Peroxiredoxins Play an Important Role in the Regulation of Immunity and Aging in Drosophila.

Aberrant immune responses and chronic inflammation can impose significant health risks and promote premature aging. Pro-inflammatory responses are largely mediated via reactive oxygen species (ROS) and reduction-oxidation reactions. A pivotal role in maintaining cellular redox homeostasis and the proper control of redox-sensitive signaling belongs to a family of antioxidant and redox-regulating thiol-related peroxidases designated as peroxiredoxins (Prx). Our recent studies in Drosophila have shown that Prxs play a critical role in aging and immunity. We identified two important 'hubs', the endoplasmic reticulum (ER) and mitochondria, where extracellular and intracellular stress signals are transformed into pro-inflammatory responses that are modulated by the activity of the Prxs residing in these cellular organelles. Here, we found that mitochondrial Prx activity in the intestinal epithelium is required to prevent the development of intestinal barrier dysfunction, which can drive systemic inflammation and premature aging. Using a redox-negative mutant, we demonstrated that Prx acts in a redox-dependent manner in regulating the age-related immune response. The hyperactive immune response observed in flies under-expressing mitochondrial Prxs is due to a response to abiotic signals but not to changes in the bacterial content. This hyperactive response, but not reduced lifespan phenotype, can be rescued by the ER-localized Prx.

Effects of menthol on esophageal motility in humans: Studies using high-resolution manometry.

BACKGROUND/AIM: The cold receptor, transient receptor potential melastatin 8 (TRPM8), has been reported to be expressed in esophageal vagal afferents. Esophageal infusion of menthol modulates esophageal perception in reflux patients via TRPM8, but the effects of menthol on esophageal motility are not well investigated. This study aimed to test the hypothesis whether the infusion of menthol into the esophagus could affect esophageal peristaltic characteristics. METHODS: Eighteen healthy adults (men 13, mean age 27) underwent high-resolution manometry (HRM) using a catheter with the injection port located in mid-esophagus. Primary peristalsis was performed with ten wet swallows, while secondary peristalsis was generated by 10 rapid air injections. Two different sessions were randomly performed including acute administration of menthol (3 mM) and the placebo. RESULTS: Menthol significantly decreased upper esophageal (UES) pressure of primary peristalsis than the placebo (p = 0.019). There was no difference in distal contractile integral (p = 0.33), distal latency (p = 0.86), basal lower esophageal sphincter pressure (p = 0.19), or 4-second integrated relaxation pressure (p = 0.75) between menthol and placebo. Menthol significantly decreased the frequency of secondary peristalsis subsequent to the administration of menthol during rapid injections with 20 mL air (p = 0.04). CONCLUSIONS: Intraluminal infusion of menthol reduces UES basal pressure and inhibits peristaltic frequency of secondary peristalsis. The data suggest that the triggering of secondary peristalsis is probably modulated by TRPM8-sensitive mechanoreceptors; however, the activation of TRPM8 from menthol does not alter esophageal motility following deglutition or distension-induced secondary peristalsis.

Esophageal acid burden in reflux patients with normal endoscopy: Does esophageal peristalsis matter?

BACKGROUND: A majority of patients with gastroesophageal reflux disease (GERD) have normal endoscopy. We aimed to investigate whether esophageal primary and secondary peristalsis influence esophageal reflux parameters in patients with normal endoscopy. METHODS: We enrolled consecutive patients with typical reflux symptoms and normal endoscopy. All patients underwent High resolution manometry (HRM) and 24-h impedance-pH studies off therapy. During HRM, secondary peristalsis was evaluated using ten 20-mL rapid air infusions into the esophagus, while primary peristalsis was evaluated using ten 5-mL water swallows. RESULTS: A total of 43 patients completed the study; 13 patients had normal motility, 20 had ineffective esophageal motility (IEM), and 10 had absent contractility. Acid exposure time (AET) (total, supine, and upright) was significantly higher in those with absent primary peristalsis (absent contractility) compared to normal motility (P = 0.001; 0.01; 0.007) and IEM (P = 0.002; 0.02; 0.03). Supine AET was significantly higher in patients without secondary peristalsis compared to those with secondary peristalsis (P = 0.04). CONCLUSION: In the setting of normal endoscopy, acid reflux burden is more profound in patients with absent primary peristalsis, as well as in patients lacking a secondary peristaltic response to esophageal air distension.

