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Ito K, Kanemitsu Y, Ueda T, Kamiya T, Kubota E, Mori Y, Fukumitsu K, Tajiri T, Fukuda S, Uemura T, Ohkubo H, Ito Y, Shibata Y, Kumamoto N, Ugawa S, Niimi A. Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma. J Allergy Clin Immunol 2024; 154:1422-1433. [PMID: 38909633 DOI: 10.1016/j.jaci.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
BACKGROUND Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 μmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts. CONCLUSION FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.
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Affiliation(s)
- Keima Ito
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshihiro Kanemitsu
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Takashi Ueda
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Takeshi Kamiya
- Department of Medical Innovation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yuta Mori
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kensuke Fukumitsu
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomoko Tajiri
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoshi Fukuda
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yutaka Ito
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhiro Shibata
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Natsuko Kumamoto
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shinya Ugawa
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Page AJ. Plasticity of gastrointestinal vagal afferents in terms of feeding-related physiology and pathophysiology. J Physiol 2024; 602:4763-4776. [PMID: 37737742 DOI: 10.1113/jp284075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023] Open
Abstract
Gastrointestinal vagal afferents play an important role in communicating food related information from the gut to the brain. This information initiates vago-vagal reflexes essential for gut functions, including gut motility and secretions. These afferents also play a role in energy homeostasis, signalling the arrival, amount and nutrient composition of a meal to the central nervous system where it is processed ultimately leading to termination of a meal. Vagal afferent responses to food related stimuli demonstrate a high degree of plasticity, responding to short term changes in nutritional demand, such as the fluctuations that occur across a 24-hr or in response to a fast, as well as long term changes in energy demand, such as occurs during pregnancy. This plasticity is disrupted in disease states, such as obesity or chronic stress where there is hypo- and hypersensitivity of these afferents, respectively. Improved understanding of the plasticity of these afferents will enable identification of new treatment options for diseases associated with vagal afferent function.
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Affiliation(s)
- Amanda J Page
- Vagal Afferent Research Group, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, South Australia, Australia
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Scarpellini E, Balsiger LM, Broeders B, Houte KVD, Routhiaux K, Raymenants K, Carbone F, Tack J. Nutrition and Disorders of Gut-Brain Interaction. Nutrients 2024; 16:176. [PMID: 38202005 PMCID: PMC10780945 DOI: 10.3390/nu16010176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/27/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Disorders of gut-brain interaction (DGBIs) have a complex pathophysiology that is often characterized by a relationship between food ingestion and triggering of symptoms. Understanding of the underlying mechanisms and the role of nutrients as a therapeutic target are rapidly evolving. AIMS AND METHODS We performed a narrative review of the literature using the following keywords, their acronyms, and their associations: nutrients, disorders of gut-brain interaction; functional dyspepsia; malabsorption; irritable bowel syndrome; diarrhea; constipation. RESULTS Functional dyspepsia displayed a significant correlation between volume, fat and/or wheat abundance, chemical composition of ingested food and symptoms of early satiety, fullness and weight loss. Carbohydrate malabsorption is related to enzyme deficiency throughout the GI tract. Food composition and richness in soluble vs. non-soluble fibers is related to constipation and diarrhea. The elimination of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) has a significant and non-unidirectional impact on irritable bowel syndrome (IBS) symptoms. CONCLUSIONS Food volume, nutritive and chemical composition, and its malabsorption are associated with symptom generation in DGBIs. Further multicenter, randomized-controlled clinical trials are needed to clarify the underlying pathophysiology.
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Affiliation(s)
- Emidio Scarpellini
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, Via Luciano Manara 7, 63074 San Benedetto del Tronto, Italy
| | - Lukas Michaja Balsiger
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Bert Broeders
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Karen Van Den Houte
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Karen Routhiaux
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Karlien Raymenants
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Florencia Carbone
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
| | - Jan Tack
- Translational Research in Gastrointestinal Disoerders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium; (E.S.); (L.M.B.); (B.B.); (K.V.D.H.); (K.R.); (K.R.); (F.C.)
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Yoshida K, Abe T, Kanbara K, Ueda K, Saka-Kouchi Y, Hasuo H. Patients with postprandial distress syndrome experience problems with their interoceptive perceptual function to the gastric region, but their heartbeat perception is normal: a case control study. Biopsychosoc Med 2023; 17:35. [PMID: 37807053 PMCID: PMC10560408 DOI: 10.1186/s13030-023-00290-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 09/24/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND Visceral hypersensitivity in functional dyspepsia can be localized or widespread, and there is no simple method of assessment. Measuring interoceptive accuracy at different sites provides an assessment of perceptual hypersensitivity to specific ecological phenomena. The purpose of this study was to characterize visceral hypersensitivity by comparing gastric sensory and cardiac perceptual tests in patients with postprandial distress syndrome and in healthy volunteers. METHODS Sixteen patients with postprandial distress syndrome (age = 47.5 ± 17.4, all female) and 16 healthy volunteers (age = 43.3 ± 16.1, all female) participated in the study after a six-hour fast. Each participant answered questionnaires about physical and mental quality of life, depression and anxiety, tendency of alexithymia, and somatosensory amplification. After completing the questionnaire, the participants took the heartbeat tracking task and the five-minute water load test. We performed statistical analysis using the Mann-Whitney U test and Spearman's rank correlation coefficient. RESULTS Subjects with postprandial distress syndrome had a lower drinking capacity than healthy volunteers (postprandial distress syndrome = 360.9 ± 170.0 mL, healthy volunteers = 644.1 ± 297 mL, P = 0.009), but there was no significant difference in the heartbeat perception score (postprandial distress syndrome = 0.599 ± 0.175, healthy volunteers = 0.623 ± 0.181, P = 0.647). There was a negative correlation (r = - 0.509, P < 0.05) between drinking capacity and the heartbeat perception score in healthy volunteers, but no correlation in postprandial distress syndrome (r = - 0.156, P = 0.564). Heartbeat perception score did not correlate with psychological measures. CONCLUSIONS Compared with healthy volunteers, only the five-minute water load test values were reduced in patients with postprandial distress syndrome, and no difference was observed in the heartbeat tracking task. Combining the 5-minute water load test and the heart rate tracking task revealed a lost cardiac-gastric perceptual relationship in patients with postprandial distress syndrome that was not observed in healthy volunteers, suggesting that there is hypersensitivity in gastric interoceptive perceptual function. Performing sensory examinations at two different sites may be useful in clarifying whether visceral hypersensitivity is localized. TRIAL REGISTRATION UMIN000057586. Registered11 March 2023(retrospectively registered).
