen Free (SPF) 4-week-old male Sprague-Dawley (SD) rats special high-calorie diet for 3 days and then randomized them to a high-calorie diet group (HCG, 10 rats) and an RSL seeds treatment group (TG, 10 rats). Ten rats of the same age served as the control group (CG). HCG and TG rats continued to be fed high-calorie feed. All of the rats were weighed every 2 days. After 3 days of treatment, the effects of RSL seeds on the regulation of intestinal motility in rats consuming a high-calorie diet were examined. ResultsAfter 3 days of consuming a high-calorie diet, body weight was significantly lower in the HCG group than in the control group, and body weight of the HCG group increased slowly with time. Serum substance P (SP) and ghrelin levels were significantly lower, while the nitric oxide (NO) level was significantly higher. There were no differences in hematoxylin-eosin (HE) staining of colon sections between the groups. The expression levels of Cx43 and BDNF protein and mRNA in colon tissue were significantly lower in the HCG group. There were no significant differences in body weight between the CG and TG groups. Serum SP and ghrelin indexes in TG group were higher than those in the HCG group, and the NO index was significantly decreased. The expression levels of Cx43 and BDNF proteins and mRNA in the colon tissue were also significantly greater. ConclusionConsumption of a short-term high-calorie diet may result in intestinal motility dysfunction and reduced intestinal motility. RSL seeds may improve the intestinal motility by regulating the secretion of gastrointestinal motility hormones and the expression of intestinal motility-related proteins, such as Cx43 and BDNF.

Immunohistochemical study of morphology and distribution of CD163+ve macrophages in the normal adult equine gastrointestinal tract

Intestinal macrophages are the largest group of mononuclear phagocytes in the body and play a role in intestinal innate immunity, neuroimmune interactions and maintaining intestinal homeostasis. Conversely, they also are implicated in numerous pathologies of the gastrointestinal tract, such as postoperative ileus and inflammatory bowel disease. As a result, macrophages could be potential therapeutic targets. To date, there are limited studies on the morphology and distribution of macrophages in the equine gastrointestinal tract (GIT). The aim of this study was to identify the location and abundance of resident macrophages in the equine GIT using CD163 as an immunohistochemical marker. Tissue samples were obtained post-mortem from 14 sites along the gastrointestinal tracts of 10 horses free from gastrointestinal disease; sample sites extended from the stomach to the small colon. CD163+ve cells were present in all regions of the equine GIT from stomach to small colon. CD163+ve cells were also identified in all tissue layers of the intestinal wall, namely, mucosa, submucosa, muscularis externa (ME), myenteric plexus and serosa. Consistent with a proposed function in regulation of intestinal motility, CD163+ve cells were regularly distributed within the ME, with accumulations closely associated with the myenteric plexus and effector cells such as neurons and the interstitial cells of Cajal (ICC).

Chinese Herbal Medicine (MaZiRenWan) Improves Bowel Movement in Functional Constipation Through Down-Regulating Oleamide.

In a prospective, randomized, three-arms, controlled clinical study, Chinese Herbal Medicine MaZiRenWan (MZRW, also known as Hemp Seed Pill) demonstrates comparable efficacy with Senna for functional constipation (FC) during an 8-week treatment period. Both MZRW and Senna are better than a placebo; relative to Senna and a placebo, MZRW displayed a more sustained effect during the 8-week follow-up period. The characteristic pharmacological mechanism responsible for this observation is still unclear. To explore this, we collected pre- and post-treatment serum samples of 85 FC patients from MZRW/Senna/placebo treatment groups for pharmacometabolomic analysis. An ultrahigh-performance liquid chromatography-mass spectrometer (UPLC-MS) was used for metabolic profiling and quantification. In vivo studies were conducted in constipated C57BL/6J mice to verify the effects and corresponding mechanism(s) of the action of MZRW. Pearson correlation analysis, paired t-test, one-way ANOVA analysis, χ2 test, and Student t-test were used to interpret the clinical and preclinical data. Changes in levels of circulating oleamide and its derivatives negatively correlate with improvement in complete spontaneous bowel movement (CSBM) in the MZRW group (Pearson r = -0.59, p = 0.00057). The same did not hold true for either Senna or placebo groups. Oleamide is a known regulator of intestinal motility. MZRW treatment resulted in reduced levels of circulating oleamide in FC patients. Experimental verification showed that MZRW attenuated oleamide-induced slow intestinal motility in mice. MZRW decreased oleamide levels in serum, ileum, and colon in normal mice, but increased expression of colonic fatty acid amide hydrolase (FAAH). In conclusion, MZRW improved bowel movement in FC by down-regulating oleamide, possibly by enhancing FAAH-mediated degradation. Our findings suggest a novel therapeutic strategy for FC.

Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice.

Cannabinoid-1 (CB1) receptors are broadly distributed in the central and peripheral nervous systems; among others, they are located in the enteric nervous system. In the gastrointestinal (GI) system, they participate in regulation of intestinal motility or ion transport. The aim of our study was to assess the effect of 1,2,3-triazole derivatives (compound 1: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(2-fluorobenzyl)acetamide, compound 2: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(4-fluorobenzyl)acetamide, compound 3: N-benzyl-2-[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]acetamide]), characterized in vitro as CB1 antagonists with high CB1 over CB2 selectivity, in the mouse GI tract. The action of compounds 1-3 was assessed in vitro (electrical field stimulated smooth muscle contractility of the mouse ileum and colon) and in vivo (whole GI transit time). Compound 1 decreased ileal (10-6M) and colonic (10-7-10-6M) smooth muscles contractility. Moreover, it prolonged whole GI transit. Compound 2 (10-10-10-8M) slightly increased the amplitude of muscle contractions in the ileum, but at a higher concentration (10-6M), the amplitude was decreased. Compound 2 reduced colonic contractility but accelerated GI transit. Compound 3 decreased the amplitude of intestinal muscle contractions in the ileum (10-6M) and colon (10-10-10-6M). Moreover, it increased the GI transit time in vivo. Triazole derivatives possess easily modifiable structure and interesting pharmacological action in the GI tract; further, alterations may enhance their efficacy at CB receptors and provide low side effect profile in clinical conditions.

Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide.

Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability, were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4,000 pmol·kg(-1)·min(-1) had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (P < 0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (P < 0.05-0.01), and increased permeability (P < 0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ∼0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips precontracted by bethanechol, NPS 1-1,000 nmol/l induced NO-dependent muscle relaxation (P < 0.05) that was sensitive also to tetrodotoxin (P < 0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

Two cholecystokinin receptor subtypes are identified in goldfish, being the CCKAR involved in the regulation of intestinal motility

Cholecystokinin (CCK) plays a key role in the digestive physiology of vertebrates. However, very little is known about the role of CCK on intestinal functions in fish. The present study identifies two CCK receptor subtypes in a stomachless teleost, the goldfish (Carassius auratus), and investigates by using an in vitro system their involvement mediating the effects of the sulfated octapeptide of CCK (CCK-8S) on the motility of isolated proximal intestine. Partial-length mRNAs encoding two CCK receptor isoforms (CCKAR and CCKBR.I) were sequenced and the structural analysis showed that both receptors belong to the G-protein coupled receptor superfamily. Both goldfish CCK receptor sequences were more closely related to zebrafish sequences, sharing the lowest similarities with cavefish and tilapia. The highest expression of goldfish CCKAR was observed along the whole intestine whereas the CCKBR gen was predominantly expressed in the hypothalamus, vagal lobe and posterior intestine. Application of CCK-8S to the organ bath evoked a concentration-dependent contractile response in intestine strips. The contractions were not blocked by either tetrodotoxin or atropine, suggesting that CCK-8S acts on the gut smooth muscle directly. Preincubations of intestine strips with devazepide and L365,260 (CCKAR and CCKBR receptor selective antagonists) showed that the CCK-8S-induced contraction could be partially mediated by the CCKAR receptor subtype, which is also the most abundant CCK receptor found in gastrointestinal tissues. In conclusion, two CCK receptors with a differential distribution pattern has been identified in goldfish, and the CCKAR subtype is mainly involved in the regulation of intestinal motility by the CCK-8S.

546 Oxytocinergic Regulation of Intestinal Motility, Inflammation, Macromolecular Permeability, and Mucosal Homeostasis

546 Oxytocinergic Regulation of Intestinal Motility, Inflammation, Macromolecular Permeability, and Mucosal Homeostasis

The G Protein‐coupled bile acid receptor, TGR5, is expressed on colonic epithelial cells and regulates ion transport

