Regulation Of Gastrointestinal Function Research Articles

The Local Activation of Toll-like Receptor 7 (TLR7) Modulates Colonic Epithelial Barrier Function in Rats.

Toll-like receptors (TLRs)-mediated host-bacterial interactions participate in the microbial regulation of gastrointestinal functions, including the epithelial barrier function (EBF). We evaluated the effects of TLR7 stimulation on the colonic EBF in rats. TLR7 was stimulated with the selective agonist imiquimod (100/300 µg/rat, intracolonic), with or without the intracolonic administration of dimethyl sulfoxide (DMSO). Colonic EBF was assessed in vitro (electrophysiology and permeability to macromolecules, Ussing chamber) and in vivo (passage of macromolecules to blood and urine). Changes in the expression (RT-qPCR) and distribution (immunohistochemistry) of tight junction-related proteins were determined. Expression of proglucagon, precursor of the barrier-enhancer factor glucagon-like peptide 2 (GLP-2) was also assessed (RT-qPCR). Intracolonic imiquimod enhanced the EBF in vitro, reducing the epithelial conductance and the passage of macromolecules, thus indicating a pro-barrier effect of TLR7. However, the combination of TLR7 stimulation and DMSO had a detrimental effect on the EBF, which manifested as an increased passage of macromolecules. DMSO alone had no effect. The modulation of the EBF (imiquimod alone or with DMSO) was not associated with changes in gene expression or the epithelial distribution of the main tight junction-related proteins (occludin, tricellulin, claudin-2, claudin-3, junctional adhesion molecule 1 and Zonula occludens-1). No changes in the proglucagon expression were observed. These results show that TLR7 stimulation leads to the modulation of the colonic EBF, having beneficial or detrimental effects depending upon the state of the epithelium. The underlying mechanisms remain elusive, but seem independent of the modulation of the main tight junction-related proteins or the barrier-enhancer factor GLP-2.

Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.

The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.

Vascular and lymphatic regulation of gastrointestinal function and disease risk

The vascular and lymphatic systems in the gut regulate lipid transport while restricting transfer of commensal gut microbiota and directing immune cell trafficking. Increased permeability of the endothelial systems in the intestine associates with passage of antigens and microbiota from the gut into the bloodstream leading to tissue inflammation, the release of pro-inflammatory mediators and ultimately to abnormalities of systemic metabolism. Recent studies show that lipid metabolism maintains homeostasis and function of intestinal blood and lymphatic endothelial cells, BECs and LECs, respectively. This review highlights recent progress in this area, and information related to the contribution of the lipid transporter CD36, abundant in BECs and LECs, to gastrointestinal barrier integrity, inflammation, and to gut regulation of whole body metabolism. The potential role of endothelial lipid delivery in epithelial tissue renewal after injury and consequently in the risk of gastric and intestinal diseases is also discussed.

Eosinophils in the Gastrointestinal Tract: Key Contributors to Neuro-Immune Crosstalk and Potential Implications in Disorders of Brain-Gut Interaction.

Eosinophils are innate immune granulocytes actively involved in defensive responses and in local and systemic inflammatory processes. Beyond these effector roles, eosinophils are fundamental to maintaining homeostasis in the tissues they reside. Gastrointestinal eosinophils modulate barrier function and mucosal immunity and promote tissue development through their direct communication with almost every cellular component. This is possible thanks to the variety of receptors they express and the bioactive molecules they store and release, including cytotoxic proteins, cytokines, growth factors, and neuropeptides and neurotrophines. A growing body of evidence points to the eosinophil as a key neuro-immune player in the regulation of gastrointestinal function, with potential implications in pathophysiological processes. Eosinophil–neuron interactions are facilitated by chemotaxis and adhesion molecules, and the mediators released may have excitatory or inhibitory effects on each cell type, with physiological consequences dependent on the type of innervation involved. Of special interest are the disorders of the brain–gut interaction (DBGIs), mainly functional dyspepsia (FD) and irritable bowel syndrome (IBS), in which mucosal eosinophilia and eosinophil activation have been identified. In this review, we summarize the main roles of gastrointestinal eosinophils in supporting gut homeostasis and the evidence available on eosinophil–neuron interactions to bring new insights that support the fundamental role of this neuro-immune crosstalk in maintaining gut health and contributing to the pathophysiology of DBGIs.