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Affiliation(s)
- Kohei Yoshida
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan.
| | - Tetsuya Abe
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan
| | - Kenji Kanbara
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan
- Psychosomatic Medicine, Department of Clinical Psychology, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Kento Ueda
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan
| | - Yukie Saka-Kouchi
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan
| | - Hideaki Hasuo
- Department of Psychosomatic and General Internal Medicine, Kansai Medical University, 2-5-1-505 Shinmachi, Hirakata, 573-1010, Osaka, Japan
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Ito K, Kanemitsu Y, Kamiya T, Fukumitsu K, Takeda N, Tajiri T, Kurokawa R, Nishiyama H, Yap J, Fukuda S, Uemura T, Ohkubo H, Maeno K, Ito Y, Oguri T, Takemura M, Niimi A. Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma. Allergol Int 2022; 72:271-278. [PMID: 36192325 DOI: 10.1016/j.alit.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/06/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS. RESULTS Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.
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Affiliation(s)
- Keima Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshihiro Kanemitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Takeshi Kamiya
- Department of Medical Innovation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kensuke Fukumitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Norihisa Takeda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomoko Tajiri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ryota Kurokawa
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirono Nishiyama
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Jennifer Yap
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoshi Fukuda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ken Maeno
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yutaka Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tetsuya Oguri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masaya Takemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Boeing T, de Souza P, da Silva LM, Gasparotto Junior A. Herbal Medicines in the Treatment of Dyspepsia: An Overview. PLANTA MEDICA 2022; 88:664-677. [PMID: 34474492 DOI: 10.1055/a-1580-7782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
This review focuses on the efficacy of herbal medicines for managing dyspepsia in humans and animals. Searches were conducted on the PubMed, Science Direct, and Medline databases, for publications in the last 3 years. In each database, the search terms used consisted of the 2 key terms describing the disorder and subtypes plus each of the terms relating to the therapy. The key terms used were "natural product" and "medicinal plant" in a cross-over with "dyspepsia" and "functional dyspepsia" (i.e., gastroprotection, Helicobacter pylori infection, prokinetic). We included all human and animal studies on the effects of herbal medicines reporting the key outcome of dyspepsia symptoms. Preclinical studies using critically validated models showed that most medicinal plants with gastroprotective action had antioxidant, anti-inflammatory, anti-apoptotic, and antisecretory effects. Moreover, several species displayed anti Helicobacter pylori and prokinetic efficacy. The data availability of controlled clinical studies is currently minimal. The use of different methodologies and the minimal number of patients raise doubts about the effects of these preparations. Only adequate clinical trials with scientifically validated methods can determine whether different herbal medicines can be used as viable alternatives to the conventional pharmacological treatments used to control dyspepsia symptoms.
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Affiliation(s)
- Thaise Boeing
- Pharmaceutical Sciences Graduate Program, University of Vale do Itajaí, Itajaí, Brazil
| | - Priscila de Souza
- Pharmaceutical Sciences Graduate Program, University of Vale do Itajaí, Itajaí, Brazil
| | - Luisa Mota da Silva
- Pharmaceutical Sciences Graduate Program, University of Vale do Itajaí, Itajaí, Brazil
| | - Arquimedes Gasparotto Junior
- Laboratory of Cardiovascular Pharmacology (LaFac), Faculty of Health Sciences, Federal University of Grande Dourados (UFGD), Dourados, MS, Brazil
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A comprehensive review of functional dyspepsia in pediatrics. Clin J Gastroenterol 2021; 15:30-40. [PMID: 34854065 DOI: 10.1007/s12328-021-01561-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 11/14/2021] [Indexed: 10/19/2022]
Abstract
Functional gastrointestinal disorders have been known as a diagnosis of exclusion since the Rome Foundation first created these criteria in 1990. Since that time, a large amount of research and clinical data has better clarified the mechanisms and treatment options for these. Functional dyspepsia is caused by physiologic, genetic, environmental, and psychological factors, as well as various functional abnormalities, such as increased sensitivity to acid, increased sensitivity to duodenal lipids and low-grade inflammation. This disorder has significant symptom overlap between other functional disorders, such as irritable bowel syndrome and gastroparesis, but has differential criteria and two new subclasses: postprandial distress syndrome and epigastric pain syndrome. Diagnosis of functional dyspepsia should be based upon appropriate clinical evaluation in tandem with Rome IV criteria. In recent years, many treatment measures for functional dyspepsia have been studied, such as pharmacologic intervention, behavioral therapy, or alternative therapy, an example being hypnotherapy. These treatment measures have proven to be effective in symptom reduction in pediatrics. Though this disorder is functional, it has been shown to cause a significant impact on pediatric patients' quality of life continuing into adulthood.
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Wilder-Smith CH, Drewes AM, Materna A, Olesen SS. Extragastrointestinal Symptoms and Sensory Responses During Breath Tests Distinguish Patients With Functional Gastrointestinal Disorders. Clin Transl Gastroenterol 2020; 11:e00192. [PMID: 32955198 PMCID: PMC7431249 DOI: 10.14309/ctg.0000000000000192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Patients with functional gastrointestinal disorders (FGIDs) are classified based on their gastrointestinal (GI) symptoms, without considering their frequent extra-GI symptoms. This study defined subgroups of patients using both GI and extra-GI symptoms and examined underlying mechanisms with fructose and lactose breath tests. METHODS Latent class analysis defined distinct clusters of patients with FGID based on their long-term GI and extra-GI symptoms. Sensory and breath gas responses after fructose and lactose ingestion were compared across symptom clusters to investigate differences in sensory function and fermentation by intestinal microbiota. RESULTS Six symptom clusters were identified in 2,083 patients with FGID. Clusters were characterized mainly by GI fermentation-type (cluster 1), allergy-like (cluster 2), intense pain-accentuated GI symptoms (cluster 3), central nervous system (cluster 4), musculoskeletal (cluster 5), and generalized extra-GI (cluster 6) symptoms. In the 68% of patients with complete breath tests, the areas under the curve of GI and central nervous system symptoms after fructose and lactose ingestion differed across the clusters (P < 0.001). The clusters with extensive long-term extra-GI symptoms had greater symptoms after the sugars and were predominantly women, with family or childhood allergy histories. Importantly, the areas under the curves of hydrogen and methane breath concentrations were similar (P > 0.05) across all symptom clusters. Rome III criteria did not distinguish between the symptom clusters. DISCUSSION Patients with FGID fall into clusters defined extensively by extra-GI symptoms. Greater extra-GI symptoms are associated with evidence of generalized sensory hypersensitivity to sugar ingestion, unrelated to intestinal gas production. Possible underlying mechanisms include metabolites originating from the intestinal microbiota and somatization.