Effects of codeine on esophageal peristalsis in humans using high resolution manometry.

BACKGROUND AND AIM: Opioid receptors agonists have been demonstrated to impair lower esophageal sphincter (LES) relaxation and induce spastic esophageal dysmotility, but little was known for their impact on distension-induced secondary peristalsis. The aim of the study was to investigate the hypothesis whether acute administration of codeine can influence physiological characteristics of primary and secondary peristalsis in healthy adults. METHODS: Eighteen healthy volunteers (13 men, mean age 27.5 years, aged 20-43 years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20 mL rapid air injections. Two different sessions including acute administration of codeine (60 mg) or the placebo were randomly performed. RESULTS: Codeine significantly increased 4-s integrated relaxation pressure (IRP-4s) (P = 0.003) and shortened distal latency (DL) (P = 0.003) of primary peristalsis. The IRP-4s of secondary peristalsis was also significantly higher after codeine than the placebo during air injections with 10 mL (P = 0.048) and 20 mL (P = 0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10 mL than the placebo (P = 0.007), but not for air injection with 20 mL (P = 0.305). CONCLUSIONS: In addition to impair LES relaxation and reduce distal latency of primary peristalsis, codeine impairs LES relaxation of secondary peristalsis and increases secondary peristaltic frequency. Our study supports the notion in human esophagus that the impact of opioids on peristaltic physiology appears to be present in both primary and secondary peristalsis.

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila.

The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (CysP), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, CysP is oxidized to catalytically inactive sulfinic (Cys-SO2) and sulfonic (Cys-SO3) forms. The Cys-SO2 form can be reduced in a reaction catalyzed by sulfiredoxin (Srx). To explore the physiological significance of peroxiredoxin overoxidation, we investigated daily variations in the oxidation state of 2-Cys peroxiredoxins in flies of different ages, or under conditions when the pro-oxidative load is high. We found no statistically significant changes in the 2-Cys Prxs monomer:dimer ratio, which indirectly reflects changes in the Prx catalytic activity. However, we found daily variations in Prx-SO2/3 that were more pronounced in older flies as well as in flies lacking Srx. Unexpectedly, the srx mutant flies did not exhibit a diminished survivorship under normal or oxidative stress conditions. Moreover, the srx mutant was characterized by a higher physiological activity. In conclusion, catalytically inactive forms of Prx-SO2/3 serve not only as a marker of cellular oxidative burden, but may also play a role in an adaptive response, leading to a positive effect on the physiology of Drosophila melanogaster.

Mitochondrial Redox Signaling Is Critical to the Normal Functioning of the Neuronal System.

Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of Drosophila models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.

Association between use of proton pump inhibitors and colorectal cancer: A nationwide population-based study.

BACKGROUND: Proton pump inhibitors (PPIs) use is associated with hypergastrinemia and gut microbiota alteration. Concern over the risk that these factors may increase chances of colorectal cancer (CRC) has risen. To investigate the association between PPIs use and CRC using a large population-based cohort and examine whether the PPIs may differ regarding the risk of CRC. METHODS: We conducted a nationwide cohort study using a database from Taiwan National Health Insurance followed up longitudinally from 1999 through 2011. Patients with PPIs use were compared with non-use controls at a 1:1 ratio, for age, sex, comorbidities, and medications. We performed Cox proportional-hazards regression analysis to estimate the association between PPIs use and the development of CRC. RESULTS: Among the 45382 eligible PPIs users, 172 (0.4%) developed CRC during a median follow-up of 5.4 years. PPIs use was associated with a higher risk of CRC with an adjusted HR of 2.03 (95% CI 1.56-2.63, P<0.001). The risk increased with more frequent use of PPIs (HR 1.59, 95% CI 1.19-2.14; 2.59, 95% CI 1.84-3.65 and 4.33, 95% CI 2.75-6.80 for ≤30 cDDD per year, 30-90 cDDD per year, and ≥90 cDDD per year, respectively). There was also a statistically significant trend toward an increased risk with long-term PPIs use for more than one year. All PPIs, except pantoprazole and rabeprazole, were associated with an increased risk of CRC. CONCLUSIONS: The present study suggests that PPIs use might increase the risk of CRC in a dose-dependent manner.