A Review of the Ethnopharmacology, Phytochemistry, Pharmacology, Application, Quality Control, Processing, Toxicology, and Pharmacokinetics of the Dried Rhizome of Atractylodes macrocephala.

The product investigated herein is the dried rhizome of Atractylodes macrocephala Koidz. [Asteraceae] (Baizhu), which is also known as Dongbaizhu, Wuzhu, Yuzhu, Zhezhu, and Zhongzhu, among others. It invigorates the spleen, replenishes qi, and removes dampness, diuresis, and hidroschesis, and impacts fetal safety. It is often used for the treatment of diseases such as spleen function deficiency, abdominal distension, diarrhea, sputum, vertigo, edema, fever, and sweating and also aids cessation of minimal vaginal bleeding during pregnancy. In this study, research pertaining to the ethnopharmacology, application, phytochemistry, analytical methods, quality control, processing, pharmacology, toxicology, and pharmacokinetics of Baizhu has been reviewed. Relevant information and data reported for Baizhu were collected from CNKI, VIP, PubMed, Web of Science, scientific databases, Chinese Medicinal Material Encyclopedia, Chinese herbal medicine classics, Chinese medicine dictionary, doctoral and master’s theses, and so on. Baizhu demonstrates diuretic, antidiuretic, anti-inflammatory effects and antitumor function and aids regulation of gastrointestinal function, hypoglycemic effect, analgesic action, protection on the liver ischemia-reperfusion injury (IRI) in rats, inhibition of aromatase, treatment of bone disease, strengthening myocardial contraction ability, detoxification and cholagogic effect, fall hematic fat action, such as the treatment of acute renal injury, and so on. It also can be an anticoagulant, improve the nervous system disease, affect the immune system, and regulate uterine smooth muscle, antioxidation, antiaging, and antibacterial effect. Sesquiterpenoids, triterpenoids, polyacetylenes, phenylpropanoids, coumarins, flavonoids, flavonoid glycosides, steroids, benzoquinones, polysaccharides, and other compounds were isolated from Baizhu. Among them, sesquiterpenoids, polysaccharides, and polyacetylenes are the main components of Baizhu. Baizhu exhibits a wide range of pharmacological effects and constitutes a considerable proportion of the composition of many proprietary crude drugs. It mainly affects the endocrine, nervous, and urinary systems. The presented information suggests that we should focus on the development of new drugs related to Baizhu, including specific components, to achieve a greater therapeutic potential that can be considered to further explore the information related to Baizhu.

Effect of NSAIDs Supplementation on the PACAP-, SP- and GAL-Immunoreactive Neurons in the Porcine Jejunum.

Side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment are a serious limitation of their use in anti-inflammatory therapy. The negative effects of taking NSAIDs include abdominal pain, indigestion nausea as well as serious complications such as bleeding and perforation. The enteric nervous system is involved in regulation of gastrointestinal functions through the release of neurotransmitters. The present study was designed to determine, for the first time, the changes in pituitary adenylate cyclase-activating polypeptide (PACAP), substance P (SP) and galanin (GAL) expression in porcine jejunum after long-term treatment with aspirin, indomethacin and naproxen. The study was performed on 16 immature pigs. The animals were randomly divided into four experimental groups: control, aspirin, indomethacin and naproxen. Control animals were given empty gelatin capsules, while animals in the test groups received selected NSAIDs for 28 days. Next, animals from each group were euthanized. Frozen sections were prepared from collected jejunum and subjected to double immunofluorescence staining. NSAIDs supplementation caused a significant increase in the population of PACAP-, SP- and GAL-containing enteric neurons in the porcine jejunum. Our results suggest the participation of the selected neurotransmitters in regulatory processes of the gastrointestinal function and may indicate the direct toxic effect of NSAIDs on the ENS neurons.

