[The brain-gut axis: insights from the obese pig model]. / L'axe tube digestif-cerveau: avancées récentes obtenues sur un modèle d'obésité chez le porc.

The pig, which shares several similarities with humans, is increasingly used for biomedical research, particularly in nutrition and neurosciences. Recent studies in minipigs have shown that a deleterious nutritional environment (e.g. a high-fat and high-sugar diet) induces obesity which, as in humans, is associated with increased adiposity, insulin resistance, modified eating behaviour, and altered gastric function and intestinal sensitivity. These changes are accompanied by differences in the activation matrices and metabolic activity of several brain areas. Using this animal model, we have revisited the concept of dual hedonic and homeostatic control of food intake. We have thus developed a minimally invasive and potentially reversible surgical approach to the control of food intake, as an alternative to bariatric surgery, based on chronic vagal stimulation at the abdominal level.

Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats.

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.

Probiotic Lactobacillus reuteri alleviates the response to gastric distension in rats.

Probiotic lactic acid bacteria have been reported to alleviate symptoms in patients with irritable bowel syndrome. However, they have not been tested for use in functional gastric disease. We therefore investigated if strains previously shown to protect from response to colorectal distension (CRD) in rats also modulate response to gastric distension (GD). Healthy, male Sprague-Dawley rats were treated with viable, heat-killed, gamma-irradiated Lactobacillus reuteri or viable Lactobacillus plantarum wild type (WT), L. plantarum Dlt¯mutant, conditioned medium or medium control (9 d), and subjected to GD under anesthesia using an i.g. Teflon catheter. Effects were measured by heart rate (HR) changes during noxious distension (60 mm Hg) compared to baseline HR values. We also investigated the localization of viable, green fluorescent protein-transfected bacteria in the stomach mucosa. Viable L. reuteri decreased the bradycardia induced by noxious GD compared to placebo controls (P < 0.001). Heat-killed or gamma-irradiated L. reuteri and conditioned medium did not have a protective effect in GD. Viable L. plantarum WT and Dlt¯mutant, previously shown to be effective antinociceptive agents in CRD, showed no protective effect in GD. All viable bacteria were associated with the pars glandularis of the rat stomach. Thus, we conclude that the antinociceptive mechanisms of action of probiotic bacteria differ between the stomach and the colon. Symptom alleviation cannot be attributed to the localization of the bacteria in the stomach. Information derived from effects of CRD cannot be extrapolated to effects in the stomach, which are likely to be strain and organ specific.

Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension-induced visceromotor response in conscious rats.

Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold.

Role of transient receptor potential A1 in gastric nociception.

Afferent fibers innervating the gastrointestinal tract have major roles in consciously evoked sensations including pain. However, little is known about the molecules involved in mechanonociception from the upper gastrointestinal tract. We recently reported that activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase cascade in primary afferent neurons, was induced by noxious gastric distention in the rat, and that the activation of ERK1/2 in dorsal root ganglion (DRG) neurons can be implicated in acute visceral pain. Transient receptor potential (TRP) A1, a member of the TRP family of cation channels, was expressed in both DRG and nodose ganglion (NG) neurons innervating the stomach and in nerve fibers in the gastric wall. TRPA1 was coexpressed with ERK1/2 in gastric primary afferent neurons, and attenuation of TRPA1 activation using antisense peptides and a specific blocker led to suppression of both ERK1/2 activation and visceromotor responses. TRPA1 also significantly colocalized with substance P (SP) and calcitonin gene-related peptide (CGRP) in the thoracolumbar DRG, NG and stomach. These data indicate that SP and CGRP may also be released by TRPA1 activation in primary afferent neurons to elicit neurogenic inflammation and promote visceral hyperalgesia.

Effect of muscarinic and nicotinic receptor antagonism on rat gastric motor activity.

BACKGROUND/AIMS: Our aim was to investigate whether muscarinic and nicotinic receptors mediate nitric oxide release during motor events in the rat stomach. METHODS: Isolated rat stomach volume changes were monitored in an organ bath setup with an intragastric balloon coupled to a barostat and studied in basal conditions and during electrical vagal stimulation (EVS). In conscious rats, the intragastric pressure (IGP) was measured during test meal infusion. RESULTS: In the presence of N(G)-nitro-L-arginine methyl ester (L-NAME; 0.1 mmol/l), EVS induced significant gastric contractions (mean +/- SEM = 0.27 +/- 0.04 ml; n = 6) that could be blocked by atropine (3 micromol/l) and hexamethonium (0.1 mmol/l). In the presence of atropine and/or hexamethonium, EVS-induced relaxations could not be blocked by L-NAME, while exogenous nitric oxide could still relax the stomach. In conscious rats, atropine (1 mg kg(-1)) initially decreased IGP, while during further distension it increased IGP. In the presence of L-NAME (30 mg kg(-1)) atropine consistently decreased IGP. L-NAME alone significantly increased IGP during the test meal infusion, but this effect was reduced in the presence of atropine. CONCLUSION: These findings indicate a role for nicotinic and muscarinic receptors in the vagal-stimulation-induced activation of nitrergic nerves in the rat stomach.

Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats.

BACKGROUND: Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats. METHODS: We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats. RESULTS: TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD. CONCLUSIONS: The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.

Identification of Genetic Susceptibility Factors Associated with Canine Gastric Dilatation-Volvulus.

Canine gastric dilatation-volvulus (GDV) is a common life-threatening condition occurring primarily in large and giant breeds with a 3.9% to 36.7% lifetime risk. The genetic correlates of GDV have not previously been systematically explored. We undertook an inter-breed genome-wide association analysis (GWAS) of 253 dogs from ten breeds including 106 healthy dogs and 147 dogs with at least one GDV episode. SNP array genotyping followed by imputation was conducted on 241 samples to identify GDV-associated single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs). A subset of 33 dogs (15 healthy dogs and 18 GDV patients from the three most represented breeds) was characterized by whole genome sequencing (WGS). After genome-wide Bonferroni correction, we identified a significant putatively protective intergenic SNP (rs851737064) across all breeds. The signal was most significant in Collies, German Shorthaired Pointers, and Great Danes. Subsequent focused analysis across these three breeds identified 12 significant additional putatively protective or deleterious SNPs. Notable significant SNPs included those occurring in genes involved in gastric tone and motility including VHL, NALCN, and PRKCZ. These data provide important new clues to canine GDV risk factors and facilitate generation of hypotheses regarding the genetic and molecular underpinnings this syndrome.

A new model of autonomic dysreflexia induced by gastric distension in the spinal cord-transected rat.

Upper gastrointestinal (GI) motility inhibition after spinal cord injury has been classically considered to result from autonomic dysreflexia (AD). Animal models have been designed in rats to evaluate the presence of AD induced by colonic or bladder distension. However, there are no animal models of AD induced by gastric distension (GD). We examined whether controlled GD could induce AD and compared the pattern of hemodynamic responses induced by GD with colonic distensions (CD) and the interaction between them. Male Wistar rats underwent spinal cord transections performed at the level of C(7)-T(1), T(4)-T(5) and T(9)-T(10) (control) vertebrae and the presence of AD was evaluated after 1 day. In animals with C(7)-T(1) lesions, each CD in a series of 4 consecutive CDs triggered AD while GD only triggered AD after the 2 initial distensions in a series of 4 consecutive GDs. In animals with T(4)-T(5) lesions, in a protocol of 4 consecutive CDs or GDs, AD was triggered only by the 2 initial distensions. In 2 other protocols, consisting of 2 consecutive CDs or GDs followed respectively by 2 GDs or CDs, the effect of 2 GDs was attenuated in animals with C(7)-T(1) and T(4)-T(5) lesions but the hemodynamic changes induced by CDs were not affected by prior GDs. In summary, this is a new model of AD triggered by GD in rats. AD is more intense in animals with C(7)-T(1) lesions than after T(4)-T(5) lesions and AD triggered by GD can be attenuated by prior CDs.

What causes intrathoracic gastric dilatation in a late-presenting diaphragmatic hernia?

A 13-year-old previously asymptomatic patient presented with abdominal pain and vomiting. Chest radiogram revealed a left intrathoracic stomach. Laparotomy confirmed a dilated, hypertrophic stomach herniating through a left Bochdalek hernia. The patient recovered after a period of prolonged gastric paresis. While highlighting the importance of considering this condition in the differential diagnosis of a cystic lesion in the chest, this article also postulates a mechanism for the hypertrophic gastric dilatation in a late presentation of a congenital diaphragmatic hernia.

Autoimmune autonomic ganglionopathy associated with Sjögren's syndrome presenting with recurrent abdominal distension.

A 65-year-old woman with Sjögren's syndrome presented with recurrent abdominal distension, constipation, weight loss, orthostatic dizziness, loss of sweating and incomplete emptying of the bladder. Gastrointestinal dilatation but no evidence of malignancy or obstruction was found on CT of the abdomen, oesophagogastroduodenoscopy or colonoscopy. Postvoiding residual urine volume was increased. Antiganglionic acetylcholine receptor antibody was positive. We diagnosed as autoimmune autonomic ganglionopathy. The patient responded to corticosteroid treatment. One year after treatment, she continued to have mild gastrointestinal symptoms, but overall condition was stable without further intervention.

Case report of gastric distension due to superior mesenteric artery syndrome mimicking hollow viscus perforation: Considerations in critical care ultrasound.