TGR5 has been implicated in the regulation of intestinal motility and has also been identified as a regulator of Cl− secretion across gallbladder epithelium. However, there is a paucity of information regarding the role of TGR5 in colonic epithelial cells (CECs). Here we sought to investigate a potential role for TGR5 in regulation of CEC ion transport.6α‐ethyl‐23(S)‐methylcholic acid (INT‐777) was used to activate TGR5. Ion transport was measured by short‐circuit current (Isc) across muscle‐stripped segments of rat colon. mRNA expression was measured by RT‐PCR. TGR5 localisation was measured by confocal microscopy.TGR5 mRNA and protein were highly expressed in CECs. TGR5 was localised bilaterally in rat colonic crypts. INT‐777 addition to rat colonic mucosa caused a rapid and transient decrease in Isc. This decrease was dependent on the presence of Cl− in the bathing solution. INT‐777 was effective from the basolateral side only. Furthermore, treatment with INT‐777 reduced subsequent Clsecretory responses to carbachol.These studies reveal a novel role for TGR5 in regulating colonic epithelial ion transport. TGR5 activation rapidly reduces basal Isc and inhibits subsequent Cl− secretory responses. Our data suggest that TGR5 may provide a new target for development of drugs to treat intestinal transport disorders.INT‐777 was supplied by Intercept Pharmaceuticals.Funded by Science Foundation Ireland.

Kynurenine and serotonin pathways: A review

This paper seeks to elucidate the two-key pathways involving tryptophan matabolism, namely, kynurenine and serotonin pathways. In the kynurenine pathway (KP), the discussion considers the steps of the oxidative degradation of tryptophan to yield nicotinate mononucleotide, a precursors for the biosynthesis of nicotinate nucleotides ( NAD+ and NADP+), while serotonin pathway (SP) considers the biosynthesis of serotonin from tryptophan. Two different isoforms of tryptophan hydroxylase (TPH) are involved in SP: Tryptophan hydroxylase -1 (TPH1) catalysis SP in enterochromaffin cells of the gut, while Tryptophan hydroxylase-2 (TPH2) catalysis SP in the nerve cells of the central nervous system, the brain. Emphasis is given to the relevance of pyridoxalphosphate (PLP) in KP and also identified in the pathway of KP is the liberation of alanine as a biproduct, a basis for the gluconeogenecity of tryptophan. Serotonin, a major bioactive end-product of SP is a potent neurotransmitter, vasoconstrictor, regulation of intestinal motility and a player in cognitive function. Foods that give an increased ratio of tryptophan to phenylalanine and leucine such as nuts of walnut, plantains, bananas, dates, pineapples and tomatoes are good sources of serotonin. Research suggests a diet rich in carbohydrates and low protein is also a good source. Owning to the significance of some the major bioactive end-products, intermediates and byproducts of these pathways for the well-being and happiness of human beings, more research should be carried out therein not only to unravel some of the disorders they may be associated with but to also help in the development and production of; therapeutic drugs for psychiatric and sexual disorders, and intestinal antidote.Keywords: Nicotinate mononucleotide, serotonin, kynurenine, dietary source of serotonin.

Rafting for gallstones by slowing mass transit

Rafting for gallstones by slowing mass transit

A holistic view of adenosine in the control of intestinal neuromuscular functions: the enteric ‘purinome’ concept

Adenosine is involved in the modulation of enteric neuromuscular functions, operating a fine tuning of smooth muscle contractility, peristaltic reflex and transit. In this issue of the BJP, Zizzo et al. report novel findings on the expression of adenosine receptors in mouse duodenum, extending our knowledge of their involvement in the control of spontaneous and neurogenic intestinal motility. In this study, particular attention was paid to the differential activation of adenosine receptors, as a result of their interplay with regulatory systems, modulating the availability of endogenous adenosine in a compartmentalised manner. This evidence will contribute to the holistic evaluation of the role played by adenosine in the regulation of intestinal motility, in accordance with the novel concept of the enteric 'purinome'. This commentary discusses the role of the 'purinome' in the modulation of enteric neuromuscular activity, pointing out its involvement in the intestinal neuroplasticity associated with bowel dysmotility.

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT(3)R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT(3)R antagonists tropisetron and palonosetron on the development of NAFLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (-29%), liver inflammation (-56%), and liver cell necrosis (-59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-α mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.

