Heinz F. Hammer

Mechanisms and Management of Antibiotic-Associated Diarrhea

Only 10%-20% of all cases of antibiotic-associated diarrhea (AAD) are caused by infection with Clostridium difficile. Other infectious organisms causing AAD include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species, and Salmonella species. Most of the clinically mild AAD cases are due to functional disturbances of intestinal carbohydrate or bile acid metabolism, to allergic and toxic effects of antibiotics on intestinal mucosa, or to pharmacological effects on motility. Saccharomyces boulardii and Enterococcus SF68 can reduce the risk of developing AAD. Patients receiving antibiotic treatment should avoid food containing high amounts of poorly absorbable carbohydrates. Mild cases of AAD that may or may not be caused by C. difficile can be resolved by discontinuation of antibiotic therapy and by dietary carbohydrate reduction. Only severe AAD caused by C. difficile requires specific antibiotic treatment.

Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders

Background and aims: Sildenafil blocks phosphodiesterase type 5 which degrades nitric oxide (NO) stimulated 3`5`-cyclic monophosphate (cGMP), thereby relaxing smooth muscle cells in various organs. We used sildenafil as a tool to investigate the role of the NO-cGMP pathway in the oesophagus of healthy volunteers and patients with hypercontractile oesophageal motility disorders. Methods: Six healthy male volunteers participated in a randomised double blind study on two separate days before and one hour after oral intake of either sildenafil 50 mg or placebo. Oesophageal manometry was performed to determine vector volume of the lower oesophageal sphincter (LOS) and pressure amplitudes of the oesophageal body. Four of the volunteers underwent 12 hour ambulatory oesophageal manometry on two separate days, once with sildenafil 50 mg and once with placebo. An activity index for spontaneous swallowing was calculated for every hour of the study. Eleven patients with hypercontractile oesophageal motility disorders took part in an open study of the effect of 50 mg sildenafil on manometric features of their disorder and on the clinical response to sildenafil taken as required. Results: In healthy subjects, sildenafil significantly reduced LOS pressure vector volume and pressure amplitudes in the distal half of the oesophageal body. In three of four subjects the inhibitory effect of sildenafil lasted at least eight hours. In nine of 11 patients, manometric improvement after sildenafil was observed but only four had an improvement in oesophageal symptoms with sildenafil taken as required. Two of these four patients however experienced side effects and did not want to continue treatment. Conclusions: Sildenafil lowers LOS pressure and propulsive forces in the body of the oesophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia. The effect of sildenafil on the oesophageal body may last for up to eight hours in healthy volunteers. A subset of patients with hypertensive LOS or nutcracker oesophagus may benefit from sildenafil but side effects are a limiting factor.

Effect of Pantoprazole on the Course of Reflux-Associated Laryngitis: a Placebo-Controlled Double-Blind Crossover Study

Background: The optimal management of patients with reflux-associated laryngitis is unclear. We performed a placebo-controlled crossover trial in patients with proven reflux disease and associated laryngitis to determine the effect of pantoprazole and to gain information on the natural course of the disease. Methods: Sixty-two consecutive non-smoking patients with hoarseness and proven laryngitis were examined. Scores with respect to the larynx and for subjective complaints were determined and 24-h pH-metry to assess acid reflux in the lower oesophagus and pharynx was performed. Patients with pathologic reflux were given the chance to enter a double-blinded randomized crossover trial with pantoprazole 40 mg b.i.d. and placebo for a duration of 3 months each, separated by a 2-week washout period. Results: Twenty-four of 62 patients showed pathological reflux; 21 patients were included in the study and 14 concluded all parts of the study. Both pantoprazole and placebo resulted in a marked improvement in laryngitis scores (decrease of 8.0 ± 1.4 versus 5.6 ± 2.6; no significant difference between the 2 treatments) and symptoms after the first 3 months (decrease of oesophageal symptom score of 2.2 ± 1.4 versus 5.4 ± 2.8; decrease of laryngeal scores of 8.3 ± 3.6 versus 10.3 ± 3.9; also no significant difference between the 2 treatments). A second pH-metry 2 weeks thereafter proved the persistence of reflux in most of these patients. Switching to pantoprazole led to a further improvement of scores. In the group switched to placebo there was recurrence only in a minority of patients. Conclusions: The self-limited nature of reflux-associated laryngitis in non-smokers is largely underestimated. Laryngitis improves despite the persistence of reflux. Pantoprazole may be helpful especially in relieving acute symptoms, but the advantage of long-term treatment over placebo has been greatly overestimated.

Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence.