Effect of prucalopride on sildenafil-induced inhibition of esophageal peristalsis in healthy adults.

BACKGROUND AND AIM: Prucalopride, a high-affinity 5-hydroxytryptamine 4 receptor agonist, promotes esophageal peristalsis, while phosphodiesterase type 5 inhibitor sildenafil inhibits esophageal peristalsis. The present study was aimed to evaluate whether prucalopride would augment esophageal peristalsis subsequent to the application of sildenafil. METHODS: Seventeen healthy adults underwent high-resolution manometry by a catheter with one injection port located in the mid-esophagus. Secondary peristalsis was assessed by rapid air injections after water swallows. Two sessions were randomly performed including acute administration of sildenafil 50 mg after pretreatment with prucalopride or the placebo. RESULTS: The frequency of primary peristalsis subsequent to the administration of sildenafil was significantly increased by prucalopride (P = 0.02). Prucalopride also significantly increased distal contractile integral of primary peristalsis subsequent to the administration of sildenafil (P = 0.03). No difference in the frequency of secondary peristalsis subsequent to the administration of sildenafil for air injects of 10 mL (P = 0.14) or 20 mL (P = 0.21) was found between prucalopride and placebo. Prucalopride did not change distal contractile integral of secondary peristalsis subsequent to the administration of sildenafil for air injections of 10 mL (P = 0.09) or 20 mL (P = 0.12). CONCLUSIONS: Prucalopride modulates sildenafil-induced inhibition of primary peristalsis by increasing its effectiveness and peristaltic wave amplitude. Our findings suggest that activation of 5-hydroxytryptamine 4 receptors plays a role in mediating sildenafil-induced inhibition of esophageal primary peristalsis rather than secondary peristalsis.

The effect of baclofen on objective and subjective sleep measures in a model of transient insomnia.

STUDY OBJECTIVES: Insomnia is a common medical complaint. Current pharmacologic treatments have modest efficacy and numerous side effects. Baclofen is a gamma-aminobutyric acid (GABA)b receptor agonist used to treat spasticity in various medical conditions. Several studies noted that baclofen, when used to treat sleep related disorders, resulted in improvement in sleep parameters. Measures of insomnia, however, were not assessed in those studies. To date, baclofen has not been assessed for efficacy in the treatment of insomnia. METHODS: We randomized 20 healthy subjects to baclofen or placebo in a cross over design. All subjects underwent two polysomnograms (PSG) assessing sleep parameters. Baclofen or placebo was given 90 min prior to lights out in random order for each subject. Lights out occurred two hours earlier than the subject's median habitual bedtime. RESULTS: Baclofen resulted in significantly less objective wake after sleep onset and stage 1 sleep, and significantly increased total sleep time (TST), sleep efficiency, and stage 3/4 sleep. There was no effect on sleep onset latency (SOL). Self-report variables indicated significantly less subjective awakenings from sleep and increased subjective sleep quality. There was no effect on subjective TST or subjective SOL. CONCLUSIONS: This study showed that baclofen was superior to placebo with regard to several objective and subjective measures used to assess sleep quality. These data support the notion that baclofen shows promise as an effective hypnotic drug.

The effect of sleep on gastrointestinal functioning in common digestive diseases.