The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons

Highly organized circuits of enteric neurons are required for the regulation of gastrointestinal functions, such as peristaltism or migrating motor complex. However, the factors and molecular mechanisms that regulate the connectivity of enteric neurons and their assembly into functional neuronal networks are largely unknown. A better understanding of the mechanisms by which neurotrophic factors regulate this enteric neuron circuitry is paramount to understanding enteric nervous system (ENS) physiology. EphB2, a receptor tyrosine kinase, is essential for neuronal connectivity and plasticity in the brain, but so far its presence and function in the ENS remain largely unexplored. Here we report that EphB2 is expressed preferentially by enteric neurons relative to glial cells throughout the gut in rats. We show that in primary enteric neurons, activation of EphB2 by its natural ligand ephrinB2 engages ERK signaling pathways. Long-term activation with ephrinB2 decreases EphB2 expression and reduces molecular and functional connectivity in enteric neurons without affecting neuronal density, ganglionic fiber bundles, or overall neuronal morphology. This is highlighted by a loss of neuronal plasticity markers such as synapsin I, PSD95, and synaptophysin, and a decrease of spontaneous miniature synaptic currents. Together, these data identify a critical role for EphB2 in the ENS and reveal a unique EphB2-mediated molecular program of synapse regulation in enteric neurons.

Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions.

The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.

Calcitonin gene‑related peptide‑mediated pharmacological effects in cardiovascular and gastrointestinal diseases (Review).

Calcitonin gene‑related peptide (CGRP) is the predominant neurotransmitter located in sensory nerves. This peptide is extensively distributed in central and peripheral tissues. CGRP causes relaxation of cardiovascular smooth muscle cells and confers protection against ischaemic myocardium and cardiac remodeling. The pharmacological effects of nitroglycerine and rutaecarpine have been demonstrated to be associated with an increase in the synthesis and release of CGRP. In the gastrointestinal tissues, CGRP participates in the regulation of gastrointestinal function, and exerts protective effects on gastric mucosa. Rutaecarpine, capsaicin and its derivatives, such as evodiamine, decrease gastric mucosal damage induced by several factors, including increased synthesis and release of CGRP. Taken together, this review focuses on the pharmacological effects of several CGRP related canonical drugs and suggests that synthesis and secretion of CGRP exhibit significant therapeutic effects in the occurrence and development of cardiovascular and gastrointestinal diseases.

Complex network analysis of combination medication of patients with kidney malignant tumor based in real world

Kidney malignant tumor is a type of primary renal cell carcinoma, and mainly refers to renal cancer. The incidence of kidney cancer and the number of hospital cases in China have been increasing. Based on the clinical medicine information of patients in the hospital information system(HIS) database of 37 hospitals in China, the combined medication of patients with kidney malignant tumor were analyzed by Tabu search algorithm, so as to analyze the combined medication of patients with kidney malignant tumor in real world. A total of 7 095 patients with kidney malignant tumor were included, the ratio of males to females was 2.11∶1, and the ratio of male patients increased gradually with age. About 3 933 patients(55.43%) showed a superior effect among those patients. The common therapies of patients with kidney malignant tumor were anti-tumor therapies and symptomatic therapies, including anti-infection, regulation of electrolyte balance, sedation and analgesia, analgesic, regulation of gastrointestinal function. The whole population of patients with kidney malignant tumor were mostly treated with anti-tumor drugs combined with more symptomatic therapies, while the anti-tumor therapies of the superiority population of patients were less combined with other drugs, with less combined medication. The result may be related to the stage of tumor or individual response to the therapeutic regimen. No matter for the whole population or for the superiority population of patients with kidney malignant tumor, the therapies was mainly Western medicines. Based on the pathogenesis of deficiency in origin and excess in superficiality with kidney malignant tumor, Chinese subgroups with formula for clearing heat and removing toxicity, formula for vigorate Qi and replenish the blood, formula for regulate Qi and invigorate the blood, laxative and hemostatic were more commonly used. In the future, further studies shall be conducted for combined therapies for patients of different stages, so as to play the advantages of multi-target, overall regulation, toxicity reduction and efficacy enhancement of traditional Chinese medicine, improve the life quality of patients with kidney malignant tumor, prolong their life time, and improve the survival rate of patients.

