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Wilder-Smith C.H.,Brain Gut Research Group | Olesen S.S.,University of Aalborg | Materna A.,Brain Gut Research Group | Drewes A.M.,University of Aalborg
Alimentary Pharmacology and Therapeutics | Year: 2017

Background: Diets low in fermentable sugars (low-FODMAP diets) are increasingly adopted by patients with functional gastrointestinal disorders (FGID), but outcome predictors are unclear. Aim: To identify factors predictive of an efficacious response to a low-FODMAP diet in FGID patients with fructose or lactose intolerance thereby gaining insights into underlying mechanisms. Methods: Fructose and lactose breath tests were performed in FGID patients to determine intolerance (positive symptom score) and malabsorption (increased hydrogen or methane concentrations). Patients with fructose or lactose intolerance consumed a low-FODMAP diet and global adequate symptom relief was assessed after 6–8 weeks and correlated with pre-diet clinical symptoms and breath test results. Results: A total of 81% of 584 patients completing the low-FODMAP diet achieved adequate relief, without significant differences between FGID subgroups or types of intolerance. Univariate analysis yielded predictive factors in fructose intolerance (chronic diarrhoea and pruritus, peak methane concentrations and fullness during breath tests) and lactose intolerance (peak hydrogen and methane concentrations and flatulence during breath tests). Using multivariate analysis, symptom relief was independently and positively predicted in fructose intolerance by chronic diarrhoea [odds ratio (95% confidence intervals): 2.62 (1.31–5.27), P = 0.007] and peak breath methane concentrations [1.53 (1.02–2.29), P = 0.042], and negatively predicted by chronic nausea [0.33 (0.16–0.67), P = 0.002]. No independent predictive factors emerged for lactose intolerance. Conclusions: Adequate global symptom relief was achieved with a low-FODMAP diet in a large majority of functional gastrointestinal disorders patients with fructose or lactose intolerance. Independent predictors of a satisfactory dietary outcome were only seen in fructose intolerant patients, and were indicative of changes in intestinal host or microbiome metabolism. © 2017 John Wiley & Sons Ltd


Li X.,National University of Singapore | Kan E.M.,Combat Care Laboratory | Lu J.,Combat Care Laboratory | Cao Y.,National University of Singapore | And 4 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Gastrointestinal (GI) symptoms are common in soldiers in combat or high-pressure operational situations and often lead to compromised performance. Underlying mechanisms are unclear, but neuroendocrine dysregulation, immune activation and increased intestinal permeability may be involved in stress-related GI dysfunction. Aim To study the effects of prolonged, intense, mixed psychological and physical stress on intestinal permeability, systemic inflammatory and stress markers in soldiers during high-intensity combat-training. Methods In 37 male army medical rapid response troops, GI symptoms, stress markers, segmental intestinal permeability using the 4-sugar test (sucrose, lactulose, mannitol and sucralose) and immune activation were assessed during the 4th week of an intense combat-training and a rest period. Results Combat-training elicited higher stress, anxiety and depression scores (all P < 0.01) as well as greater incidence and severity of GI symptoms [irritable bowel syndrome symptom severity score (IBS-SSS), P < 0.05] compared with rest. The IBS-SSS correlated with depression (r = 0.41, P < 0.01) and stress (r = 0.40, P < 0.01) ratings. Serum levels of cortisol, interleukin-6, and tumour necrosis factor-α, and segmental GI permeability increased during combat-training compared with rest (all P < 0.05). The lactulose:mannitol ratio was higher in soldiers with GI symptoms (IBS-SSS ≥75) during combat-training than those without (IBS-SSS <75) (P < 0.05). Conclusions Prolonged combat-training not only induces the expected increases in stress, anxiety and depression, but also GI symptoms, pro-inflammatory immune activation and increased intestinal permeability. Identification of subgroups of individuals at high-risk of GI compromise and of long-term deleterious effects of operational stress as well as the development of protective measures will be the focus of future studies. © 2013 Blackwell Publishing Ltd.


