Anton Emmanuel

Guidelines on the irritable bowel syndrome: mechanisms and practical management

Background: IBS affects 5–11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. Aim: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. Methods: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. Results: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients’ concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT3 antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT4 agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. Conclusions: Better ways of identifying which patients will respond to specific treatments are urgently needed.

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3). Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER. Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.

Prucalopride, a systemic enterokinetic, for the treatment of constipation

Background : Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin‐4 receptors, which are involved in initiating peristalsis.

Gut microbiota and gastrointestinal health: current concepts and future directions

Background The microbial community of the human gut – the enteric microbiota – plays a critical role in functions that sustain health and is a positive asset in host defenses. In recent years, our understanding of this so‐called human ‘super organism’ has advanced, following characterization of fecal metagenomes which identified three core bacterial enterotypes, and based on basic and clinical research into the impact and consequences of microbiota biodiversity and change on gastrointestinal disorders and diseases.

Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers

Background—Stronger prokinetic agents which specifically enhance transit in different parts of the gut are required. R093877 is a novel 5-HT4 agonist prokinetic compound which is chemically related to cisapride but believed to have greater effect on colonic activity. Aims—To evaluate the effects of R093877 on bowel function, upper and lower gut transit, visceral sensitivity, and sphincter function in healthy volunteers in a double blind, placebo controlled, crossover study. Methods—The study consisted of five consecutive one week periods: no drug treatment; active drug treatment with either 1 or 2 mg daily or placebo; washout; active drug or placebo; no treatment. Seventeen male subjects maintained a detailed diary of bowel function for the entire study. Orocaecal transit (breath hydrogen), whole gut transit (radio-opaque markers), and anorectal function were assessed at the end of each of the two treatment periods. Blood testing was performed to confirm compliance and for safety analysis. Results—One subject withdrew from the study due to side effects while on placebo. Eight subjects completed the study on 1 mg and a further eight on 2 mg. Blood testing showed non-compliance in one subject on the 2 mg dose, and he was excluded from analysis of all diary and physiological data. Treatment increased the number of stools per week (placebo versus 1 mg, 7.8 versus 13.6, p=0.003; placebo versus 2 mg, 8.9 versus 11.3, p=0.15) and the percentage of loose or watery stools (24.2% versus 61.5%, p<0.04; 9.9% versus 40.0%, p<0.02). Stool frequency and consistency reverted to normal immediately after treatment. Treatment shortened orocaecal and whole gut transit in all subjects on both doses. Treatment accelerated orocaecal (76 versus 51 minutes, p=0.007; 63 versus 47 minutes, p=0.07) and whole gut (38.2 versus 27.0 hours, p=0.05; 44.8 versus 24.0 hours, p<0.04) transit, and decreased the number of retained markers ingested 36 hours previously (4.8 versus 1.8, p=0.016; 7.0 versus 4.3, p=0.033). Gut sensitivity to distension and electrical stimulation, and anal manometry, were unchanged. Transient headache occurred in seven subjects on R093877 and one subject had mild elevation of liver aminotransferases which resolved on drug cessation. Conclusions—R093877 is well tolerated by healthy subjects and has a marked and consistent effect on stool frequency and consistency, and upper gut and colonic transit. It does not affect visceral sensitivity or sphincter function. It holds promise for patients with large bowel symptoms or slow gut transit.

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinsons disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long‐term l‐dopa therapy. Neurohormonal aspects of the brain‐gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric‐derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD.

