Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study

Background  Intestinal immune infiltration contributes to symptoms in patients with irritable bowel syndrome (IBS).
Aim  To assesses the effect of mesalazine (mesalamine) on mucosal immune cells in patients with IBS, through a pilot study.
Methods  A randomized, double-blind, placebo-controlled trial in 20 patients with IBS in tertiary care setting. Patients were randomized to receive placebo or 800 mg mesalazine three times daily for 8 weeks. The primary endpoint was a significant reduction in total colonic immune cells on biopsies obtained at the end of treatment compared to baseline. Secondary endpoints included effects on subsets of immune cells, inflammatory mediators and symptom severity. Intention-to-treat analysis was performed.
Results  Mesalazine markedly reduced immune cells as compared with placebo ( P  = 0.0082); this effect was ascribed to a marked inhibition of mast cells ( P  = 0.0014). Mesalazine significantly increased general well-being ( P  = 0.038), but had no significant effects on abdominal pain ( P  = 0.084), bloating ( P  = 0.177) or bowel habits. No serious drug-related adverse events were reported during the study.
Conclusions  Mesalazine is an effective and safe approach to reduce mast cell infiltration and may improve general well-being in patients with IBS. These results support the hypothesis that immune mechanisms represent potential therapeutic targets in IBS.     

Effects of bisacodyl on ascending colon emptying and overall colonic transit in healthy volunteers

Background  The mechanism of action of bisacodyl in the unprepared human colon remains unclear.
Aim  To evaluate the effect of oral bisacodyl on the overall and regional colonic transit in humans.
Methods  In a double-blind, randomized, placebo-controlled study of 25 healthy participants, effects of oral bisacodyl (5 mg p.o. per day) and placebo on colonic transit were compared. A validated scintigraphy method was used to measure colonic transit. The primary transit endpoints, ascending colon emptying t _1/2 and geometric centre of colon isotope at 24 h (overall transit), were compared (Wilcoxon rank sum test).
Results  There were significant treatment effects on ascending colon t _1/2, with the bisacodyl group demonstrating accelerated emptying [median 6.5 h, interquartile range 5.0–8.0 h] relative to the placebo group [11.0 h (7.0–17.1); P  = 0.03]. Numerical differences in colonic geometric centre 24 h [bisacodyl median 3.0 (2.2–3.8), placebo 4.0 (3.1–4.6)] were not significant ( P  = 0.19). There were no significant differences observed in geometric centre 4 h.
Conclusion  Oral 5 mg bisacodyl accelerates ascending colon in the unprepared colon in healthy adults; this action may contribute to the drug's efficacy in constipation.     

Relationship between rectal sensitivity, symptoms intensity and quality of life in patients with irritable bowel syndrome

Background  Relationships between pain threshold during rectal distension and both symptoms intensity and alteration in quality of life (QoL) in irritable bowel syndrome (IBS) patients have been poorly evaluated.
Aim  To evaluate relationships between rectal sensitivity, IBS symptom intensity and QoL in a multicentre prospective study.
Methods  Rectal threshold for moderate pain was measured during rectal distension in IBS patients (Rome II), while IBS symptoms intensity was assessed by a validated questionnaire and QoL by the Functional Digestive Disorder Quality of Life questionnaire.
Results  Sixty-eight patients (44.2 ± 12.7 years, 48 women) were included. The mean rectal distending volume for moderate pain was 127 ± 35 mL while 45 patients (66%) had rectal hypersensitivity (pain threshold <140 mL). Rectal threshold was not significantly related either to overall IBS intensity score ( r  = −0.66, P  =   0.62) or to its different components, or to FDDQL score ( r  = 0.30, P  =   0.14). Among FDDQL domains, only anxiety ( r  = 0.30, P  =   0.01) and coping ( r  = 0.31, P  =   0.009) were significantly related with pain threshold.
Conclusions  In this study, two-thirds of IBS patients exhibited rectal hypersensitivity. No significant correlation was found between rectal threshold and either symptom intensity or alteration in QoL.     