Gastrointestinal taste receptors: could tastants become drugs?

Numerous studies have pointed to profound nongustatory roles of tastants and the corresponding taste receptors expressed in the alimentary canal in the modulation of digestive and metabolic functions. Already in early reports, the intriguing possibility to use tastants as drug-like effectors for the treatment of metabolic diseases was raised. With this review, focusing on the most recent literature, we intend to question how close we meanwhile came to the initial promise - the use of tastants as medicines. Although the enormous complexity and experimental variability of studies investigating the effects of tastants on physiological functions still has not revealed a common fundament from which subsequent therapeutic measures could be designed, more and more evidence is mounting on an involvement of taste receptors and taste signaling molecules in the maintenance and fine regulation of gastrointestinal functions and immunity. Although the initial goal - using tastants to treat metabolic disorders - has, by far, not been reached, numerous promising findings suggest that dietary interventions could be devised to support conventional therapies in the future.

Effect of Artemisia rupestris L. Extract on Gastrointestinal Hormones and Brain-Gut Peptides in Functional Dyspepsia Rats.

Artemisia rupestris L. is the perennial herb of rupestris belonging to Artemisia (Compositae), which is wildly distributed in Xinjiang (China), middle Asia, and Europe. It is known to have anti-inflammatory, hepatoprotective, immune function regulation, and gastrointestinal function regulation effects. AR is used to treat digestive diseases, but the effects of AR on antifunctional dyspepsia (FD) activity have not yet been reported. In this study, we aimed to investigate the therapeutic effects of Artemisia rupestris L. extract (ARE) on gastrointestinal hormones and brain-gut peptide in functional dyspepsia (FD) rats. Sixty Sprague-Dawley rats were randomly divided into 6 groups. An FD rat model was established by irregular tail clamp stimulation for 14 days except the blank group. After FD rat models, the blank group and model group were given menstruum, and the medicated rats were given corresponding medicine for 14 days. The general observations, bodyweight, and food intake were observed, and the content of serum gastrin (GAS), plasma motilin (MTL), plasma vasoactive intestinal peptide (VIP), and plasma somatostatin (SS) by the enzyme-linked immunosorbent assay was observed. The content of plasma VIP and plasma SS in the ARE group was significantly lower than in the model group, and the content of serum GAS and plasma MTL was increased in the ARE group; the GAS expression of antrum and hypothalamus was increased in the ARE group, and SS expression of antrum and hypothalamus was decreased in the ARE group by immunohistochemical detection; the results of semiquantitative reverse transcription polymerase chain reaction (RT-PCR) indicate that ARE inhibits the mRNA expression of VIP. Our results suggest that ARE can recover gastrointestinal hormone levels and regulation of the peripheral and central nervous system and alter gut peptide levels, which confirm the therapeutic effect of ARE on functional dyspepsia.

Protective factors in mature human milk: a look into the proteome and peptidome of adolescent mothers’ breast milk

The characterisation of proteome and peptidome of adolescent mothers' breast milk brings important information to both mother's and infant's health; however, it has not been investigated. Bioactive peptides derived from milk proteins have numerous functions. The bioactivity of breast milk peptides includes anti-inflammatory and antimicrobial activities and regulation of gastrointestinal function. We aimed to characterise the proteome and peptidome of mature breast milk of adolescent mothers and investigate whether it is affected by lactational period. We used a combination of electrophoretic and nano-scale LC-quadrupole time-of-flight MS/MS (nLC-Q-TOF-MS/MS) techniques and bioinformatics to explore the proteome of human skimmed milk expressed by lactating adolescents in two groups according to postpartum period (up to 3 and over 5 weeks postpartum). This is the first study that analysed the proteome of adolescent mothers' breast milk produced during two periods of lactation using 1D-electrophoresis combined with nLC-Q-TOF-MS/MS analysis. Our results showed that the protein composition of adolescent milk varies independently of lactation stage and showed high inter-individual variation. A total of 424 proteins were identified in skimmed milk, of which 137 proteins were common to both groups. Most of the peptides found in adolescents' breast milk were not derived from major proteins in milk. Association maps showed several interactions between groups of peptides that pointed to the relevance of breast milk peptides to neonatal defensive system.