Laser Doppler measurement of rectal mucosal blood flow

BACKGROUND Gut mucosal blood flow measurement is used to study a variety of disorders and possibly extrinsic neural function. AIMS To determine optimal measurement criteria and validate this technique as a measure of level of activity of extrinsic autonomic gut innervation. METHODS In 26 healthy volunteers a laser Doppler mucosal probe was applied 10 cm from the anus. Response to inhaled salbutamol 200 μg and ipratropium 40 μg, intravenous metoprolol 2.5 mg, and direct sacral nerve electrostimulation (in nine incontinent patients) was also studied. RESULTS The coefficient of variation for subjects studied under identical conditions on two, three, and four days was 0.06, 0.05, and 0.06, respectively. Mean mucosal blood flow increased after a standard meal. Blood flow decreased for 15 minutes after smoking and returned to baseline at 30 minutes. Fasted measurements at 0900, 1200, 1600, and 2200 were similar. There was a negative correlation between blood flow and body size but not age. Follicular phase mucosal flow was less and more reproducible than luteal. Mucosal blood flow was highest in men and lowest in postmenopausal women. Inhaled salbutamol did not change blood flow; ipratropium significantly reduced, and metoprolol and sacral nerve stimulation increased flow. CONCLUSIONS Measurement of gut mucosal blood flow by laser Doppler flowmetry is highly reproducible. Eating, smoking, body size, sex, ovulatory status, and menstrual phase influence blood flow. Changes in mucosal blood flow induced by autonomically active drugs and nerve stimulation confirm the role of the mucosal microcirculation as a measure of extrinsic nerve activity.

Laser Doppler flowmetry as a measure of extrinsic colonic innervation in functional bowel disease

BACKGROUND In functional disorders it is unknown whether disturbed function is due to an intrinsic gut abnormality or altered extrinsic innervation. AIMS To study whether measurement of mucosal blood flow could be used as a quantitative direct measure of gut extrinsic nerve autonomic activity in patients with idiopathic constipation. METHODS Seventy two patients with idiopathic constipation and 26 healthy volunteers had rectal mucosal blood flow measurements by a laser Doppler flowmetry probe applied 10 cm from the anus. Measurements were made at rest and after inhaled placebo and ipratropium 40 μg. RESULTS Constipated subjects had lower baseline rectal blood flow than controls. Patients with slow transit had lower mucosal blood flow than normal transit. The number of retained markers on x ray was inversely correlated with blood flow. Ipratropium reduced blood flow compared with placebo, reduced it less in constipated patients than controls, and reduced it less in patients with slow compared with normal transit. Constipated patients, not controls, showed a significantly attenuated RR interval (the interval between successive R waves on the ECG) variability, and blood flow correlated with vagal function. CONCLUSIONS Laser Doppler mucosal flowmetry is a gut specific, quantitative measure of extrinsic autonomic nerve activity. The technique has shown that patients with idiopathic constipation have impaired extrinsic gut nerve activity, and this is more notable in those with slow transit. The degree of slow transit correlates with the degree of impaired extrinsic innervation.

Effect of sacral nerve stimulation on autonomic nerve function

Sacral nerve stimulation has been used successfully to treat motility disorders of the bladder and bowel. The mechanism of action remains unknown. This study examined the effect of stimulation on rectal blood flow as a measure of autonomic nerve function.

Opioid-Induced Constipation: Pathophysiology, Clinical Consequences, and Management

Although opioids offer potent analgesia for severe acute and chronic noncancer pain, adverse gastrointestinal effects potentially undermine their clinical utility. In particular, between 40% and 95% of patients develop opioid-induced constipation (OIC). Therefore, there is a consensus that patients should commence laxatives at the start of opioid therapy and continue throughout treatment. Nevertheless, laxatives are not routinely coprescribed with opioids. Even when concurrent laxatives are prescribed, approximately half the patients treated for OIC do not achieve the desired improvement. Moreover, laxatives do not target the underlying cause of OIC (opioid binding to the μ -receptors in the enteric system) and as such are not very effective at managing OIC. The failure of lifestyle modification and laxatives to treat adequately many cases of OIC led to the concurrent use of peripherally acting opioid antagonists (such as methylnaltrexone bromide and naloxone) to reduce the incidence of gastrointestinal adverse events without compromising analgesia. Judicious use of the various options to manage OIC should allow more patients to benefit from opioid analgesia. Therefore, this paper reviews the causes, consequences, and management of OIC to help clinicians optimise opioid analgesia.