Background and aims Recent publications have found that the CC genotype of the DNA variant −13910 T/C upstream of the LCT gene is associated with lactase non-persistence. We therefore compared the value of DNA testing for this variant (DNA test) with the lactose hydrogen breath test (H2 test), which is the clinical standard for the diagnosis of lactase non-persistence. Patients and methods One hundred and twenty-three consecutive patients with suspected lactose malabsorption were tested for the presence of the −13910 T/C variant by polymerase chain reaction-restriction fragment length polymorphism analysis. These patients also underwent the H2 test after ingestion of 50 g lactose. Results Thirty-seven subjects had a CC genotype of the −13910 T>C polymorphism suggesting lactase non-persistence; 36 (97%) had also a positive H2 test. Eighty-six subjects had either a TC or a TT genotype suggestive of lactase persistence. Seventy-four (86%) of these tested negative on the H2 test, while 12 patients had a positive H2 test. In eight of these 12 patients duodenal biopsies showed no evidence of small bowel disease. One patient carrying a CC genotype had a negative H2 test. In this patient the rise in serum glucose after oral lactose was normal, furthermore H2 non-excretion was also excluded. Conclusions An excellent correlation is observed between a CC genotype and a positive H2 test, whereas the correlation between a TC or TT genotype and a negative H2 test result is less strong. Analysis of the −13910 T/C variant can be considered a good test for predicting the presence of lactase non-persistence in a patient population with suspected lactose malabsorption.

Chemical nociception in the jejunum induced by capsaicin

Background and aims: Chemonociception in the human small intestine has not been studied extensively. Although capsaicin can cause intestinal sensations, it is not known if this is due to stimulation of chemoreceptors or to motor changes. Our aims were to evaluate motor activity during capsaicin induced nociception and to compare qualities of jejunal nociception induced by capsaicin and mechanical distension. Methods: Twenty nine healthy subjects swallowed a tube with a perfusion site at the ligament of Treitz and, 7 cm distally, a barostat balloon. Phasic motor activity was measured around the perfusion site and the balloon. Capsaicin solutions (40, 200, and 400 μg/ml) 2.5 ml/min were perfused for 60 minutes or until severe discomfort occurred. A graded questionnaire for seven different sensations was completed every 10 minutes and after capsaicin perfusion was replaced by saline perfusion because of severe discomfort. Sensations arising from pressure controlled distensions were assessed before and after capsaicin perfusion when sensations had stopped (n = 19), or during capsaicin administration when no discomfort was reported (n = 5). Results: Capsaicin perfusion induced feelings of pressure, cramps, pain, and warmth. The quality and abdominal location of these sensations were similar to those induced by distension, except for warmth (p<0.01) and pressure (p<0.05). Seven of 12 subjects receiving 40 μg/ml capsaicin and all subjects receiving higher capsaicin concentrations developed discomfort. Perfusion had to be stopped after 55 (3.3), 15 (5.7), and 10 (2.2) minutes with 40, 200, and 400 μg/ml capsaicin, respectively, whereafter the sensations disappeared within 10 minutes. Repeated capsaicin (200 μg/ml) applications significantly reduced the time until discomfort occurred (p = 0.01). Jejunal tone was not altered by capsaicin but phasic activity proximal to the perfusion site was reduced during capsaicin induced discomfort (p<0.001). Pain thresholds during distensions were not different before and after capsaicin perfusion. Conclusion: Despite the similarities in abdominal localisation and perceptional quality of capsaicin and distension induced sensations, our results rule out the fact that abdominal discomfort evoked by capsaicin involves sensitisation of mechanoreceptors or an increase in phasic and tonic motor activity. Capsaicin evokes abdominal sensations by stimulation of chemoreceptors which proves the existence of chemonociception in the human small intestine.

Gut Microbiota and Inflammatory Bowel Disease

Bacteria play an important role in the pathogenesis of inflammatory bowel disease (IBD), its complications and its symptoms. Antibiotics can decrease tissue invasion and eliminate aggressive bacterial species. They are used in IBD to treat infective complications and for altering bacterial flora, which may result in specific anti-inflammatory effects. In addition, suppression of bacterial metabolic activities or direct effects of antibiotics on intestinal structures and functions may result in symptoms which cannot be differentiated from symptoms caused by inflammation. Although current clinical trials do not fulfill criteria of evidence-based treatment, a few placebo- or standard treatment-controlled studies suggest that metronidazole and ciprofloxacin are effective in Crohn’s colitis and ileocolitis, perianal fistulae and pouchitis. Administration of probiotics, prebiotics and synbiotics can restore a predominance of beneficial species. However, beneficial effects of probiotics in IBD are modest, strain-specific and limited to certain manifestations of disease and duration of use of the probiotic. For probiotics there is reasonable evidence of efficacy in relapse prevention in chronic pouchitis and ulcerative colitis, and suggestive evidence for postoperative prevention in pouchitis. Therapeutic manipulation of the intestinal flora offers considerable promise for treating IBD, but must be supported by large controlled therapeutic trials before widespread clinical acceptance. These agents may become a component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents. Probiotic strategies, based on metagenomic or metabonomic analyses, and new classes of probiotics might play an important role in the future management of IBD.