Involvement of endogenous CCK and CCK1 receptors in colonic motor function

Cholecystokinin (CCK) is a brain-gut peptide; it functions both as a neuropeptide and as a gut hormone. Although the pancreas and the gallbladder were long thought to be the principal peripheral targets of CCK, CCK receptors are found throughout the gut. It is likely that CCK has a physiological role not only in the stimulation of pancreatic and biliary secretions but also in the regulation of gastrointestinal motility. The motor effects of CCK include postprandial inhibition of gastric emptying and inhibition of colonic transit. It is now evident that at least two different receptors, CCK(1) and CCK(2) (formerly CCK-A and CCK-B, respectively), mediate the actions of CCK. Both localization and functional studies suggest that the motor effects of CCK are mediated by CCK(1) receptors in humans. Since CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating and abdominal pain that are often characteristic of functional gastrointestinal disorders in general and irritable bowel syndrome (IBS), in particular. CCK(1) receptor antagonists are therefore currently under development for the treatment of constipation-predominant IBS. Clinical studies suggest that CCK(1) receptor antagonists are effective facilitators of gastric emptying and inhibitors of gallbladder contraction and can accelerate colonic transit time in healthy volunteers and patients with IBS. These drugs are therefore potentially of great value in the treatment of motility disorders such as constipation and constipation-predominant IBS.     

Gastrointestinal complaints among subjects with depressive symptoms in the general population

Background  Patients with depression have irritable bowel syndrome (IBS) more often than do nondepressed patients, but the comorbidity of depression and gastrointestinal (GI) symptoms in the general population has received little study.
Aim  To study the co-occurrence of depressive and GI symptoms in a general population sample and to assess the rate of health-care utilization particularly for GI reasons among subjects with depressive symptoms.
Methods  A questionnaire containing the Finnish version of the Beck Depression Inventory Short Form and questions covering GI symptoms according to Rome II criteria was mailed to 5000 randomly selected adults.
Results  Response rate was 73%. Prevalence of depressive symptoms was 17% (95% CI: 15.7–18.2). Frequent abdominal pain, diarrhoea, constipation, dyspepsia or IBS were present in 54% of those with depressive symptoms and in 29% of nondepressed controls ( P  < 0.0001). Of those with depressive symptoms, 24% had visited a physician at least once because of abdominal symptoms during the previous year, compared to 13% of controls ( P  < 0.0001).
Conclusions  Depressive symptoms are prevalent in the general population. They are associated with a high rate of GI symptoms, leading to increased use of health-care services and work absenteeism because of abdominal complaints.     

Alosetron

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.     

Review article: abdominal bloating and distension in functional gastrointestinal disorders--epidemiology and exploration of possible mechanisms

Background A sensation of abdominal bloating, sometimes accompanied by an increase in girth (distension), is one of the most common and most intrusive features of functional bowel disorders. Aim To conduct a systematic, evidence‐based review of the epidemiology and pathophysiology of abdominal bloating and its relationship to distension. Methods The terms bloating, distension, functional bowel, irritable bowel syndrome, constipation and diarrhoea were searched on MEDLINE up to 2006. References from selected articles and relevant abstracts were also included. Results Approximately 50% of irritable bowel syndrome patients with bloating also experience an increase in abdominal girth and this is more pronounced with constipation than diarrhoea. Bloating appears to be more frequently associated with visceral hypersensitivity, whereas distension is more often related to hyposensitivity and delayed transit. Although there is little evidence for excessive gas as a cause of bloating, gas infusion studies suggest that handling of gas may be impaired in irritable bowel syndrome and there may also be abnormal relaxation of the anterior abdominal musculature in these patients. Conclusions There is unlikely to be a single cause for bloating and distension, which probably have different, but overlapping, pathophysiological mechanisms. Relieving constipation might help distension, but the treatment of bloating may need more complex approaches involving sensory modulation.     

The serotonin reuptake inhibitor citalopram does not affect colonic sensitivity or compliance in rats

Altered serotonin signaling has been implicated in the pathophysiology of irritable bowel syndrome (IBS). Selective serotonin reuptake inhibitors (SSRI) improve IBS symptoms, although the mechanism of action remains unclear. We assessed the effects of the SSRI, citalopram, on colonic sensitivity and compliance in rats after acute and repeated administration. Colorectal distension was performed in conscious rats. Pressure–volume relationships during colorectal distension (2–20 mmHg), fitted using a power exponential model [Vol = V_max × exp[− (κ × RelP)^β], were used as a measure of colonic compliance. The visceral pain-related visceromotor response during colorectal distension (10–80 mmHg) was used to assess visceral sensitivity. Pressure–volume curves and visceromotor responses were assessed after acute citalopram (3 or 10 mg/kg, ip) or vehicle and after repeated treatment (7 and 14 days; 3 or 10 mg/kg/day). In vehicle-treated animals, pressure–volume curves were similar over time. Citalopram (acute or repeated treatment) did not affect neither the pressure–volume curves nor the visceromotor response to colorectal distension. Thus, citalopram, after acute or repeated administration, had no significant effects on colon compliance or visceral pain during colorectal distension in rats. These results agree with recent observations in humans suggesting that the therapeutic actions of citalopram in IBS are independent of any effects on colonic sensorimotor function.     