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Affiliation(s)
| | - Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Andrea Materna
- Brain-Gut Research Group, Gastroenterology Group Practice, Bern, Switzerland
| | - Søren S. Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
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Abstract
Taste is a homeostatic function that conveys valuable information, such as energy density, readiness to eat, or toxicity of foodstuffs. Taste is not limited to the oral cavity but affects multiple physiological systems. In this review, we outline the ergogenic potential of substances that impart bitter, sweet, hot and cold tastes administered prior to and during exercise performance and whether the ergogenic benefits of taste are attributable to the placebo effect. Carbohydrate mouth rinsing seemingly improves endurance performance, along with a potentially ergogenic effect of oral exposure to both bitter tastants and caffeine although subsequent ingestion of bitter mouth rinses is likely required to enhance performance. Hot and cold tastes may prove beneficial in circumstances where athletes' thermal state may be challenged. Efficacy is not limited to taste, but extends to the stimulation of targeted receptors in the oral cavity and throughout the digestive tract, relaying signals pertaining to energy availability and temperature to appropriate neural centres. Dose, frequency and timing of tastant application likely require personalisation to be most effective, and can be enhanced or confounded by factors that relate to the placebo effect, highlighting taste as a critical factor in designing and administering applied sports science interventions.
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Li H, Buisman-Pijlman FTA, Nunez-Salces M, Christie S, Frisby CL, Inserra A, Hatzinikolas G, Lewis MD, Kritas S, Wong ML, Page AJ. Chronic stress induces hypersensitivity of murine gastric vagal afferents. Neurogastroenterol Motil 2019; 31:e13669. [PMID: 31241809 DOI: 10.1111/nmo.13669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/22/2019] [Accepted: 06/18/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. METHODS Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. KEY RESULTS The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. CONCLUSIONS AND INFERENCES In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.
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Affiliation(s)
- Hui Li
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Femke T A Buisman-Pijlman
- Behavioural Neuroscience, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Maria Nunez-Salces
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Stewart Christie
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Claudine L Frisby
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Antonio Inserra
- Neuropsychiatric Laboratory of Mental Health Disorder, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - George Hatzinikolas
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Martin D Lewis
- Neuropsychiatric Laboratory of Mental Health Disorder, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.,School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.,College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
| | - Stamatiki Kritas
- Women's and Children's Hospital, North Adelaide, South Australia, Australia
| | - Ma-Li Wong
- Neuropsychiatric Laboratory of Mental Health Disorder, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.,Nutrition, Diabetes and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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11
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Luo L, Du L, Shen J, Cen M, Dai N. Benefit of small dose antidepressants for functional dyspepsia: Experience from a tertiary center in eastern China. Medicine (Baltimore) 2019; 98:e17501. [PMID: 31593119 PMCID: PMC6799471 DOI: 10.1097/md.0000000000017501] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Traditional treatment of functional dyspepsia (FD) is unsatisfactory in a subgroup of patients with FD, and the potential role of antidepressant medications also has not been definitely clarified. To provide more evidence for future optimal practice recommendations, we reviewed a 1-year clinical database of antidepressant agents applied in outpatients with FD. METHODS Clinical presentations, treatment course, and outcomes were determined by chart review of patients referring to the functional gastrointestinal disorders specialist clinic. One hundred thirty patients with FD were included for further analysis. RESULTS Patients were treated with different antidepressant drugs according to individual symptoms. The most commonly used drugs were flupenthixol melitracen and fluoxetine. Improvement and complete remission occurred in 93.8% and 54.6% of patients, respectively. There was a trend toward superior outcome for citalopram compared to sulpiride and mirtazapine in overall analysis. Meanwhile, regimens containing fluoxetine had significant increased remission rate compared to any other antidepressant regimens in postprandial distress syndrome subgroup analysis. Furthermore, older patients were more likely to achieve remission. However, sex and symptom duration were not associated with symptom remission. Finally, 11.5% of patients experienced adverse events. CONCLUSIONS This retrospective cohort study indicated that small dose antidepressant therapy, especially citalopram and fluoxetine, is an effective and well tolerated treatment option for refractory FD.
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Affiliation(s)
- Liang Luo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Lijun Du
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Jinhua Shen
- Department of Gastroenterology, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Mengsha Cen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Ning Dai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
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12
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Di Stefano M, Pucci E, Miceli E, Pagani E, Brondino N, Nappi G, Corazza GR, Di Sabatino A. Prevalence and pathophysiology of post-prandial migraine in patients with functional dyspepsia. Cephalalgia 2019; 39:1560-1568. [DOI: 10.1177/0333102419857596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Migraine is a condition frequently associated with gastrointestinal disorders. Previous reports have shown the relationship between irritable bowel syndrome and migraine, but no data are yet available in patients with functional dyspepsia. We therefore evaluated whether alteration of gastric sensorimotor activity may be related to migraine. Methods Sixty patients affected by functional dyspepsia, 38 with postprandial distress syndrome and 22 with epigastric pain syndrome were enrolled in a cohort study. Presence and severity of dyspeptic symptoms, migraine presence and severity, gastric sensitivity thresholds during fasting and postprandial period, gastric accommodation and gastric emptying time were evaluated. Results In epigastric pain syndrome, 12/22 (54%) patients suffered from migraine and this condition was never correlated with meal ingestion. In postprandial distress syndrome patients, 29/38 (76%) suffered from migraine, in 26/29 (89%) its onset was considered as meal-related, and migraine severity was significantly correlated with postprandial modification of the gastric discomfort threshold (r = −0.73; p < 0.001). In patients with postprandial distress syndrome, in the subgroup with moderate to severe migraine, the severity of fullness and early satiation was significantly higher than in patients with mild or absent migraine. In patients with moderate to severe migraine, gastric accommodation, sensitivity thresholds and gastric emptying time were similar to patients with mild or no migraine. Conclusions In patients with functional dyspepsia and postprandial symptoms, migraine is a very frequent comorbidity. On clinical grounds, it is associated with an increased severity of fullness and early satiation and, on pathophysiological grounds, it seems correlated with postprandial hypersensitivity.