Wong R.K.,National University of Singapore | Van Oudenhove L.,Catholic University of Leuven | Li X.,National University of Singapore | Cao Y.,National University of Singapore | And 3 more authors.
United European Gastroenterology Journal | Year: 2016

Background: The MRI scanner environment induces marked psychological effects, but specific effects on pain perception and processing are unknown and relevant to all brain imaging studies. Objectives and methods: We performed visceral and somatic quantitative sensory and pain testing and studied endogenous pain modulation by heterotopic stimulation outside and inside the functional MRI scanner in 11 healthy controls and 13 patients with irritable bowel syndrome. Results: Rectal pain intensity (VAS 0–100) during identical distension pressures increased from 39 (95% confidence interval: 35–42) outside the scanner to 53 (43–63) inside the scanner in irritable bowel syndrome, and from 42 (31–52) to 49 (39–58), respectively, in controls (ANOVA for scanner effect: p=0.006, group effect: p=0.92). The difference in rectal pain outside versus inside correlated significantly with stress (r=-0.76, p=0.006), anxiety (r=-0.68, p=0.02) and depression scores (r=-0.67, p=0.02) in controls, but not in irritable bowel syndrome patients, who a priori had significantly higher stress and anxiety scores. ANOVA analysis showed trends for effect of the scanner environment and subject group on endogenous pain modulation (p=0.09 and p=0.1, respectively), but not on somatic pain (p>0.3). Conclusion: The scanner environment significantly increased visceral, but not somatic, pain perception in irritable bowel syndrome patients and healthy controls in a protocol specifically aimed at investigating visceral pain. Psychological factors, including anxiety and stress, are the likely underlying causes, whereas classic endogenous pain modulation pathways activated by heterotopic stimulation play a lesser role. These results are highly relevant to a wide range of imaging applications and need to be taken into account in future pain research. Further controlled studies are indicated to clarify these findings. © Author(s) 2016.


Li X.,National University of Singapore | Cao Y.,National University of Singapore | Wong R.K.M.,National University of Singapore | Ho K.Y.,National University of Singapore | And 2 more authors.
Neurogastroenterology and Motility | Year: 2013

Background Visceral hypersensitivity is one of the proposed underlying mechanisms in functional dyspepsia (FD). It is not clear whether visceral hypersensitivity in FD is a manifestation of a central sensitization also encompassing somatic sensitization. Transient receptor potential vanilloid-1 (TRPV1) pathways are involved in gastric mechanosensory physiology and the TRPV1 receptor agonist, capsaicin, has been used as a chemical stimulant. Methods In this double-blind, randomized study we evaluated both visceral and somatic sensory function in 34 FD patients and 42 healthy controls using quantitative sensory testing. Visceral pain sensitivity was assessed using a validated gastric pain model with oral capsaicin capsule titration and somatic pain sensitivity was determined by foot heat and hand electric stimulation. Key Results The median capsaicin dose required to attain moderate pain was 0.5mg in FD and 1mg in controls (P=0.03). At these doses, mean pain intensities on a 0-100 visual analog scale were greater for FD than controls [56.9 (95% confidence intervals, 52.2-61.5) vs 45.1 (41.6-48.6), resp.] (P=0.005). Overall, mean somatic sensory and pain thresholds were similar in FD and control groups, but in a subgroup of FD pain hypersensitivity was seen on the hand and on the foot at different stimulation thresholds. Conclusions & Inferences A majority of patients with FD have visceral chemo-hypersensitivity involving TRPV1 pathways. A substantial subgroup also has somatic hypersensitivity as evidence of central sensitization. © 2012 Blackwell Publishing Ltd.


Cao Y.,National University of Singapore | Wilder-Smith C.H.,National University of Singapore | Wilder-Smith C.H.,Brain Gut Research Group | Li X.H.,National University of Singapore | And 3 more authors.
Neurogastroenterology and Motility | Year: 2011

Background Sensory sensitization is one of the main pathophysiological hypotheses in functional gastrointestinal disorders (FGIDs). As sensitization may affect various sensory modalities, we aimed to develop a reproducible gastric pain model utilizing polymodal pathways for use in functional and other pain disorders. Methods In this double-blind, cross-over study 42 healthy subjects swallowed one capsule containing either capsaicin 0.5mg or nocebo every 15min until moderate pain (intensity >30 on 100mm visual analogue scale) was attained for at least 5min. Pain was rated every minute. Capsaicin titration was repeated thrice for reliability calculation. Key Results Moderate pain in the upper abdomen was successfully achieved in 38 of 42 subjects (90%) with capsaicin titration and in one of 42 (2%) with nocebo. The median dosage required to induce moderate pain for at least 5min was two capsules (interquartile range 1-3) and the median gastric pain intensity was 47 (41-53). The median duration of moderate pain was 8min (5-12). Moderate pain was successfully reproduced with capsaicin in all subjects on study days 2 and 3, with an excellent Cronbach reliability coefficient of >0.8. Conclusions & Inferences Standardized gastric pain can be conveniently achieved in a majority of healthy subjects using a simple oral capsaicin titration, with minimal adverse events. The between-test reproducibility is high and nocebo responses are negligible. This technique stimulating a multimodal physiological pathway will be useful in the investigation of sensory changes in FGIDs, including functional dyspepsia. © 2011 Blackwell Publishing Ltd.