Clinical benefit of oral lactulose for postoperative care of pateints with complicated appendicitis using propensity score matching analysis

ObjectiveThe aim of this study was to investigate the effect of oral lactulose for pediatric patients with complicated appendicitis, who underwent appendectomy.BackgroundOral lactulose was widely used for gastrointestinal function regulation. However, clinical benefit for oral lactulose regarding its effects on recent postoperative gastrointestinal (GI) recovery and long term adhesive small bowel obstruction (ASBO) incidence, especially in the postoperative pediatric population has not yet defined.MethodsA total of 525 pediatric patients with complicated appendicitis underwent appendectomy were retrospectively reviewed. Among them, 317 cases were subjected to oral lactulose management and 208 patients without, served as control. Propensity score 1:1 matching was carried out to adjust for any potential baseline variables. In 189 paired patients, clinical outcomes, including gastrointestinal recovery variables, incidence of ABSO, as well as adverse events, were compared according to the oral lactulose administration or not.ResultsPatients who received oral lactulose administration achieved early gastrointestinal function recovery, including, first bowel movement (Risk ratio [RR], 1.34; 95% confidence interval [CI] 1.02–2.63, p = 0.005) and first solid feeding (RR, 1.26; 95% CI, 1.01–1.92, p = 0.012). A lower occurrence of ASBO (OR, 0.47; 95% CI, 0.25–0.87; p = 0.011) and lower constipation (Odds ratio [OR], 0.25; 95% CI, 0.13–0.46; p < 0.001), were noted in patients received oral lactulose than in patients without. Furthermore, significantly fewer patients required readmission (OR, 0.56; 95% CI, 0.32–0.99; p = 0.031) and reoperation (OR, 0.29; 95% CI, 0.09–0.92; p = 0.022) in the patients who received oral lactulose administration.ConclusionsBeneficial effects of oral lactulose administration in pediatric patients undergone appendectomy were indicated, such as accelerating gastrointestinal function recovery, reducing the postoperative incidence of ASBO and constipation, so reduced readmission and reoperation.

Exercise induces tissue hypoxia and HIF-1α redistribution in the small intestine

BackgroundExercise induces blood flow redistribution among tissues, leading to splanchnic hypoperfusion. Intestinal epithelial cells are positioned between the anaerobic lumen and the highly metabolic lamina propria with an oxygen gradient. Hypoxia-inducible factor (HIF)-1α is pivotal in the transcriptional response to the oxygen flux. MethodsIn this study, the pimonidazole hydrochloride staining was applied to observe the tissue hypoxia in different organs, which might be affected by the blood flow redistribution. The HIF-1α luciferase reporter ROSA26 oxygen-dependent degradation domain (ODD)-Luc/+ mouse model (ODD domain-Luc; female, n = 3–6/group) was used to detect the HIF-1α expression in the intestine. We used 3 swimming models: moderate exercise for 30 min, heavy-intensity exercise bearing 5% bodyweight for 1.5 h, and long-time exercise for 3 h. ResultsWe found that 1 session of swimming at different intensities could induce tissue hypoxia redistribution in the small intestine, colon, liver and kidney, but not in the spleen, heart, and skeletal muscle. Our data showed that exercise exacerbated the extent of physiological hypoxia in the small intestine. Next, using ODD-Luc mice, we found that moderate exercise increased the in vivo HIF-1α level in the small intestine. The post-exercise HIF-1α level was gradually decreased in a time-dependent manner. Interestingly, the redistribution of tissue hypoxia and the increase of HIF-1α expression were not related to the exercise intensity and duration. ConclusionThis study provided evidence that the small intestine is the primary target organ for exercise-induced tissue hypoxia and HIF-1α redistribution, suggesting that HIF-1α may be a potential target for the regulation of gastrointestinal functions after exercise.