Sleep quality and sleep disorders affect symptom manifestation and the pathogenesis of digestive diseases. Sleep is largely regulated by the light-dark cycle and associated circadian rhythms. These occurrences are closely regulated through several mechanisms with direct effects on the gastrointestinal tract. Misalignment of the circadian system is a common cause of sleep complaints, which play an important role in the presentation of many gastrointestinal disorders. This Review will focus on sleep disorders and how these alterations in sleep play an important role in many commonly encountered digestive diseases, such as gastro-oesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, and non-alcoholic fatty liver disease. Therapeutic interventions focusing on resolving sleep disorders could optimise treatment and improve quality of life in these patients.

Impact of concomitant dyspepsia and irritable bowel syndrome on symptom burden in patients with gastroesophageal reflux disease.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) frequently report symptoms like dyspepsia or/and irritable bowel syndrome (IBS). The aim of the study was to investigate the impact of symptom overlap on GERD symptom burden. We also investigate whether GERD overlapping dyspepsia or/and IBS would have different clinical and psychological features as compared with GERD alone. METHODS: A total of 2752 subjects were screened from a health check-up population. We compared the clinical and psychological factors among subjects with GERD alone and with overlap of two or all three diseases. All participants underwent an evaluation with questionnaires including Reflux Disease Questionnaire score, Pittsburgh Sleep Quality Index, Taiwanese Depression Questionnaire, and State-Trait Anxiety Inventory before receiving endoscopic exam. RESULTS: Among the GERD population, we identified 26 with IBS (GERD-IBS), 60 with dyspepsia (GERD-D), and 25 subjects with overlap of all three conditions (GERD-D-IBS). GERD-D and GERD-D-IBS subjects had more severe GERD symptoms as compared subjects with GERD alone (p < 0.001). Subjects with overlapping dyspepsia or/and IBS showed a significant increase in the severity of depression and poorer sleep quality than subjects with GERD alone. Notably, anxiety scores did not differ significantly between subjects with overlapping diseases and GERD alone. CONCLUSION: Our study demonstrates that disease overlap in GERD population is associated with greater symptom burden, higher depression and poorer sleep quality, but not with anxiety. This study highlights the importance of identifying overlapping conditions as a therapeutic strategy for better management of GERD.

Overexpression of antimicrobial peptides contributes to aging through cytotoxic effects in Drosophila tissues.

The innate immune response tends to become hyperactive and proinflammatory in older organisms. We investigated connections between activity of the immune-related genes and aging using the Drosophila model. A hallmark of Drosophila immunity is the production of antimicrobial peptides (AMP), whose expression is triggered via activation of the Toll and Imd immune pathways and regulated by NF-ĸB-like transcription factors, Dif/Dorsal and Relish. It was previously shown that overexpression of the upstream component of the immune pathways shortens lifespan via activation of the Relish-dependent immune response. Here we show that direct overexpression of the Relish target AMP genes broadly at high levels or in the fat body induced apoptosis, elicited depolarization of the mitochondria and significantly shortened lifespan. Underexpression of Relish in the fat body beginning in the second half of lifespan prevented overactivation of AMPs and extended longevity. Unlike infection-induced responses, the age-related increase in AMPs does not require the upstream recognition/transduction module of the Imd pathway. It does however require downstream elements, including Relish and Ird5, a component of the downstream IKK complex. Together, these results established causal links between high-level production of antimicrobial peptides and longevity.

The Multifaceted Impact of Peroxiredoxins on Aging and Disease.

