Guy E. Boeckxstaens

Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway.

Acetylcholine released by efferent vagus nerves inhibits macrophage activation. Here we show that the anti-inflammatory action of nicotinic receptor activation in peritoneal macrophages was associated with activation of the transcription factor STAT3. STAT3 was phosphorylated by the tyrosine kinase Jak2 that was recruited to the α7 subunit of the nicotinic acetylcholine receptor. The anti-inflammatory effect of nicotine required the ability of phosphorylated STAT3 to bind and transactivate its DNA response elements. In a mouse model of intestinal manipulation, stimulation of the vagus nerve ameliorated surgery-induced inflammation and postoperative ileus by activating STAT3 in intestinal macrophages. We conclude that the vagal anti-inflammatory pathway acts by α7 subunit–mediated Jak2-STAT3 activation.

Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia.

BACKGROUND Many experts consider laparoscopic Hellers myotomy (LHM) to be superior to pneumatic dilation for the treatment of achalasia, and LHM is increasingly considered to be the treatment of choice for this disorder. METHODS We randomly assigned patients with newly diagnosed achalasia to pneumatic dilation or LHM with Dors fundoplication. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). The primary outcome was therapeutic success (a drop in the Eckardt score to ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for retreatment, pressure at the lower esophageal sphincter, esophageal emptying on a timed barium esophagogram, quality of life, and the rate of complications. RESULTS A total of 201 patients were randomly assigned to pneumatic dilation (95 patients) or LHM (106). The mean follow-up time was 43 months (95% confidence interval [CI], 40 to 47). In an intention-to-treat analysis, there was no significant difference between the two groups in the primary outcome; the rate of therapeutic success with pneumatic dilation was 90% after 1 year of follow-up and 86% after 2 years, as compared with a rate with LHM of 93% after 1 year and 90% after 2 years (P=0.46). After 2 years of follow-up, there was no significant between-group difference in the pressure at the lower esophageal sphincter (LHM, 10 mm Hg [95% CI, 8.7 to 12]; pneumatic dilation, 12 mm Hg [95% CI, 9.7 to 14]; P=0.27); esophageal emptying, as assessed by the height of barium-contrast column (LHM, 1.9 cm [95% CI, 0 to 6.8]; pneumatic dilation, 3.7 cm [95% CI, 0 to 8.8]; P=0.21); or quality of life. Similar results were obtained in the per-protocol analysis. Perforation of the esophagus occurred in 4% of the patients during pneumatic dilation, whereas mucosal tears occurred in 12% during LHM. Abnormal exposure to esophageal acid was observed in 15% and 23% of the patients in the pneumatic-dilation and LHM groups, respectively (P=0.28). CONCLUSIONS After 2 years of follow-up, LHM, as compared with pneumatic dilation, was not associated with superior rates of therapeutic success. (European Achalasia Trial Netherlands Trial Register number, NTR37, and Current Controlled Trials number, ISRCTN56304564.).

Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice.

BACKGROUND AND AIMS Postoperative ileus after abdominal surgery largely contributes to patient morbidity and prolongs hospitalization. We aimed to study its pathophysiology in a murine model by determining gastric emptying after manipulation of the small intestine. METHODS Gastric emptying was determined at 6, 12, 24, and 48 hours after abdominal surgery by using scintigraphic imaging. Intestinal or gastric inflammation was assessed by immune-histochemical staining and measurement of tissue myeloperoxidase activity. Neuromuscular function of gastric and intestinal muscle strips was determined in organ baths. RESULTS Intestinal manipulation resulted in delayed gastric emptying up to 48 hours after surgery; gastric half-emptying time 24 hours after surgery increased from 16.0 +/- 4.4 minutes after control laparotomy to 35.6 +/- 5.4 minutes after intestinal manipulation. The sustained delay in gastric emptying was associated with the appearance of leukocyte infiltrates in the muscularis of the manipulated intestine, but not in untouched stomach or colon. The delay in postoperative gastric emptying was prevented by inhibition of intestinal leukocyte recruitment. In addition, postoperative neural blockade with hexamethonium (1 mg/kg intraperitoneally) or guanethidine (50 mg/kg intraperitoneally) normalized gastric emptying without affecting small-intestinal transit. The appearance of intestinal infiltrates after intestinal manipulation was associated with increased c-fos protein expression in sensory neurons in the lumbar spinal cord. CONCLUSIONS Sustained postoperative gastroparesis after intestinal manipulation is mediated by an inhibitory enterogastric neural pathway that is triggered by inflammatory infiltrates recruited to the intestinal muscularis. These findings show new targets to shorten the duration of postoperative ileus pharmacologically.