Gastroprokinetic agent, mosapride inhibits 5-HT3 receptor currents in NCB-20 cells.

Mosapride accelerates gastric emptying by acting on 5-hydroxytryptamine type 4 (5-HT4) receptor and is frequently used in the treatment of gastrointestinal (GI) disorders requiring gastroprokinetic efficacy. We tested the effect of mosapride on 5-hydroxytryptamine type 3 (5-HT3) receptor currents because the 5-HT3 receptors are also known to be expressed in the GI system and have an important role in the regulation of GI functions. Using the whole-cell voltage clamp method, we compared the currents of the 5-HT3 receptors when 5-HT was applied alone or was co-applied with mosapride in cultured NCB-20 cells known to express 5-HT3 receptors. The 5-HT3 receptor current amplitudes were inhibited by mosapride in a concentration-dependent manner. Mosapride blocked the peak currents evoked by the application of 5-HT in a competitive manner because the EC50 shifted to the right without changing the maximal effect. The rise slopes of 5-HT3 receptor currents were decreased by mosapride. Pre-application of mosapride before co-application, augmented the inhibitory effect of mosapride, which suggests a closed channel blocking mechanism. Mosapride also blocked the opened 5-HT3 receptor because it inhibited the 5-HT3 receptor current in the middle of the application of 5-HT. It accelerated desensitization of the 5-HT3 receptor but did not change the recovery process from the receptor desensitization. There were no voltage-, or use-dependency in its blocking effects. These results suggest that mosapride inhibited the 5-HT3 receptor through a competitive blocking mechanism probably by binding to the receptor in closed state, which could be involved in the pharmacological effects of mosapride to treat GI disorders.

Interactions between Bitter Taste, Diet and Dysbiosis: Consequences for Appetite and Obesity.

The type 2 family of taste receptors (T2Rs) detect and respond to bitter tastants. These receptors are expressed throughout the gastrointestinal (GI) tract, with location dependant roles. In the oral cavity, T2Rs are involved in the conscious perception of bitter tastants, while in the lower GI tract they have roles in chemoreception and regulation of GI function. Through these diverse roles, these receptors may be involved in modulating appetite and diet, with consequences for weight regulation and obesity. Interestingly, the concentration of T2Rs in the GI tract is greatest in the large intestine, the organ with the densest colonisation of bacteria. The gut microbiome has been the subject of intense research, as a plethora of roles linking microbiota to human health continue to be uncovered. Of particular interest is the microbial signature associated with obesity. Obesity is a leading health concern, and advances in our understanding of this disease are needed. Diet is a known modifiable factor in the development of obesity. However, diet only partially explains disease risk. Changes in microbial energy harvesting by the microbiota plays a role in obesity, and the composition of these energy harvesting populations may be controlled by taste receptors. This review explores T2Rs as a potential link between obesity and the human GI microbiome.

The nature of catecholamine-containing neurons in the enteric nervous system in relationship with organogenesis, normal human anatomy and neurodegeneration.

The gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudo- unipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine- containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions.The gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudounipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine-containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as including Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions.

Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine.

BackgroundGastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system.ObjectiveWe aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes.DesignSeven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge.ResultsElevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level.ConclusionAltered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.

Mast cells in gastrointestinal disorders

Mast cells are constitutively found in the gastrointestinal (GI) tract. The three major physiological functions of GI mast cells comprise of – as far as we know – regulation of GI functions, namely epithelial and endothelial functions, crosstalk with the enteric nervous system, and contribution to the host defense against bacterial, viral and parasitic agents. A number of chronic GI diseases, including inflammatory bowel disease (Crohn's disease, ulcerative colitis), celiac disease, irritable bowel syndrome, and food allergies, are thought to be associated with mast cell hyperplasia and humoral activity. Clinical conditions characterized by a decrease in mast cell functionality are not known so far. In the present review, we summarize current evidence which show that human mast cells play a central role at the GI barrier, both in health and disease.