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Affiliation(s)
- Michele Di Stefano
- 1st Department of Medicine, University of Pavia, Foundation IRCCS “S.Matteo” Hospital, Pavia, Italy
| | - Ennio Pucci
- University Centre for Adaptive Disorders and Headache (UCADH), University of Pavia, IRCCS “C.Mondino” Pavia, Italy
| | - Emanuela Miceli
- 1st Department of Medicine, University of Pavia, Foundation IRCCS “S.Matteo” Hospital, Pavia, Italy
| | - Elisabetta Pagani
- 1st Department of Medicine, University of Pavia, Foundation IRCCS “S.Matteo” Hospital, Pavia, Italy
| | - Natascia Brondino
- Department of Brain and behavioral sciences, University of Pavia, Pavia, Italy
| | - Giuseppe Nappi
- University Centre for Adaptive Disorders and Headache (UCADH), University of Pavia, IRCCS “C.Mondino” Pavia, Italy
| | - Gino Roberto Corazza
- 1st Department of Medicine, University of Pavia, Foundation IRCCS “S.Matteo” Hospital, Pavia, Italy
| | - Antonio Di Sabatino
- 1st Department of Medicine, University of Pavia, Foundation IRCCS “S.Matteo” Hospital, Pavia, Italy
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13
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den Boer C, Dries L, Terluin B, van der Wouden JC, Blankenstein AH, van Wilgen CP, Lucassen P, van der Horst HE. Central sensitization in chronic pain and medically unexplained symptom research: A systematic review of definitions, operationalizations and measurement instruments. J Psychosom Res 2019; 117:32-40. [PMID: 30665594 DOI: 10.1016/j.jpsychores.2018.12.010] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/05/2018] [Accepted: 12/21/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Central sensitization (CS), a mechanism explaining the persistence of symptoms, has been the focus of many research projects. Explanations given to patients with chronic pain are often based on this mechanism. It is hypothesized that CS also plays an important role in the persistence of medically unexplained symptoms (MUS). However, definitions and operationalizations of CS vary. We conducted a systematic review of definitions, operationalizations and measurement instruments of CS. METHODS We searched in PubMed, EMBASE, PsycINFO, Cinahl and The Cochrane Library till September 2017 and included papers that addressed CS in relation to chronic pain and/or MUS. Two reviewers independently selected, analysed and classified information from the selected publications. We performed a thematic analysis of definitions and operationalizations. We listed the measurement instruments. RESULTS We included 126 publications, 79 publications concerned chronic pain, 47 publications concerned MUS. Definitions of CS consistently encompass the theme hyperexcitability of the central nervous system (CNS). Additional themes are variably present: CNS locations, nature of sensory input, reduced inhibition and activation and modulation of the NDMA receptor. Hyperalgesia and allodynia are widely mentioned as operationalizations of CS. Quantitative sensory testing (QST) and (f)MRI are the most reported measurement instruments. CONCLUSIONS There is consensus that hyperexcitability is the central mechanism of CS. Operationalizations are based on this mechanism and additional components. There are many measurement instruments available, whose clinical value has still to be determined. There were no systematic differences in definitions and operationalizations between the publications addressing MUS and those addressing chronic pain.
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Affiliation(s)
- Carine den Boer
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands.
| | - Linne Dries
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands
| | - Berend Terluin
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands
| | - Johannes C van der Wouden
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands
| | - Annette H Blankenstein
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands
| | - C Paul van Wilgen
- Transcare, transdisciplinary pain management centre, Groningen, the Netherlands; Pain in Motion International Research Group, Department of Physiotherapy, Physiology and Anatomy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter Lucassen
- Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Primary and Community care, Nijmegen, the Netherlands
| | - Henriëtte E van der Horst
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of general practice and elderly care medicine, Amsterdam Public Health research institute, the Netherlands
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14
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Black CJ, Houghton LA, Ford AC. Insights into the evaluation and management of dyspepsia: recent developments and new guidelines. Therap Adv Gastroenterol 2018; 11:1756284818805597. [PMID: 30397412 PMCID: PMC6207968 DOI: 10.1177/1756284818805597] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 09/17/2018] [Indexed: 02/04/2023] Open
Abstract
Dyspepsia is a very common gastrointestinal (GI) condition worldwide. We critically examine the recommendations of recently published guidelines for the management of dyspepsia, including those produced jointly by the American College of Gastroenterology and the Canadian Association of Gastroenterology, and those published by the UK National Institute for Health and Care Excellence. Dyspepsia is a symptom complex, characterized by a range of upper GI symptoms including epigastric pain or burning, early satiety, and post-prandial fullness. Although alarm features are used to help prioritize access to upper GI endoscopy, they are of limited utility in predicting endoscopic findings, and the majority of patients with dyspepsia will have no organic pathology identified at upper GI endoscopy. These patients are labelled as having functional dyspepsia (FD). The Rome IV criteria, which are used to define FD, further subclassify patients with FD as having either epigastric pain syndrome or post-prandial distress syndrome, depending on their predominant symptoms. Unfortunately, the Rome criteria perform poorly at identifying FD without the need for upper GI endoscopy. This has led to the investigation of alternative diagnostic approaches, including whether a capsaicin pill or combined serum biomarkers can accurately identify patients with FD. However, there is insufficient evidence to support either of these approaches at the present time. Patients with FD should be tested for H. pylori infection and be prescribed eradication therapy if they test positive. If they continue to have symptoms following this, then a trial of treatment with a proton pump inhibitor (PPI) should be given for up to 8 weeks. In cases where symptoms fail to adequately respond to PPI treatment, a tricyclic antidepressant may be of benefit, and should be continued for 6 to 12 months in patients who respond. Prokinetics demonstrate limited efficacy for treating FD, but could be considered if other strategies have failed. However, there are practical difficulties due to their limited availability in some countries and the risk of serious side effects. Patients with FD who fail to respond to drug treatments should be offered psychological therapy, where available. Overall, with the exception of recommendations relating to H. pylori testing and the prescription of PPIs, which are made on the basis of high-quality evidence, the evidence underpinning other elements of dyspepsia management is largely of low-quality. Consequently, there are still many aspects of the evaluation and management of dyspepsia that require further research.
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Affiliation(s)
| | - Lesley A. Houghton
- Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Alexander C. Ford
- Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
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15
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Hammer J. Identification of Individuals with Functional Dyspepsia With a Simple, Minimally Invasive Test: A Single Center Cohort Study of the Oral Capsaicin Test. Am J Gastroenterol 2018. [PMID: 29533398 DOI: 10.1038/ajg.2018.16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The diagnosis of functional dyspepsia (FD) is challenging due to the lack of reliable biological markers to support the diagnosis. We assessed the relevance of a previously validated simple test for chemical hypersensitivity in the setting of a gastrointestinal outpatient department. METHODS A total of 224 outpatients who were referred for evaluation of gastrointestinal symptoms in the absence of alarm symptoms swallowed a capsule containing 0.75 mg capsaicin. Severity of symptoms before and after capsule ingestion was assessed by a graded questionnaire and the difference in aggregate symptom scores (delta) was calculated. RESULTS Sensitivity of the test was between 0.51-0.59, specificity was 0.84-0.89 and positive predictive value for the diagnosis of FD 70-71%. FD patients had significantly higher median delta symptom scores (10.0; 25% quartile: 3.0; 75% quartile: 16.0) as compared to inflammatory bowel disease (2.5; 1.0/8.5)(P=0.003), peptic ulcer disease (0.0; -1.5/4.5) (P<0.001), irritable bowel syndrome (3.0;0.5/8.5)(P=0.001), and patients classified with "other disease" (2.5;0.0/5.0)(P<0.001). Patients with gastroesophageal reflux disease had significantly lower symptom scores if FD was not concomitantly diagnosed (2.0; 0.0/6.0) than if FD was present (10.0; 4.0/15.0). CONCLUSIONS Hypersensitivity for capsaicin discriminates functional dyspepsia from patients with other GI disorders. The capsaicin test is a simple and non invasive method to detect a large subgroup of functional dyspepsia with chemical hypersensitivity. These findings might open new diagnostic options in functional dyspepsia and possibly new therapeutic options by targeting the specific capsaicin receptor TRPV1.