Intraluminal capsaicin does not affect fluid and electrolyte absorption in the human jejunum but does cause pain

Background—Stimulation of sensory nerves with capsaicin regulates ion transport in the small intestine in animal experiments. Aim—To investigate whether sensory nerves that are stimulated by capsaicin administration influence fluid and electrolyte absorption in the human jejunum in vivo. Method—Intestinal perfusion studies were performed in 12 healthy subjects using a four lumen tube with a proximal occlusion balloon and a plasma-like electrolyte solution. After an initial control period, 5 (n = 3), 10 (n = 8), or 50 (n = 1) μg/ml capsaicin was added to the perfusate, and this was followed by a final control period. Rates of absorption of water, sodium, potassium, chloride, and bicarbonate were determined in a 30 cm segment of jejunum using a non-absorbable volume marker. Results—At all three concentrations of capsaicin there were no significant changes in water and electrolyte absorption as compared with control periods. Two subjects who received 10 μg/ml and the subject receiving 50 μg/ml experienced crampy abdominal pain. Conclusion—The results do not support the hypothesis that capsaicin sensitive afferent nerves are involved in the physiological regulation of net absorption or secretion across the human jejunal mucosa. Chemical stimulation of these nerves, however, gives rise to abdominal pain.

Acupuncture has a Placebo Effect on Rectal Perception but not on Distensibility and Spatial Summation: A Study in Health and IBS

BACKGROUND:Recent data suggest that acupuncture has effects on gut physiology and perception. Spatial summation is a central mechanism of perception and describes the phenomenon that thresholds for perception are lower if more receptors are stimulated.OBJECTIVES:We assessed perception thresholds for rectal distension and cutaneous referral of symptoms, while inflating one or two rectal balloons and the effect of both electro-acupuncture and placebo-acupuncture on rectal distensibility, perception, and spatial summation.METHODS:A tube with two barostat balloons was placed in the rectum of 12 healthy subjects and nine irritable bowel syndrome (IBS) patients with rectal symptoms. Volume-controlled stepwise distension of the distal balloon only or both balloons was performed first as a control, and thereafter with simultaneous placebo- or electro-acupuncture in dermatomes S3 and S4. A symptom questionnaire and anatomic questionnaire was completed during each distension.RESULTS:Rectal elastance increased from 42.0 ± 19.6 log mmHg/ml during one-balloon distension to 59.6 ± 33.1 log mmHg/ml during two-balloon distension (p < 0.05) in healthy subjects, and from 48.8 ± 14.4 log mmHg/ml (one balloon) to 77.6 ± 24.2 log mmHg/ml (p < 0.001) in patients with IBS. Electro-acupuncture had no effect on rectal sensation, elastance, and cutaneous referral when compared to placebo-acupuncture. However, acupuncture (both electro- and placebo-) increased volume thresholds for sensation compared to control experiments, while objective parameters like rectal tone and elastance were unaltered.CONCLUSIONS:Acupuncture has a placebo effect on rectal perception but has no effect on rectal distensibility and visceral referral. Spatial summation affected both rectum distensibility and perception, but was also not altered by acupuncture.

Low potential of dobutamine and dopexamine to block intestinal peristalsis as compared with other catecholamines

ObjectiveCatecholamines are frequently used in critically ill patients to restore stable hemodynamics and to improve organ perfusion. One effect of short-term or long-term administration of catecholamines may be inhibition of propulsive motility in the intestine. We therefore analyzed the effect of dopexamine, dobutamine, and dopamine on ileal peristalsis and compared their action with that of epinephrine and norepinephrine, which have long been known to suppress intestinal peristalsis. DesignIn vitro study on excised guinea pig ileum segments. SettingLaboratory for experimental studies at the University. SubjectsIsolated guinea pig ileum. InterventionsSegments of ileum excised from guinea pigs were mounted in a tissue bath in Krebs-Henseleit solution and bubbled with 95% oxygen/5% CO2. Luminal perfusion with the same solution was performed at a rate of 0.35 mL/min. The bath temperature was kept at 36.5°C. Peristalsis was recorded via changes in the intraluminal pressure. The drugs under investigation (dopamine, epinephrine, norepinephrine, dobutamine, and dopexamine) were added to the tissue bath. Measurements and Main ResultsLow concentrations of each catecholamine, except epinephrine, caused a decrease in the pressure threshold, which reflects a stimulatory effect on peristalsis. Higher catecholamine concentrations caused a concentration-related increase in the threshold, cumulating in a complete block of peristalsis. The rank order of inhibitory potency was epinephrine > norepinephrine > dopamine > dobutamine ∼ dopexamine. Dobutamine and dopexamine were about 500-fold less active than epinephrine in suppressing peristalsis. ConclusionsThis study shows that dobutamine and dopexamine have the least potential to block propulsive motility in the intestine, whereas epinephrine demonstrates the most adverse inhibitory effect. Because at low concentrations dobutamine and dopexamine even stimulate peristalsis, these drugs appear to be superior compared with other catecholamines with regard to their direct effects on intestinal motility.

Effects of lactulose and polyethylene glycol on colonic transit.

Background : The effects of lactulose and polyethylene glycol on colonic transit are poorly established.