Amitriptyline modifies the visceral hypersensitivity response to acute stress in the irritable bowel syndrome

Background  Acute physical stress causes alteration in gut autonomic function and visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We have developed a model to measure this stress response.
Aim  To assess whether treatment with a drug effective in treating IBS (amitriptyline) alters the response to acute stress in IBS patients.
Methods  Nineteen patients with IBS were given amitriptyline 25–50 mg. Patients underwent physical stress (cold pressor) test at baseline and after 3 months of treatment. Physiological parameters measured were: stress perception; systemic autonomic tone [heart rate (HR) and blood pressure (BP)]; gut specific autonomic innervation [rectal mucosal blood flow (RMBF)] and visceral sensitivity (rectal electrosensitivity).
Results  Fourteen of 19 (74%) patients improved symptomatically after 3 months of amitriptyline. Acute stress induced increased perception of stress and systemic autonomic tone and reduced RMBF in symptomatic responders and nonresponders ( P  > 0.05 for all). All nonresponders but only 3 of 14 responders continued to exhibit stress-induced reduced pain threshold at 3 months (change from baseline −31% vs. +2%, P  < 0.03 respectively).
Conclusion  In this open study, amitriptyline appears to decrease stress-induced electrical hypersensitivity; this effect is independent of autonomic tone. The gut response to acute stress deserves further study as a model to study drug efficacy in IBS.     

Review article: probiotics and prebiotics in irritable bowel syndrome

Background  The human gut harbours a complex community of bacteria whose relationship with their host is normally mutually beneficial. Recent studies suggest a disturbance of this relationship in irritable bowel syndrome (IBS) and the potential to correct this using prebiotics and probiotics.
Aim  To review the mechanisms of action of probiotics and prebiotics in IBS and to assess their performance in clinical trials.
Methods  Articles relating to modes of action and randomized control trials of treatment were reviewed by searching PubMed using terms 'probiotic', 'prebiotic' and 'irritable bowel'. Small uncontrolled studies in IBS were excluded.
Results  Probiotics can enhance gut barrier function, inhibit pathogen binding and modulate gut inflammatory response. They can also reduce visceral hypersensitivity associated with both inflammation and psychological stress. Probiotics can alter colonic fermentation and stabilize the colonic microbiota. Several large randomized, placebo-controlled trials of adequate design have shown an improvement in flatulence and abdominal distension with a reduction in composite IBS symptoms scores.
Conclusions  Each probiotic has unique features and IBS patients are heterogeneous. Future efforts should be directed to identifying biomarkers of responsiveness to facilitate better targeting of treatment and hence improved efficacy.     

Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome

Background  Gut microflora-mucosal interactions may be involved in the pathogenesis of irritable bowel syndrome (IBS).
Aim  To investigate the efficacy of a novel prebiotic trans-galactooligosaccharide in changing the colonic microflora and improve the symptoms in IBS sufferers.
Methods  In all, 44 patients with Rome II positive IBS completed a 12-week single centre parallel crossover controlled clinical trial. Patients were randomized to receive either 3.5 g/d prebiotic, 7 g/d prebiotic or 7 g/d placebo. IBS symptoms were monitored weekly and scored according to a 7-point Likert scale. Changes in faecal microflora, stool frequency and form (Bristol stool scale) subjective global assessment (SGA), anxiety and depression and QOL scores were also monitored.
Results  The prebiotic significantly enhanced faecal bifidobacteria (3.5 g/d P  < 0.005; 7 g/d P  < 0.001). Placebo was without effect on the clinical parameters monitored, while the prebiotic at 3.5 g/d significantly changed stool consistency ( P  < 0.05), improved flatulence ( P  < 0.05) bloating ( P  < 0.05), composite score of symptoms ( P  < 0.05) and SGA ( P  < 0.05). The prebiotic at 7 g/d significantly improved SGA ( P  < 0.05) and anxiety scores ( P  < 0.05).
Conclusion  The galactooligosaccharide acted as a prebiotic in specifically stimulating gut bifidobacteria in IBS patients and is effective in alleviating symptoms. These findings suggest that the prebiotic has potential as a therapeutic agent in IBS.     