Morphological alterations of the enteric nervous system in young male patients with rectal prolapse

The pathogenesis of rectal prolapse (RP) defined by a circumferential, full-thickness invagination of the rectal wall into the anal canal is controversial. RP is normally encountered in elderly women and attributed to several etiological factors (e.g., advanced age, pudendal nerve injury, laxity of supporting ligaments). RP affecting young male patients is unlikely to be explained by these factors and may be due to a rectal motility disorder. Therefore, the enteric nervous system (ENS) as key regulator of intestinal motility was evaluated by a systematic morphometric analysis. Full-thickness rectosigmoid specimens obtained from young male patients with symptomatic RP (n = 5) and male controls (n = 15) were processed for conventional histology and immunohistochemistry using anti-HuC/D as pan-neuronal marker. Enteric ganglia, nerve and glial cells were quantified separately in the myenteric (MP) and submucosal plexus (SMP). Compared to controls, patients with RP showed significantly (p < 0.05) increased mean ganglionic area both in MP and SMP, increased mean neuronal content of submucosal ganglia, and nearly threefold higher frequency of submucosal ganglia containing ≥7 neurons. The morphometric analysis reveals distinct quantitative alterations of the ENS in young male patients with RP mainly characterized by submucosal hyperganglionosis similar to histopathological features described in intestinal neuronal dysplasia. The data give evidence that RP in this unusual subgroup is associated with morphological changes of enteric ganglia which may contribute to the development of RP and complement established etiological concepts.

710 AZATHIOPRINE PRODUCES OXIDIZATION OF 53 KDA AND 67 KDA PROTEINS AND INDUCES MITOCHONDRIAL DEPENDENT APOPTOSIS IN GSH DEPLETED HEPG2 CELLS

Background and Aims: Results of human and animal studies have suggested that alterations in intestinal motility, small intestinal bacterial overgrowth and increased intestinal permeability are involved in the development of NAFLD. Serotonin and its receptor 5-HT3R are key factors in the regulation of intestinal motility and recently have also been suggested to be involved in regulating permeability. Therefore, the aim of the present study was to investigate the effect of the intestinal 5-HT3R antagonist tropisetron on the development of steatohepatitis in genetically obese ob/ob mice. Methods: Four week old ob/ob knockout and C57/Bl6 wild-type mice had ad libitum access to plain water or water containing tropisetron for 6 weeks. Markers of liver damage were assessed. In addition mRNA expression of TNFa and MyD88 were determined by real time RT-PCR and endotoxin levels in portal plasma were determined using a LAL test. Serotonin reuptake transporter (SERT) and occludin protein concentrations were determined by Western blot and the number of 5-HT-positive cells was measured by immunhistochemistry in the small intestine. Results: Treatment with tropisetron significantly inhibited the development of NASH in ob/ob mice, leading to a marked decrease in hepatic steatosis and inflammation. In addition, tropisetron treatment blocked hepatic MyD88 and TNFa expression in ob/ob mice down to a level of wild-type controls. In vehicle treated ob/ob mice portal endotoxin levels were significantly increased by ~10-fold in comparison to wildtype controls. In contrast, in tropisetron treated mice, endotoxin levels in portal plasma were even lower than in wild-type controls. Moreover, concentration of the tight junction protein occludin and of SERT in the duodenum of tropisetron treated ob/ob mice was markedly increased in comparison to all other groups. However, the number of 5-HT-positive cells in the duodenum was not affected by tropisetron treatment. Conclusion: Our data suggests that alterations in the intestinal serotonergic system and herein practically the 5-HT3R may be involved in the regulation of intestinal permeability and subsequently the development of NASH in obese ob/ob mice and that the 5-HT3R might be a new target for the therapy against NASH.

Role of acylethanolamides in the gastrointestinal tract with special reference to food intake and energy balance

Acylethanolamides (AEs) are a group of lipids occurring in both plants and animals. The best-studied AEs are the endocannabinoid anandamide (AEA), the anti-inflammatory compound palmitoylethanolamide (PEA), and the potent anorexigenic molecule oleoylethanolamide (OEA). AEs are biosynthesized in the gastrointestinal tract, and their levels may change in response to noxious stimuli, food deprivation or diet-induced obesity. The biological actions of AEs within the gut are not limited to the modulation of food intake and energy balance. For example, AEs exert potential beneficial effects in the regulation of intestinal motility, secretion, inflammation and cellular proliferation. Molecular targets of AEs, which have been identified in the gastrointestinal tract, include cannabinoid CB(1) and CB(2) receptors (activated by AEA), transient receptor potential vanilloid type 1 (TRPV1, activated by AEA and OEA), the nuclear receptor peroxisome proliferators-activated receptor-alpha (PPAR-alpha, activated by OEA and, to a less extent, by PEA), and the orphan G-coupled receptors GPR119 (activated by OEA) and GPR55 (activated by PEA and, with lower potency, by AEA and OEA). Modulation of AE levels in the gut may provide new pharmacological strategies not only for the treatment of feeding disorders but also for the prevention or cure of widespread intestinal diseases such as inflammatory bowel disease and colon cancer.