RATIONALE: Critical care ultrasound identifies the signs of free intraperitoneal air and echogenic free fluid always indicates hollow viscus perforation (HVP) and needs immediate surgical interventions. However, in rare cases, these classic signs may also mislead proper clinical decisions. We report perforated viscus associated large peritoneal effusion with initial critical care ultrasound findings, whereas computed tomography (CT) examination confirmed a giant stomach due to superior mesenteric artery syndrome (SMAS). PATIENT CONCERNS: A 70-year-old man was admitted to our emergency department with a complaint of recurrent vomiting with coffee ground emesis for 15 hours and worsen with hypotension for 6 hours. During gastric tube placement, the sudden cardiac arrest occurred. With 22 minutes resuscitation, sinus rhythm was restored. DIAGNOSES: Quick ultrasound screen showed large echogenic fluid distributed in the whole abdomen. Diagnostic paracentesis collected "unclotted blood" and combined with a past history of duodenal ulcer, HVP was highly suspected. However, surgical intervention was not performed immediately as unstable vital signs and unfavorable coma states. After adequate resuscitation in intensive care unit, the patient was transferred to perform enhanced CT. Surprisingly, there was no evidence of HVP. Instead, CT showed a giant stomach possibly explained by SMAS. INTERVENTIONS: Continuous gastric decompression was performed and 3100 mL coffee ground content was drainage within 24 hours of admission. OUTCOMES: Abdominal distension was significantly relieved with improved vital signs. However, as the poor neurological outcome, family members abandon further treatment, and the patient died. LESSONS: SMAS is a rare disorder, characterized by small bowel obstruction and severe gastric distension. Nasogastric tube insertion should be aware to protect airway against aspiration. Caution should be utilized to avoid over interpretation of ultrasonography findings on this condition.

Evaluation of echocardiography and cardiac biomarker concentrations in dogs with gastric dilatation volvulus.

OBJECTIVE: To assess abnormalities in concentrations of cardiac troponin I (cTnI), lactate, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in relation to arrhythmias, echocardiographic measurements, and survival in dogs with gastric dilatation volvulus (GDV). DESIGN: Prospective observational study. SETTING: University hospital. ANIMALS: Twenty-two dogs with naturally occurring GDV. SAMPLES: Concentrations of cTnI, plasma lactate, and NT-proBNP were recorded at presentation to the emergency room, the time closest to echocardiography, and the highest recorded concentrations during hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cardiac rhythms were categorized on a 0-4 scale (0 = no ventricular premature complexes [VPCs], 1 = single VPCs, 2 = bigeminy or trigeminy, 3 = couplets or triplets, and 4 = R-on-T phenomenon or ventricular tachycardia). Echocardiography was performed 6-18 hours postoperatively. Fifteen dogs had ventricular arrhythmias during hospitalization (Grade 1 [n = 9], Grade 4 [n = 6]). The highest recorded cTnI concentration was significantly higher in the dogs with Grade 4 (P = 0.002) or Grade 1 (P = 0.001) arrhythmias compared to dogs without arrhythmias. Plasma lactate was significantly correlated with left ventricular internal diameter in diastole (r = -0.52, P = 0.01) and systole (r = -0.57, P = 0.006), left ventricular free wall in diastole (LWDd, r = 0.59, P = 0.004), and interventricular septal thickness in diastole (IVDs, r = 0.65, P = 0.001). Dogs that did not survive to 1 week postdischarge (3/22) had a significantly thicker LVWd (P = 0.04) and IVSd (P = 0.05), and received significantly less fluids in the first 24 (P = 0.02) and 48 hours (P = 0.03) of hospitalization. CONCLUSIONS: Concentrations of cTnI and NT-proBNP increased during hospitalization, but only cTnI concentrations were significantly higher in dogs with a higher arrhythmia grade. Additional research on the potential role of serial measurement of biomarkers in dogs with GDV is warranted.

Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone-responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation.

Nesfatin-1, a recently discovered neuropeptide involved in satiety. Recent studies have revealed that central nesfatin-1 inhibits gastric emptying and gastric acid secretion, though the mechanisms involved in these processes are not known. We aim to explore the effects of nesfatin-1 on a population of gastric distension (GD)-sensitive neurons in the lateral hypothalamus (LHA), gastric motility, and gastric secretion and the role for an arcuate nucleus (Arc)-LHA neural pathway in these processes. Single unit extracellular discharge recordings were made in of LHA. Further, gastric motility and gastric secretion in rats were monitored. Retrograde tracing and fluorescent immunohistochemical staining were used to explore nesfatin-1 neuron projection. The results revealed that administration of nesfatin-1 to the LHA or electric stimulation of the Arc could alter the neuronal activity of melanin-concentrating hormone (MCH)-responsive, GD-responsive neurons in LHA, which could be blocked by pretreatment with MCH receptor-1 antagonist PMC-3881-PI or weakened by pretreatment of a nesfatin-1 antibody in LHA. Administration of nesfatin-1 into LHA could inhibit gastric motility and gastric secretion, and these effects could be enhanced by administration of PMC-3881-PI. Electrical stimulation of Arc promoted the gastric motility and gastric secretion. Nesfatin-1 antibody or PMC-3881-PI pretreatment to LHA had no effect on Arc stimulation-induced gastric motility, but these pretreatments did alter Arc stimulation-induced effects on gastric secretion. Our findings suggest that nesfatin-1 signaling in LHA participates in the regulation of efferent information from the gastrointestinal tract and gastric secretion which also involve MCH signaling. Further, they show that a nesfatin-1-positive Arc to LHA pathway is critical for these effects.