The Selective Serotonin Reuptake Inhibitor Fluoxetine Does Not Change Rectal Sensitivity and Symptoms in Patients With Irritable Bowel Syndrome: A Double Blind, Randomized, Placebo-Controlled Study

BACKGROUND & AIMS Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to increased sensory thresholds during rectal distention and improvement of symptoms, in particular in IBS patients with visceral hypersensitivity. METHODS Forty non-depressed IBS patients underwent a rectal barostat study to assess the sensitivity to rectal distention before and after 6 weeks of treatment with fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal symptoms, global symptom relief, and psychologic symptoms were assessed before and after the intervention. RESULTS At baseline, 21 of 40 patients showed hypersensitivity to rectal distention. Fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo, either in hypersensitive (19 +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4 mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and 76% of placebo-treated patients reported significant abdominal pain scores after 6 weeks (not significant). In contrast, in hypersensitive patients only, fluoxetine significantly reduced the number of patients reporting significant abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic symptoms were not altered. CONCLUSIONS Fluoxetine does not change rectal sensitivity in IBS patients. Possible beneficial effects on pain perception need to be confirmed in larger trials.

Outcomes of Treatment for Achalasia Depend on Manometric Subtype

BACKGROUND & AIMS Patients with achalasia are treated with either pneumatic dilation (PD) or laparoscopic Heller myotomy (LHM), which have comparable rates of success. We evaluated whether manometric subtype was associated with response to treatment in a large population of patients treated with either PD or LHM (the European achalasia trial). METHODS Esophageal pretreatment manometry data were collected from 176 patients who participated in the European achalasia trial. Symptoms (weight loss, dysphagia, retrosternal pain, and regurgitation) were assessed using the Eckardt score; treatment was considered successful if the Eckardt score was 3 or less. Manometric tracings were classified according to the 3 Chicago subtypes. RESULTS Forty-four patients had achalasia type I (25%), 114 patients had achalasia type II (65%), and 18 patients had achalasia type III (10%). After a minimum follow-up period of 2 years, success rates were significantly higher among patients with type II achalasia (96%) than type I achalasia (81%; P < .01, log-rank test) or type III achalasia (66%; P < .001, log-rank test). The success rate of PD was significantly higher than that of LHM for patients with type II achalasia (100% vs 93%; P < .05), but LHM had a higher success rate than PD for patients with type III achalasia (86% vs 40%; P = .12, difference was not statistically significant because of the small number of patients). For type I achalasia, LHM and PD had similar rates of success (81% vs 85%; P = .84). CONCLUSIONS A higher percentage of patients with type II achalasia (based on manometric tracings) are treated successfully with PD or LHM than patients with types I and III achalasia. Success rates in type II are high for both treatment groups but significantly higher in the PD group. Patients with type III can probably best be treated by LHM. Trialregister.nl number NTR37; ISRCTN56304564.

Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study

OBJECTIVES:Chronic constipation is a common, persistent disorder with limited effective treatment options. This study investigated the efficacy, safety, and tolerability of tegaserod in the treatment of chronic constipation.METHODS:After a 2-wk baseline period, patients were randomized to double-blind treatment of 12 wk with tegaserod (2 or 6 mg b.i.d.) or placebo. Response during weeks 1–4 (primary variable) was defined as an increase in complete spontaneous bowel movement (CSBM)/wk. Secondary variables included response during weeks 1–12, patient evaluation of individual symptoms, and global assessment of bowel habits and constipation.RESULTS:One thousand two hundred and sixty-four patients were randomized to tegaserod or placebo. Responder rates for the primary efficacy variable were 35.6% for tegaserod 2 mg b.i.d. (p = 0.0059 vs placebo), 40.2% for 6 mg b.i.d. (p < 0.0001 vs placebo) and 26.7% for placebo. The number needed to treat was 7.3 for the 6 mg b.i.d. dose compared with 11.1 for tegaserod 2 mg b.i.d. Tegaserod 6 mg b.i.d. reduced straining, abdominal bloating/distension, and abdominal pain/discomfort during the 12-wk treatment period compared with placebo (p < 0.05 for all symptoms). Significant improvements were also seen in stool form and in global assessment of bowel habits and constipation. The most common adverse events, headache and abdominal pain, were more frequent with placebo than with tegaserod.CONCLUSIONS:Tegaserod was efficacious in relieving symptoms of chronic constipation and was well tolerated.

Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis.

BACKGROUND & AIMS Nitric oxide (NO) is well accepted as an inhibitory neurotransmitter in the gastrointestinal tract; however, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) in humans remains to be determined. Therefore, the effect of NG-monomethyl-L-arginine (L-NMMA), a specific NO synthase blocker, on gastric distention-induced TLESRs was investigated. METHODS Esophageal manometry was performed using a perfused sleeve assembly. The effect of L-NMMA was evaluated on water swallow-evoked primary peristalsis (n = 8; single-blind, placebo-controlled) and on the rate of TLESRs during gastric distention (n = 8; double-blind, placebo-controlled). RESULTS L-NMMA increased the amplitude of peristaltic pressure waves in the distal esophagus and increased peristaltic velocity in the proximal esophagus. In contrast, L-NMMA had no effect on basal lower esophageal sphincter pressure, nadir pressure, duration, and area under the curve of lower esophageal sphincter relaxation. L-NMMA significantly inhibited the increase in TLESRs during gastric distention. L-NMMA also increased the intraballoon pressure during distention. CONCLUSIONS NO is one of the neurotransmitters involved in the reflex arc mediating the triggering of TLESRs. NO is involved in the timing of human esophageal peristalsis and may exert a tonic inhibition on the proximal stomach.

Neuroimmune mechanisms in postoperative ileus.

Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.

Diagnosis and treatment of chronic constipation – a European perspective

Background  Although constipation can be a chronic and severe problem, it is largely treated empirically. Evidence for the efficacy of some of the older laxatives from well‐designed trials is limited. Patients often report high levels of dissatisfaction with their treatment, which is attributed to a lack of efficacy or unpleasant side‐effects. Management guidelines and recommendations are limited and are not sufficiently current to include treatments that became available more recently, such as prokinetic agents in Europe.

Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.

BACKGROUND & AIMS Many patients with persistent dysphagia and regurgitation after therapy have low or no lower esophageal sphincter (LES) pressure. Distensibility of the esophagogastric junction (EGJ) largely determines esophageal emptying. We investigated whether assessment of the distensibility of the EGJ is a better and more integrated parameter than LES pressure for determining efficacy of treatment for patients with achalasia. METHODS We measured distensibility of the EGJ using an endoscopic functional luminal imaging probe (EndoFLIP) in 15 healthy volunteers (controls; 8 male; age, 40 ± 4.1 years) and 30 patients with achalasia (16 male; age, 51 ± 3.1 years). Patients were also assessed by esophageal manometry and a timed barium esophagogram. Symptom scores were assessed using the Eckardt score, with a score <4 indicating treatment success. The effect of initial and additional treatment on distensibility and symptoms was evaluated in 7 and 5 patients, respectively. RESULTS EGJ distensibility was significantly reduced in untreated patients with achalasia compared with controls (0.7 ± 0.9 vs 6.3 ± 0.7 mm(2)/mm Hg; P < .001). In patients with achalasia, EGJ distensibility correlated with esophageal emptying (r = -0.72; P < .01) and symptoms (r = 0.61; P < .01) and was significantly increased with treatment. EGJ distensibility was significantly higher in patients successfully treated (Eckardt score <3) compared with those with an Eckardt score >3 (1.6 ± 0.3 vs 4.4 ± 0.5 mm(2)/mm Hg; P = .001). Even when LES pressure was low, EGJ distensibility could be reduced, which was associated with impaired emptying and recurrent symptoms. CONCLUSIONS EGJ distensibility is impaired in patients with achalasia and, in contrast to LES pressure, is associated with esophageal emptying and clinical response. Assessment of EGJ distensibility by EndoFLIP is a better parameter than LES pressure for evaluating efficacy of treatment for achalasia.