Mucosal interleukin-1β production and acid secretion in enlarged fold gastritis

Background : We have previously shown that eradication of Helicobacter pylori increases acid secretion in H. pylori -associated enlarged fold gastritis.
Aim : To investigate whether locally produced interleukin-1β is possibly involved in the inhibition of acid secretion in H. pylori gastritis.
Methods : IL-1β release from the gastric body mucosa was determined by short-term culture of biopsy specimens in 13 patients with enlarged fold gastritis (all H. pylori -positive), five H. pylori -positive and 10 H. pylori -negative patients without enlarged folds. The acid-inhibitory effect of locally produced IL-1β was examined by [¹⁴C]-aminopyrine uptake assay using isolated rabbit gastric glands.
Results : IL-1β release was significantly greater in patients with enlarged fold gastritis, significantly correlated with both basal and tetragastrin-stimulated acid outputs in the H. pylori -positive patients ( r  = −0.591 and r  = −0.641, respectively; P  < 0.01), and significantly decreased with concomitant increases in acid secretions after eradication of H. pylori . [¹⁴C]-aminopyrine uptake was inhibited by IL-1β in a dose-dependent manner.
Conclusions : Increased production of IL-1β caused by H. pylori infection is possibly involved in the inhibition of acid secretion in enlarged fold gastritis.     

A randomized, placebo-controlled, crossover, double-blind trial of the NK1 receptor antagonist aprepitant on gastrointestinal motor function in healthy humans

Background  Little is known about the role of tachykinins on human gastrointestinal motility and no data exist on the possible effect of an NK1 receptor antagonist.
Aim  To examine the effect of an antiemetic dose of the selective NK1 receptor antagonist aprepitant on gastrointestinal propulsion in healthy humans.
Methods  Twelve healthy volunteers participated in a crossover, double-blind study. In random order, each volunteer had a 125-mg capsule of aprepitant or placebo on day 1 followed by an 80-mg capsule of aprepitant or placebo on days 2–5. Gamma camera imaging was used to measure gastric emptying, small intestinal transit and colonic transit of a radiolabelled, 1600-kJ mixed liquid and solid meal ingested on day 2.
Results  Aprepitant did not change gastric retention at 15 min, gastric half emptying time, gastric mean transit time, time to small intestinal transit of 10%, small intestinal mean transit time or colonic geometric centre after 24, 48 and 72 h.
Conclusion  A 125-mg capsule of aprepitant followed by an 80-mg capsule of aprepitant each of the next 2–5 days did not induce major changes in the propulsive function of the gastrointestinal tract in the small number of healthy volunteers investigated.     

Effect of peppermint oil and caraway oil on gastrointestinal motility in healthy volunteers: a pharmacodynamic study using simultaneous determination of gastric and gall-bladder emptying and orocaecal transit time

BACKGROUND: Although peppermint oil and caraway oil are frequently used in herbal drugs for abdominal discomfort and pain, the pharmacological insights into their effects on the gastrointestinal tract are poor. METHODS: The pharmacodynamic effects of 90 mg peppermint oil (WS 1340) and 50 mg caraway oil (WS 1520) on the motility of the stomach and gall-bladder, and on the orocaecal transit time, in comparison with placebo, 10 mg cisapride and 10 mg n-butylscopolamine, were studied in 12 healthy volunteers. The study involved simultaneous ultrasonic determination of gastric and gall-bladder emptying, together with assessment of the orocaecal transit time using the lactulose H2 breath test. The combination of these methods allows three gastrointestinal organs to be studied in one subject simultaneously. RESULTS: The antral filling time was comparable with placebo, peppermint oil, caraway oil and cisapride, whereas it was significantly shortened (P = 0.04, two-sided paired t-test) with n-butylscopolamine. The gastric emptying time did not differ significantly between placebo, peppermint oil, caraway oil and cisapride, but was significantly prolonged by n-butylscopolamine (P = 0.04, two-sided paired t-test). Complete inhibition of gall-bladder emptying was caused by both oils and n-butylscopolamine. Cisapride significantly shortened gall-bladder emptying compared with placebo (P = 0.02, two-sided signed rank test). The orocaecal transit time was significantly prolonged by peppermint oil (P = 0.004) and n-butylscopolamine (P = 0.002), but not significantly prolonged by caraway oil (P = 0.06); it was significantly shortened by cisapride (P = 0.04, all two-sided paired t-test). CONCLUSIONS: Peppermint oil and caraway oil show a relaxing effect on the gall-bladder and the former slows small intestinal transit. Further studies should investigate the effects of both oils on a maximal contraction stimulus on the gall-bladder, and in patients suffering from motility disorders.     