SIGNIFICANCE: Peroxiredoxins (Prxs), a family of thiol-associated peroxidases, are purported to play a major role in sensing and managing hydrogen peroxide concentrations and transducing peroxide-derived signals. Recent Advances: Prxs can act as detoxifying factors and impart effects to cells that can be either sparing or suicidal. Advances have been made to address the qualitative changes in Prx function in response to quantitative changes in the signal level and to understand how Prx activity could be affected by their own substrates. Here we rationalize the basis for both positive and negative effects on signaling pathways and cell physiology, summarizing data from model organisms, including invertebrates. CRITICAL ISSUES: Resolving the relationship between the promiscuous behavior of reactive oxygen species and the specificity of Prxs toward different targets in redox-sensitive signaling pathways is a key area of research. Attempts to understand Prx function and underlying mechanisms were conducted in vitro or in vivo under nonphysiological conditions, leaving the physiological relevance yet to be defined. Other issues: Why despite the high degree of homology and similarities in subcellular and tissue distribution between Prxs do they display differential effects on signaling? How is the specificity of post-translational protein modifications determined? Other than chaperone-like activity, how do hyperoxidized Prxs function? FUTURE DIRECTIONS: Genetic models with mutated catalytic and resolving cysteines should be further exploited to dissect the functional significance of individual Prxs in their different states together with their alternative reducing partners. Such an analysis may then be extended to help identify Prx-specific targets.

Risk of acute myocardial infarction in patients with gastroesophageal reflux disease: A nationwide population-based study.

OBJECTIVE: Gastroesophageal reflux disease (GERD) is a common disease which can cause troublesome symptoms and affect quality of life. In addition to esophageal complications, GERD may also be a risk factor for extra-esophageal complications. Both GERD and coronary artery disease (CAD) can cause chest pain and frequently co-exist. However, the association between GERD and acute myocardial infarction (AMI) remain unclear. The purpose of the study was to compare the incidence of acute myocardial infarction in GERD patients with an age-, gender-, and comorbidity matched population free of GERD. We also examine the association of the risk of AMI and the use of acid suppressing agents in GERD patients. METHODS: We identified patients with GERD from the Taiwan National Health Insurance Research Database. The study cohort comprised 54,422 newly diagnosed GERD patients; 269,572 randomly selected age-, gender-, comorbidity-matched subjects comprised the comparison cohort. Patients with any prior CAD, AMI or peripheral arterial disease were excluded. Incidence of new AMI was studied in both groups. RESULTS: A total 1,236 (0.5%) of the patients from the control group and 371 (0.7%) patients from the GERD group experienced AMI during a mean follow-up period of 3.3 years. Based on Cox proportional-hazard model analysis, GERD was independently associated with increased risk of developing AMI (hazard ratio (HR) = 1.48; 95% confidence interval (CI): 1.31-1.66, P < 0.001). Within the GERD group, patients who were prescribed proton pump inhibitors (PPIs) for more than one year had slightly decreased the risk of developing AMI, compared with those without taking PPIs (HR = 0.57; 95% CI: 0.31-1.04, P = 0.066). CONCLUSIONS: This large population-based study demonstrates an association between GERD and future development of AMI, however, PPIs use only achieved marginal significance in reducing the occurrence of AMI in GERD patients. Further prospective studies are needed to evaluate whether anti-reflux medication may reduce the occurrence of acute ischemic event in GERD patients.

Relevance of sleep disturbance to the integrity and characteristics of secondary peristalsis in patients with gastroesophageal reflux disease.

OBJECTIVE: Sleep disturbance is common in patients with gastroesophageal reflux disease (GERD). Secondary peristalsis is important for clearance of the refluxate from the esophagus. We aimed to test the hypothesis whether secondary peristalsis is impaired in GERD patients with sleep disturbance. METHODS: Secondary peristalsis was stimulated with slow and rapid air injections into mid-esophagus in 8 age-matched health controls and 41 patients with GERD. Sleep disturbance was assessed by the Pittsburg Sleep Quality Index (PSQI). Objective sleep measures were assessed by ambulatory actigraphy. RESULTS: The threshold volume for inducing secondary peristalsis during slow air injection was significantly higher in GERD patients with sleep disturbance than healthy controls (14.3 ± 1.2 vs. 8.9 ± 0.5 mL, p < .05). GERD patients with sleep disturbance had higher threshold volume of secondary peristalsis during rapid air injection than GERD patients without sleep disturbance (5.1 ± 0.4 vs. 3.9 ± 0.2 mL, p < .05) and healthy controls (5.1 ± 0.4 vs. 3.6 ± 0.2 mL, p < .05). There was a negative correlation between PSQI score and peristaltic frequency during rapid air injection (r = -.39, p = .01). Secondary peristaltic amplitude during rapid air injection was negatively correlated with wake after sleep onset (r = -.34, p = .04). CONCLUSIONS: Sleep disturbance is associated with secondary peristaltic response to distension-induced esophageal stimulation in patients with GERD. Our study suggests that sleep disturbance per se may adversely influence the effectiveness of esophageal peristalsis and bolus clearance during sleep in patients with GERD.