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Affiliation(s)
- Johann Hammer
- Abteilung fìr Gastroenterologie und Hepatologie, Universitätsklinik fìr Innere Medizin 3, Vienna, Austria
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16
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Hammer J, Führer M. Clinical characteristics of functional dyspepsia depending on chemosensitivity to capsaicin. Neurogastroenterol Motil 2017; 29:1-12. [PMID: 28547912 DOI: 10.1111/nmo.13103] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/07/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Augmented chemosensitivity to capsaicin has been demonstrated in approximately half of functional dyspepsia (FD) patients. AIM We determined clinical characteristics of FD patients with and without chemical hypersensitivity at baseline and after capsaicin ingestion for 4 weeks. METHODS N=49 outpatients with confirmed FD received an oral sensitivity test with 0.75 mg capsaicin at three occasions, before and after ingesting 0.25 mg capsaicin tid for 4 weeks. Symptomatic response to capsaicin allowed stratification to a capsaicin positive (chemosensitive) and a capsaicin negative (not chemosensitive) patient group. Symptom diaries were completed in the week before and during capsaicin ingestion. RESULTS A total of 53% FD had a positive capsaicin test, Crohnbach alpha was 0.85. Basic clinical characteristics were comparable in capsaicin positive and negative FD, but median daily aggregate upper gastrointestinal symptoms scores were significantly higher in capsaicin positive (median: 9.4; 5.4/11.7) than in capsaicin negative patients (6.6; 4.1/8.1) (P<.05). After capsaicin ingestion, upper gastrointestinal symptoms scores were reduced by -3.3 (-4.9/-1.9; P<.001) in capsaicin positive and -2.6 (-3.8/-0.3; P<.05) in capsaicin negative patients. Lower abdominal symptoms were comparable in capsaicin positive and negative patients at baseline (NS). After capsaicin ingestion lower gastrointestinal symptoms scores were reduced by -1.0 (-1.8/-0.1; P<.05) in capsaicin positive but not significantly altered (-0.6; -1.7/+0.9; NS) in capsaicin negative patients. After long-term capsaicin ingestion, the capsaicin test turned negative in 53% of chemosensitive patients (P<.01). CONCLUSIONS Differences in upper GI symptoms distinguished capsaicin positive and negative patients. Symptom improvement after long-term capsaicin ingestion was indirect proportional to the capsaicin test result.
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Affiliation(s)
- J Hammer
- Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria
| | - M Führer
- Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria
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17
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Singh R, Ghoshal UC, Kumar S, Mittal B. Genetic variants of immune-related genes IL17F and IL10 are associated with functional dyspepsia: A case-control study. Indian J Gastroenterol 2017; 36:343-352. [PMID: 28965252 DOI: 10.1007/s12664-017-0788-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 09/11/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Low-grade inflammation may play an important role in pathogenesis of functional dyspepsia (FD). Since cytokines may influence gastric mucosal inflammation, which is associated with FD, we evaluated singe nucleotide polymorphisms (SNPs) of pro-inflammatory IL17F and anti-inflammatory IL10 cytokine genes in patients with FD and healthy subjects (HS). METHODS Two hundred and thirty-seven consecutive patients with FD (Rome III) and 250 HS were genotyped for IL17F (rs2397084: A/G, rs763780: T/C) and IL10 (rs1800896: G/A, rs1800871: C/T) (PCR-RFLP). RESULTS Patients with FD [173 (73%) men, age 38.4±12 years] were comparable with HS [195 (78%) men, age 37.3±12 years] with respect to age and gender. Out of 237 patients, 26 (11%) had epigastric pain, 55 (23.2%) had post-prandial distress syndromes (EPS, PDS), and 156 (65.8%) had EPS-PDS overlap. Among 237 patients with FD, GG (variant) genotype of IL17F (rs2397084) was more common than HS [15 (6.3%) vs. 4 (1.6%), p=0.015, odds ratio (OR)=4.0, 95% confidence interval (CI)=1.3-12.3]. IL17F (rs763780) and IL10 (rs1800896) were comparable among patients and HS (p=0.56, 0.28), respectively. However, TT (variant) genotype of IL10 (rs1800871) was more common among patients than HS [39 (16.5%) vs. 32 (12.8%), p=0.06, OR=1.7, 95% CI=0.98-2.98]. SNPs of IL17F and IL10 (rs2397084, rs763780, rs1800896 and rs1800871) were comparable among patients among sub-types of FD (p=0.80 and 0.44). CONCLUSION SNPs of IL17F (rs2397084) and IL10 (rs1800871) genes are associated with FD.
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Affiliation(s)
- Rajan Singh
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India.
| | - Sushil Kumar
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Balraj Mittal
- Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
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18
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Balemans D, Boeckxstaens GE, Talavera K, Wouters MM. Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 2017; 312:G635-G648. [PMID: 28385695 DOI: 10.1152/ajpgi.00401.2016] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 03/21/2017] [Accepted: 04/01/2017] [Indexed: 01/31/2023]
Abstract
Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.
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Affiliation(s)
- Dafne Balemans
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Karel Talavera
- Laboratory of Ion Channel Research and TRP Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven Belgium
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
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19
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Ford AC, Luthra P, Tack J, Boeckxstaens GE, Moayyedi P, Talley NJ. Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis. Gut 2017; 66:411-420. [PMID: 26567029 DOI: 10.1136/gutjnl-2015-310721] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 10/13/2015] [Accepted: 10/24/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Functional dyspepsia (FD) is a chronic gastroduodenal disorder. Individuals with FD demonstrate visceral hypersensitivity, abnormal central pain processing, and low mood, but it is unclear whether psychotropic drugs are an effective treatment for the condition. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs). DESIGN MEDLINE, EMBASE, EMBASE Classic, PsychINFO and the Cochrane Controlled Trials Register were searched (up to June 2015) for RCTs recruiting adults with FD comparing psychotropic drugs with placebo. We contacted authors directly to maximise trial eligibility and minimise risk of bias for studies. Dichotomous symptom data were pooled to obtain relative risk (RR) of remaining symptomatic after therapy, with 95% CIs. RESULTS The search identified 2795 citations; 13 RCTs (1241 patients) were eligible. Ten trials were at low risk of bias. The RR of FD symptoms not improving with psychotropic drugs versus placebo was 0.78 (95% CI 0.68 to 0.91) (number needed to treat=6; 95% CI 4 to 16). However, benefit was limited to antipsychotics and tricyclic antidepressants. When only studies that excluded individuals with coexistent mood disorder were considered, there was no benefit. Total numbers of adverse events and adverse events leading to withdrawal were significantly more common, with a number needed to harm of 21 for both. CONCLUSIONS Psychotropic drugs may be an effective treatment for FD, but the effect appears to be limited to antipsychotics and tricyclic antidepressants with fewer trials for other agents, meaning that firm conclusions for efficacy cannot be made. More data from high quality RCTs are required to support their use in the treatment of FD.