Wilder-Smith C.H.,Brain Gut Research Group | Wilder-Smith C.H.,National University of Singapore
Gut | Year: 2011

Functional gastrointestinal disorders (FGIDs) are characterised by visceral pain or discomfort with an unknown cause. There is increasing evidence for abnormal processing of sensory input in FGIDs. Modulation of sensory input occurs at all levels of the nervous system, with a dynamic balance between facilitation and inhibition and close integration with the body's wider homoeostatic control. Cognitive, emotional, autonomic and spinal reflex pathways effectively orchestrate supraspinal and spinal pain modulation, as demonstrated in neurophysiological and brain imaging studies. Endogenous pain modulation has been studied in visceral pain conditions and abnormal regulation has been shown in irritable bowel syndrome (IBS) and functional dyspepsia, as well as other chronic pain syndromes. A majority of patients with IBS have diminished pain inhibition or even pain facilitation compared with healthy controls. Brain imaging during specific activation of endogenous pain modulation demonstrates a fairly consistent functional hub of mainly frontal, limbic and brainstem modulatory regions in healthy humans. Patients with IBS have a different pattern of activation and a correlation between the imaging and sensory changes. Because the modulatory balance of inhibition and facilitation appears to be distributed within the same functional network, future imaging studies of modulation mechanisms should include conditions allowing quantification of inhibitory and facilitatory components. An altered modulatory balance may well be a unifying pathophysiological mechanism in FGID as it can be driven by both top-down (ie, CNS pathology) and bottom-up (ie, peripheral immune activation) influences, but further validation in diverse FGID groups over time is required. Therapeutic manipulation of the modulatory system is possible by both pharmacological and nonpharmacological means.


Wilder-Smith C.H.,Brain Gut Research Group | Wilder-Smith C.H.,National University of Singapore | Li X.,National University of Singapore | Shen L.,National University of Singapore | And 3 more authors.
Neurogastroenterology and Motility | Year: 2014

Background: Endogenous pain modulation (EPM) is central to the processing of sensory information. Visceral and somatic EPM are abnormal in irritable bowel syndrome, but have not been studied in functional dyspepsia (FD). Methods: Visceral EPM was assessed in 34 FD patients and 42 healthy controls. Gastric pain was induced with oral capsaicin and EPM was studied by adding heterotopic thermal foot stimulation or distraction by STROOP test. Somatic EPM was assessed using foot heat stimulation with heterotopic hand electrical stimulation. Key Results: Endogenous pain modulation by distraction reduced mean gastric pain by 11.9 on the 0-100 visual analog scale (95% CI: 3.8-20.1) in controls (p = 0.006) and by 2.0 (-6.18 to 10.44) in FD (p = 0.6), with greater EPM in controls than in FD (difference -13.3 [-26.1 to -0.5]; p = 0.04). Endogenous pain modulation by heterotopic foot stimulation reduced gastric pain by 6.5 (-0.7 to 13.6) in controls (p = 0.07) and by 7.1 (-2.29 to 16.47) in FD (p = 0.1), with no significant difference in EPM between controls and FD (-2.0 [-14.5 to 10.5]; p = 0.75). In patients with prominent FD pain, greater pain correlated with decreased visceral EPM by distraction (r = 0.51, p = 0.04). Somatic EPM by heterotopic stimulation significantly decreased foot pain in controls (p = 0.004), but not in FD (p = 0.80). Conclusions & Inferences: In FD, visceral pain modulation by distraction was dysfunctional compared to controls. Somatic pain modulation was also decreased in FD. These data and the correlation of abnormal pain modulation by distraction with clinical pain in pain-predominant FD suggest a potential pathophysiological significance of abnormal pain modulation in FD. © 2013 John Wiley & Sons Ltd.