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging.

Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.

Differences in the Control of Secondary Peristalsis in the Human Esophagus: Influence of the 5-HT4 Receptor versus the TRPV1 Receptor.

OBJECTIVE: Acute administration of 5-hydroxytryptamine4 (5-HT4) receptor agonist, mosapride or esophageal infusion of the transient receptor potential vanilloid receptor-1 (TRPV1) agonist capsaicin promotes secondary peristalsis. We aimed to investigate whether acute esophageal instillation of capsaicin-containing red pepper sauce or administration of mosapride has different effects on the physiological characteristics of secondary peristalsis. METHODS: Secondary peristalsis was induced with mid-esophageal air injections in 14 healthy subjects. We compared the effects on secondary peristalsis subsequent to capsaicin-containing red pepper sauce (pure capsaicin, 0.84 mg) or 40 mg oral mosapride. RESULTS: The threshold volume for generating secondary peristalsis during slow air distensions was significantly decreased with capsaicin infusion compared to mosapride (11.6 ± 1.0 vs. 14.1 ± 0.8 mL, P = 0.02). The threshold volume required to produce secondary peristalsis during rapid air distension was also significantly decreased with capsaicin infusion (4.6 ± 0.5 vs. 5.2 ± 0.6 mL, P = 0.02). Secondary peristalsis was noted more frequently in response to rapid air distension after capsaicin infusion than mosapride (80% [60-100%] vs. 65% [5-100%], P = 0.04). Infusion of capsaicin or mosapride administration didn't change any parameters of primary or secondary peristalsis. CONCLUSIONS: Esophageal infusion with capsaicin-containing red pepper sauce suspension does create greater mechanosensitivity as measured by secondary peristalsis than 5-HT4 receptor agonist mosapride. Capsaicin-sensitive afferents appear to be more involved in the sensory modulation of distension-induced secondary peristalsis.

Sleep disturbance and enhanced esophageal capsaicin sensitivity in patients with gastroesophageal reflux disease.

BACKGROUND AND AIM: Esophageal infusion of capsaicin-containing red pepper sauce induced heartburn symptoms in patients with gastroesophageal reflux disease (GERD). We aimed to test the hypothesis whether sleep disturbance modulates esophageal sensitivity to capsaicin infusion in patients with GERD. METHODS: We enrolled 40 patients with their sleep quality measured by the Pittsburg Sleep Quality Index with > 5 indicating sleep disturbance. Esophageal sensation to capsaicin infusion was documented via measures of lag time to initial heartburn perception, heartburn intensity rating, and sensitivity score by esophageal infusion of capsaicin-containing red pepper sauce. Objective sleep measures were assessed by ambulatory actigraphy. RESULTS: We found 22 patients with sleep disturbance. The patients with sleep disturbance had shorter lag time to initial heartburn perception (P = 0.03) and greater sensory intensity rating (P = 0.02). The sensitivity score for capsaicin infusion was greater in patients with sleep disturbance when compared with those without sleep disturbance (P = 0.04). Actigraphy measures revealed that patients with sleep disturbance also had poor sleep efficiency (P = 0.04), longer average awakening time (P = 0.03), and greater total activity account (P = 0.04). The lag time for perceiving capsaicin infusion was positively correlated with total sleep time (r = 0.43, P = 0.03). CONCLUSIONS: We have shown that GERD patients with sleep disturbance have significantly enhanced heartburn perception to capsaicin infusion as compared with those with normal sleep. Our findings suggest that sleep disturbance is associated with esophageal hypersensitivity to capsaicin infusion in patients with GERD.