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Affiliation(s)
- Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Pavit Luthra
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Catholic University Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Catholic University Leuven, Leuven, Belgium
| | - Paul Moayyedi
- Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, Ontario, Canada
| | - Nicholas J Talley
- Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia
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20
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Gupta A, Mayer EA, Fling C, Labus JS, Naliboff BD, Hong JY, Kilpatrick LA. Sex-based differences in brain alterations across chronic pain conditions. J Neurosci Res 2017; 95:604-616. [PMID: 27870423 PMCID: PMC5120652 DOI: 10.1002/jnr.23856] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/18/2016] [Accepted: 07/06/2016] [Indexed: 12/17/2022]
Abstract
Common brain mechanisms are thought to play a significant role across a multitude of chronic pain syndromes. In addition, there is strong evidence for the existence of sex differences in the prevalence of chronic pain and in the neurobiology of pain. Thus, it is important to consider sex when developing general principals of pain neurobiology. The goal of the current Mini-Review is to evaluate what is known about sex-specific brain alterations across multiple chronic pain populations. A total of 15 sex difference and 143 single-sex articles were identified from among 412 chronic pain neuroimaging articles. Results from sex difference studies indicate more prominent primary sensorimotor structural and functional alterations in female chronic pain patients compared with male chronic pain patients: differences in the nature and degree of insula alterations, with greater insula reactivity in male patients; differences in the degree of anterior cingulate structural alterations; and differences in emotional-arousal reactivity. Qualitative comparisons of male-specific and female-specific studies appear to be consistent with the results from sex difference studies. Given these differences, mixed-sex studies of chronic pain risk creating biased data or missing important information and single-sex studies have limited generalizability. The advent of large-scale neuroimaging databases will likely aid in building a more comprehensive understanding of sex differences and commonalities in brain mechanisms underlying chronic pain. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Arpana Gupta
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Emeran A Mayer
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Psychiatry, UCLA, Los Angeles, CA, USA
- Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, USA
| | - Connor Fling
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
| | - Jennifer S Labus
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Psychiatry, UCLA, Los Angeles, CA, USA
- Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, USA
| | - Bruce D Naliboff
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Jui-Yang Hong
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Lisa A Kilpatrick
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, USA
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Triantafyllou K, Kourikou A, Gazouli M, Karamanolis GP, Dimitriadis GD. Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms in the Greek population. Neurogastroenterol Motil 2017; 29. [PMID: 27430937 DOI: 10.1111/nmo.12913] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 06/27/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Functional dyspepsia (FD) susceptibility might be influenced by polymorphisms of genes related to inflammation (CD14, macrophage migration inhibitory factor [MIF]), motor (GNB3), and sensory dysfunction (GNB3, TRPV1). We examined the association between CD14 rs2569190, GNB3 rs5443, MIF rs222747, and TRPV1 rs755622 gene polymorphisms with FD (Rome III criteria) in the Greek population. METHODS We genotyped 174 dyspeptics (115 with epigastric pain syndrome; 41% Helicobacter pylori positive) and 181 controls using polymerase chain reaction-based methods and we measured disease symptoms' burden with a modified Gastrointestinal Symptoms Related Scale. KEY RESULTS Homozygous for the TT genotype and the T allele of the CD14 gene were significantly associated (OR [95% CI]) with FD (2.65 [1.42-4.94] and 1.67 [1.23-2.26], respectively). The CT, TT genotypes, and T allele frequencies of GNB3 showed also significant association with FD (2.18 [1.35-3.54], 3.46 [1.30-9.23], and 2.18 [1.48-3.19]). While heterozygous GC MIF genotype was more common in dyspeptics (1.67 [1.07-2.60]), homozygous CC genotype and the C allele of TRPV1 gene were more prevalent in controls (0.47 [0.25-0.87] and 0.69 [0.51-0.92], respectively). None of the gene polymorphism was related either to dyspepsia clinical syndrome type or to the H. pylori infection. Among dyspeptics, CD14 TT genotype was related to lower epigastric pain burden score (p<.011); CD14 CT genotype was related to higher epigastric burning and nausea burden scores (p<.04) while belching score was lower (p=.027) in MIF CG dyspeptics. CONCLUSION & INFERENCES Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms, while CD14 and MIF gene variants are also associated with dyspepsia symptoms burden.
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Affiliation(s)
- K Triantafyllou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - A Kourikou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - M Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University, Athens, Greece
| | - G P Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - G D Dimitriadis
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
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Abstract
As defined by Rome III, there are 4 abdominal pain-related functional gastrointestinal disorders in children: irritable bowel syndrome, functional dyspepsia (FD), abdominal migraine, and functional abdominal pain. Dyspepsia is a constellation of symptoms referable to the gastroduodenal region of the upper gastrointestinal tract. FD refers to dyspeptic symptoms that cannot currently be explained by an organic cause, and affects 25% to 40% of the adult population over a lifetime. In children, this condition results in increased specialist consultations, with reported prevalence between 3% and 27%. The Rome III criteria for pediatric FD include the presence or persistence of recurrent pain or discomfort centered in the upper abdomen, without evidence of organic disease or change in frequency of stools. Symptoms must be chronic, occurring at least weekly and over a period of at least 6 months. The goal of this article is to provide a narrative review of diagnosis and management of the FD in the pediatric population. A comprehensive search of published literature using the PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) database was carried out to identify all articles published in English from 1998 to November 2015, using 3 key terms; "FD," "functional gastrointestinal disorders," and "children."