Li X.,National University of Singapore | Wilder-Smith C.H.,National University of Singapore | Wilder-Smith C.H.,Brain Gut Research Group | Kan M.E.,Combat Care Laboratory | And 3 more authors.
Neuroendocrinology Letters | Year: 2014

BACKGROUND: Experimental data suggest stress-related cognitive dysfunction may be associated with increased blood-brain-barrier (BBB) permeability secondary to immune activation. METHODS: We investigated the relationship between prolonged and intense physical and psychological combat-training stress, immune activation and bloodbrain-barrier permeability in 37 healthy male army medical rapid response troops. RESULTS: Soldiers during intense combat training showed greater self-reported stress, anxiety and depression levels than at rest, as assessed by specific questionnaires. S100B, a marker of BBB permeability, as well as serum cortisol, IL-6 and TNF-α concentrations, were significantly increased in soldiers during combat training compared to rest (all p<0.05). Serum S100B correlated negatively with morning serum cortisol in soldiers during combat training, but not during the rest period (r=-0.387,p<0.05). CONCLUSION: We conclude that combat training inducing significant levels of stress, depression and anxiety is accompanied by evidence of increased blood-brain barrier permeability and by increases in systemic pro-inflammatory mediators. ©2014 Neuroendocrinology Letters.


PubMed | Brain Gut Research Group and University of Bern
Type: Journal Article | Journal: United European gastroenterology journal | Year: 2015

Dental erosion is a complication of gastro-oesophageal reflux disease (GORD) according to the Montreal consensus statement. However, GORD has not been comprehensively characterized in patients with dental erosions and pH-impedance measures have not been reported.Characterize GORD in patients with dental erosions using 24-h multichannel intraluminal pH-impedance measurements (pH-MII) and endoscopy.This single-centre study investigated reflux in successive patients presenting to dentists with dental erosion using pH-MII and endoscopy.Of the 374 patients, 298 (80%) reported GORD symptoms <2 per week, 72 (19%) had oesophagitis and 59 (16%) had a hiatal hernia. In the 349 with pH-MII the mean percentage time with a pH <4 (95% CI) was 11.0 (9.3-12.7), and 34.4% (31.9-36.9) for a pH <5.5, a critical threshold for dental tissue. The mean numbers of total, acidic and weakly acidic reflux episodes were 71 (63-79), 43 (38-49) and 31 (26-35), respectively. Of the reflux episodes, 19% (17-21) reached the proximal oesophagus. In 241 (69%) patients reflux was abnormal using published normal values for acid exposure time and reflux episodes. No significant associations between the severity of dental erosions and any reflux variables were found. The presence of GORD symptoms and of oesophagitis or a hiatal hernia was associated with greater reflux, but not with increased dental erosion scores.Significant oligosymptomatic gastro-oesophageal reflux occurs in the majority of patients with dental erosion. The degree of dental erosion did not correlate with any of the accepted quantitative reflux indicators. Definition of clinically relevant reflux parameters by pH-MII for dental erosion and of treatment guidelines are outstanding. Gastroenterologists and dentists need to be aware of the widely prevalent association between dental erosion and atypical GORD.


Wilder-Smith C.,Brain Gut Research Group | Rohss K.,Astrazeneca | Bokelund Singh S.,Astrazeneca | Sagar M.,Astrazeneca | Nagy P.,Astrazeneca
Alimentary Pharmacology and Therapeutics | Year: 2010

Aliment Pharmacol Ther 2010; 32: 1249-1256 Summary Background Symptoms of gastro-oesophageal reflux disease (GERD) may persist despite daily treatment with a proton pump inhibitor (PPI). Aim To compare the pharmacodynamic effect of various esomeprazole dosage and timing regimens in healthy volunteers. Methods The effect of different esomeprazole dosage regimens [20 mg once daily (od) before breakfast or dinner; 20 mg twice daily (b.d.); 40 mg od before breakfast, dinner or at bedtime; and 40 mg b.d.] on 24-h, daytime and night-time acid inhibition was evaluated in a randomized, seven-way crossover study in healthy volunteers. Each regimen was taken for 5 days. Results Over the 24-h period (day 5), esomeprazole 20 mg b.d. was associated with superior acid inhibition vs. all 20 mg and 40 mg od regimens (P < 0.05), but was less effective than esomeprazole 40 mg b.d. (P < 0.05). Dosing with esomeprazole 20 mg or 40 mg od before breakfast gave improved 24-h and daytime acid inhibition vs. the corresponding administration before dinner or at bedtime (all P < 0.05). Night-time acid inhibition was improved when esomeprazole 40 mg od was administered before dinner or at bedtime vs. before-breakfast dosing (P < 0.05). Conclusion Varying the dose and timing of esomeprazole administration may provide acid inhibition appropriate for the symptom pattern of individual patients with GERD. © 2010 Blackwell Publishing Ltd.

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