Clinical trial: effectiveness of chewing-gum in accelerating capsule endoscopy transit time--a prospective randomized, controlled pilot study

Background  Capsule endoscopy (CE) fails to reach the caecum in approximately 20% of patients. Data suggest that chewing-gum, simulating sham feeding, provokes the cephalic phase of gastrointestinal (GI) motor response and may increase GI motility.
Aim  To determine whether chewing-gum increases the ability of CE reaching the caecum.
Methods  Prospective, randomized, single-blinded controlled trial. Ninety-three consecutive patients were randomized either to use chewing-gum ( n  = 47) or not ( n  = 46). All patients received the identical bowel preparation. Patients chewed one piece of gum for approximately 30 min every 2 h. Two blinded gastroenterologists examined all studies. The number of CE that reached the caecum within 8-h, gastric transit time (GTT) and small bowel transit time (SBTT) were evaluated in all patients.
Results  The CE percentage passed into the caecum was higher in the chewing-gum group compared with those in the other (83.0% vs. 71.7% respectively, P  = 0.19). Both GTT and SBTT were significantly shorter in the chewing-gum vs. control group [40.8 min (interquartile range: 21–61 min) vs. 56.1 min (interquartile range: 22–78 min) ( P  = 0.045) and 229.1 min (interquartile range: 158–282 min) vs. 266.2 min (interquartile range: 204–307 min) ( P  = 0.032) respectively]. Chewing-gum did not adversely affect CE image quality.
Conclusions  Chewing-gum significantly reduces GTT and SBTT during CE. Its use may improve the likelihood of the capsule reaching the caecum without affecting CE image quality.     

Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis

Background  Patients with chronic hepatitis C virus and advanced fibrosis or cirrhosis are at risk for disease progression and hepatic decompensation.
Aim  To determine the effects on hepatic histology of treatment with peginterferon alfa-2a (90 or 180 μg/week) or interferon alfa-2a (3 million units three times weekly) for 48 weeks in patients with paired biopsies.
Methods  Liver biopsies were obtained at baseline and 6 months after end of treatment. Histological and virological responses were compared.
Results  Patients attaining sustained virological response ( n  = 40) demonstrated the greatest improvements in fibrosis (−1.0, P  < 0.0001) and inflammation (−0.65, P  < 0.0001). Patients who cleared hepatitis C virus during treatment, but later relapsed ( n  = 59), experienced less improvement in fibrosis (−0.04, P  < 0.0001) and inflammation (−0.14, P  = 0.0768). Nonresponders ( n  = 85) showed no significant improvement in inflammation or fibrosis. Multiple regression analysis showed that the only factors contributing to improvement in fibrosis were sustained virological response (vs. nonresponder, P  = 0.0005; vs. relapse, P  = 0.7525) and body mass index ≤30 kg/m² ( P  = 0.0995).
Conclusions  These findings indicate that virological response to peginterferon alfa-2a improves inflammation and fibrosis in hepatitis C virus patients with advanced fibrosis or cirrhosis. Improving virological response and maintaining ideal body weight are critical for achieving optimal histological outcomes in hepatitis C virus patients.     

Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease

Background  Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.
Aim  To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.
Methods  We identified 135 patients (74 women; median age 40 years) with Crohn's disease ( n  = 88) or ulcerative colitis ( n  = 47) and reviewed their medical records.
Results  A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362–1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8–92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P  = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4–15.3) vs. 11.8 (9.6–14.2) U/mL red blood cells; P  = 0.04; n  = 81].
Conclusions  A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.     

Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia

Background  Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common functional disorders without defined pathology. Mast cells and eosinophils interact with T lymphocytes and may alter enteric nerve and smooth muscle function.
Aim  To examine mast cell, eosinophil and intraepithelial lymphocyte populations in duodenal biopsies of subjects with IBS and FD.
Methods  A random sample of an adult Swedish population ( n  = 1001; mean age 54 years; 51% female) underwent upper endoscopy and biopsy; 51 cases with FD and 41 cases with IBS were compared with 48 randomly selected controls. Eosinophils were identified by light microscopy; mast cells by immunocytochemistry (CD117). Intraepithelial lymphocytes were counted per 100 enterocytes. Cell counts were quantified by counting the number per high power field (HPF) in 5HPFs in the bulb (D1) and second part of duodenum (D2), summed over 5HPFs at each site.
Results  Cases and controls showed similar demographics. Compared to controls, IELs in IBS-constipation were significantly increased ( P  = 0.005). Mast cells were significantly increased in IBS in D2 ( P  < 0.001), while eosinophils were significantly increased in FD in D1 and D2 ( P  < 0.001).
Conclusion  Duodenal mast cell hyperplasia is linked to IBS and eosinophilia to FD, and duodenal biopsy may identify subsets of these disorders.     

Baseline microbiota activity and initial bifidobacteria counts influence responses to prebiotic dosing in healthy subjects

Background  Dietary intervention with prebiotics can cause changes in the colonic microbiota and their metabolic activities.
Aim  To investigate whether the response to prebiotic dosing is influenced by the baseline metabolic activity of the colonic flora and bifidobacteria counts.
Methods  The 4-week effect of lactulose (10 g bid.; n  = 29) and oligofructose-enriched inulin (10 g bid.; n  = 19) was evaluated in healthy human volunteers. Lactose-[¹⁵N, ¹⁵N]-ureide was used to study the colonic NH₃-metabolism. Urine (48 h) and faeces (72 h) were collected and analysed for p-cresol and ¹⁵N-content by gas chromatography–mass spectrometry and isotope ratio mass spectrometer, respectively. Faecal bifidobacteria were quantified by real-time polymerase chain reaction.
Results  After the 4-week prebiotic administration period, the urinary excretion of p-cresol and ¹⁵N was significantly decreased in both groups ( P  < 0.05) corresponding to a significantly higher faecal excretion of ¹⁵N ( P  < 0.05). The decrease in urinary ¹⁵N and p-cresol excretion significantly correlated with baseline ¹⁵N and p-cresol levels ( P  < 0.05), indicating that subjects with higher baseline levels showed a higher response to prebiotic dosing. Furthermore, a significant correlation was seen between baseline bifidobacteria counts and the effect of prebiotic intake ( P  < 0.05).
Conclusion  The response to prebiotic dosing, as indicated by the fate of NH₃, p-cresol and bifidobacteria, is determined by the initial colonic conditions.     

NSAID-induced antral ulcers are associated with distinct changes in mucosal gene expression

Background  The basis for individual variation in gastroduodenal vulnerability to NSAIDs is not well understood.
Aim  To assess whether a gene expression signature is associated with susceptibility to gastroduodenal ulcerations.
Methods  Twenty-five Helicobacter pylori negative adults were treated for 7 days with naproxen 500 mg b.d. Subjects underwent baseline and post-treatment endoscopy, during which biopsies were taken from antrum and duodenum. RNA extraction and cDNA synthesis were performed, followed by PCR of 23 genes relevant to mucosal injury and repair. Fold changes in gene expression were compared between subjects who developed ulcers and those who did not.
Results  Compared with subjects who did not develop ulcers ( n  = 18), subjects who developed antral ulcers ( n  = 7) had significantly greater mucosal up-regulation of interleukin-8 [Fold change = 33.5 (S.E.M. = 18.5) vs. −7.7 (3.2)] and of cyclo-oxygenase-2 [2.3 (1.7) vs. −10.8 (2.2)]. Conversely, non-ulcer subjects had significantly greater up-regulation of toll-like receptor-4, cyclo-oxygenase-1 and hepatocyte growth factor [14.0 (2.2) vs. −0.8 (1.0), 9.8 (2.4) vs. 0.0 (0.7) and 8.2 (2.6) vs. −2.2 (0.3) respectively].
Conclusions  NSAID-induced antral ulcers are associated with a specific pattern of gastroduodenal mucosal gene expression. These patterns may provide an insight into the molecular basis of individual susceptibility to mucosal injury.