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Affiliation(s)
- Claudio Romano
- *Pediatric Department, University of Messina, Messina, Italy †Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Centre, Amsterdam, The Netherlands
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Lee SY, Masaoka T, Han HS, Matsuzaki J, Hong MJ, Fukuhara S, Choi HS, Suzuki H. A prospective study on symptom generation according to spicy food intake and TRPV1 genotypes in functional dyspepsia patients. Neurogastroenterol Motil 2016; 28:1401-8. [PMID: 27094759 DOI: 10.1111/nmo.12841] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/24/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Capsaicin is an ingredient of red peppers that binds to transient receptor potential vanilloid subtype 1 (TRPV1), and Koreans eat more capsaicin-rich food than do Japanese. This study aimed to compare symptom generation according to TRPV1 genotypes and the intake of spicy foods. METHODS Consecutive functional dyspepsia (FD) patients who were evaluated at Konkuk University Medical Centre (Korea) and Keio University Hospital (Japan) were included. Questionnaires on spicy food intake, patient assessment of gastrointestinal symptoms (PAGI-SYM), patient assessment of quality of life, and hospital anxiety and depression scale were provided. Blood was sampled for the detection of TRPV1 polymorphisms, and upper gastrointestinal endoscopy was performed with biopsies. KEY RESULTS Of 121 included subjects, 35 and 28 carried the TRPV1 CC and GG genotypes, respectively, with the prevalence rates not differing between Japan and Korea. The prevalence of FD subtypes did not differ with the spicy food intake, TRPV1 genotypes, or Helicobacter pylori infection. Neither TRPV1 polymorphisms nor H. pylori infections were related to scores on the PAGI-SYM questionnaires, but spicy food intake was positively correlated with the scores for stomach fullness (p = 0.001) and retching (p = 0.001). Using the linear regression analysis, stomach fullness was associated with spicy food intake (p = 0.007), whereas retching was related to younger age (p < 0.001) and female gender (p = 0.014). CONCLUSIONS & INFERENCES Upper gastrointestinal symptoms are more common in subjects with a higher consumption of spicy foods, younger age and female gender, regardless of TRPV1 genotypes and the H. pylori infection status. Capsaicin-rich foods may induce stomach fullness.
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Affiliation(s)
- S-Y Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - T Masaoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - H S Han
- Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - J Matsuzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - M J Hong
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - S Fukuhara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - H S Choi
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - H Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Medical Education Center, Keio University School of Medicine, Tokyo, Japan
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Choi YJ, Kim N, Kim J, Lee DH, Park JH, Jung HC. Upregulation of Vanilloid Receptor-1 in Functional Dyspepsia With or Without Helicobacter pylori Infection. Medicine (Baltimore) 2016; 95:e3410. [PMID: 27175641 PMCID: PMC4902483 DOI: 10.1097/md.0000000000003410] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The etiological basis of functional dyspepsia (FD) is incompletely understood. The aim of this study was to evaluate the involvement of nociceptor-related genes and Helicobacter pylori (HP) in the pathogenesis of FD. The expression of nociceptor-related genes was measured in gastric cell lines that were co-cultured with HP. FD patients (n = 117) and controls (n = 55) were enrolled from a tertiary hospital gastroenterology clinic. Expression of the genes nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the gastric mucosa were detected by reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemical staining of TRPV1 was analyzed. These measurements were repeated after 1 year. TRPV1, GDNF, and NGF expression was elevated in gastric cell lines co-cultured with HP. TRPV1 immunostaining was stronger in HP-positive than HP-negative subjects. The FD group showed higher expression levels of TRPV1, GDNF, and NGF and increased TRPV1 immunostaining compared with those of the control group (all P < 0.05). Among 61 subjects who were followed up at 1 year, controls with successful HP eradication and patients whose symptoms had improved both showed significant reductions in the expression of TRPV1 and NGF (all P < 0.05) compared with controls without HP eradication and patients whose symptoms had not improved, respectively. The expression of NGF, GDNF, and TRPV1 may be associated with the pathogenesis of FD. Since HP infection may induce the increased expression of these genes, anti-HP therapy could be beneficial for HP-positive patients with FD.
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Affiliation(s)
- Yoon Jin Choi
- From the Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do (YJC, NK, DHL); and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul (NK, JK, DHL, JHP, HCJ), South Korea
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Singh R, Mittal B, Ghoshal UC. Functional dyspepsia is associated with GNβ3 C825T and CCK-AR T/C polymorphism. Eur J Gastroenterol Hepatol 2016; 28:226-232. [PMID: 26551933 DOI: 10.1097/meg.0000000000000511] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND A polymorphism (C825T) in G-protein β polypeptide-3 (GNβ3) gene alters intracellular signal transduction, which may cause motor or sensory abnormalities in the gastrointestinal tract. Cholecystokinin-A receptor (CCK-AR) gene T/C polymorphism is associated with a defective splicing of the primary transcript of CCK-AR mRNA, which may modulate satiety signal and delay gastric emptying. Therefore, we evaluated the role of these polymorphisms in patients with functional dyspepsia (FD) as compared with healthy controls (HC). PATIENTS AND METHODS A total of 237 consecutive patients with FD (Rome III) and 250 HC were genotyped for GNβ3 C825T and CCK-AR T/C polymorphisms (PCR-RFLP). RESULTS Patients with FD [173 (73%) men, age: 38 ± 12 years] were comparable with HC [195 (78%) men, age: 37 ± 12 years] with respect to age and sex. Out of 237 patients, 26 (11%) had epigastric pain syndrome (EPS), 55 (23.2%) had postprandial distress syndrome (PDS), and 156 (65.8%) had EPS-PDS overlap. Among 237 patients with FD, TT genotype (associated with increased intracellular signal transduction) of GNβ3 C825T polymorphism was more common among patients than among HC [26 (11%) vs. 12 (4.8%), P=0.014; odds ratio (OR): 2.47, 95% confidence interval (CI): 1.2-5.1]. CC (variant) genotype of CCK-AR T/C polymorphism was infrequent among patients than among HC [19 (8%) vs. 46 (18.4%), P=0.001; OR: 0.36, 95% CI: 0.19-0.66]. However, these polymorphisms were comparable among patients with different subtypes of FD (P=0.80 and 0.44). CONCLUSION TT genotype of GNβ3 C825T is more common among patients with FD than among HC, suggesting that increased signal transduction associated with this genotype may be important in its pathophysiology. However, CCK-AR polymorphism is protective against FD.
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Affiliation(s)
- Rajan Singh
- Departments of aGastroenterology bGenetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Yu X, Yu M, Liu Y, Yu S. TRP channel functions in the gastrointestinal tract. Semin Immunopathol 2015; 38:385-96. [PMID: 26459157 DOI: 10.1007/s00281-015-0528-y] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/07/2015] [Indexed: 12/14/2022]
Abstract
Transient receptor potential (TRP) channels are predominantly distributed in both somatic and visceral sensory nervous systems and play a crucial role in sensory transduction. As the largest visceral organ system, the gastrointestinal (GI) tract frequently accommodates external inputs, which stimulate sensory nerves to initiate and coordinate sensory and motor functions in order to digest and absorb nutrients. Meanwhile, the sensory nerves in the GI tract are also able to detect potential tissue damage by responding to noxious irritants. This nocifensive function is mediated through specific ion channels and receptors expressed in a subpopulation of spinal and vagal afferent nerve called nociceptor. In the last 18 years, our understanding of TRP channel expression and function in GI sensory nervous system has been continuously improved. In this review, we focus on the expressions and functions of TRPV1, TRPA1, and TRPM8 in primary extrinsic afferent nerves innervated in the esophagus, stomach, intestine, and colon and briefly discuss their potential roles in relevant GI disorders.
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Affiliation(s)
- Xiaoyun Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Mingran Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Yingzhe Liu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Shaoyong Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA.
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27
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Hwang SW, Kim N, Jung HK, Park JH, Choi YJ, Kim H, Kim J, Kim JS, Jung HC. Association of SLC6A4 5-HTTLPR and TRPV1 945G>C with functional dyspepsia in Korea. J Gastroenterol Hepatol 2014; 29:1770-7. [PMID: 24720453 DOI: 10.1111/jgh.12596] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/27/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM The association of various genetic polymorphisms with functional dyspepsia (FD) has been suggested, but the results were still controversial. The aim of the present study was to assess the association of GNB3 825C>T, SLC6A4 5-HTTLPR, ADRA2A-1291C>G, CCK-1R intron 779T>C, and TRPV1 945G>C polymorphisms with FD based on Rome III criteria in Korea. METHODS Study subjects were prospectively recruited from visitors to Seoul National University Bundang Hospital between 2009 and 2012. One hundred and twelve FD patients and 269 controls were enrolled. RESULTS In SLC6A4 5-HTTLPR polymorphism, the frequency of S/S genotype was significantly lower than that of L/L + L/S genotype in FD compared to controls (P < 0.05). After stratification according to Helicobacter pylori infection, the S/S genotype was significantly associated with H. pylori-positive epigastric pain syndrome (EPS) patients (adjusted odds ratio (OR) 0.46; 95% confidence interval (CI) 0.22-0.99; P = 0.048). In TRPV1 945G>C polymorphism, the frequency of C/C genotype was lower in FD compared to controls (P = 0.057). The C carrier and C/C genotype was significantly associated with postprandial distress syndrome (PDS) and EPS, respectively (adjusted OR 0.47 and 0.43; 95% CI 0.25-0.90 and 0.20-0.93; P = 0.021 and 0.033). After stratification, the significant associations remained in H. pylori-positive PDS and EPS patients (adjusted OR 0.37 and 0.28; 95% CI 0.16-0.88 and 0.09-0.85; P = 0.024 and 0.025). CONCLUSIONS The genetic polymorphism of SLC6A4 5-HTTLPR and TRPV1 945G>C could be one of the pathophysiological factors of FD, especially in the case of H. pylori-positive patients in Korea.
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Affiliation(s)
- Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Gyeonggi-do, Korea
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28
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Rosen JM, Cocjin JT, Schurman JV, Colombo JM, Friesen CA. Visceral hypersensitivity and electromechanical dysfunction as therapeutic targets in pediatric functional dyspepsia. World J Gastrointest Pharmacol Ther 2014; 5:122-138. [PMID: 25133041 PMCID: PMC4133438 DOI: 10.4292/wjgpt.v5.i3.122] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/20/2014] [Accepted: 07/17/2014] [Indexed: 02/06/2023] Open
Abstract
Functional gastrointestinal disorders (FGID) are common clinical syndromes diagnosed in the absence of biochemical, structural, or metabolic abnormalities. They account for significant morbidity and health care expenditures and are identifiable across variable age, geography, and culture. Etiology of abdominal pain associated FGIDs, including functional dyspepsia (FD), remains incompletely understood, but growing evidence implicates the importance of visceral hypersensitivity and electromechanical dysfunction. This manuscript explores data supporting the role of visceral hypersensitivity and electromechanical dysfunction in FD, with focus on pediatric data when available, and provides a summary of potential therapeutic targets.
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Choi YJ, Hwang SW, Kim N, Park JH, Oh JC, Lee DH. Association Between SLC6A4 Serotonin Transporter Gene Lainked Polymorphic Region and ADRA2A -1291C>G and Irritable Bowel Syndrome in Korea. J Neurogastroenterol Motil 2014; 20:388-99. [PMID: 24917480 PMCID: PMC4102162 DOI: 10.5056/jnm14020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 04/26/2014] [Accepted: 04/28/2014] [Indexed: 12/11/2022] Open
Abstract
Background/Aims Despite numerous studies on the relation of genetic polymorphisms with irritable bowel syndrome (IBS), the results still remain inconclusive. The aim of this study was to assess the possible association between SLC6A4 serotonin transporter gene linked polymorphic region (5-HTTLPR), ADRA2A −1291C>G, GNB3 825C>T, CCK1R intron 779T>C and TRPV1 945G>C polymorphisms and IBS based on Rome III criteria in Korea. Methods Study subjects were prospectively recruited from visitors to Seoul National University Bundang Hospital between July 2009 and January 2014. Ninety-nine IBS patients and 171 healthy controls were enrolled. Polymorphisms of above-mentioned 5 genes were genotyped. Serum serotonin from 101 participants was measured by ELISA and compared according to SLC6A4 5-HTTLPR polymorphisms and IBS subtypes. Results Regarding SLC6A4 5-HTTLPR polymorphism, L/L genotype was significantly associated with the total IBS, constipation predominant IBS (IBS-C) and mixture of diarrhea and constipation IBS (IBS-M) (adjusted OR: 4.35, 95% CI: 1.04–16.67; adjusted OR: 11.11, 95% CI: 1.69–50.00 and adjusted OR: 5.56, 95% CI: 1.05–33.33, respectively). Carrying ADRA2A −1291G allele was significantly associated with total IBS and diarrhea predominant IBS (adjusted OR: 3.37, 95% CI: 1.16–9.77 and adjusted OR: 5.64, 95% CI: 1.18–27.01, respectively). IBS-C patients showed reduced level of serum serotonin compared to controls and patients with diarrhea predominant IBS (50.2 ng/mL vs. 69.0 ng/mL and 92.9 ng/mL, P = 0.017 and P = 0.001, respectively). Conclusions Genetic polymorphisms of SLC6A4 5-HTTLPR and ADRA2A −1291C>G could be one of the pathophysiological factors of IBS in Korea. Reduced serum serotonin shown in the IBS-C group suggested a role of serotonin in IBS, but large study is needed for confirming genotypic difference in serum serotonin level.
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jane C Oh
- Yonsei Plus Clinic, Seongnam, Gyeonggi-do, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Abstract
Crohn's disease is complicated by the development of fibrosis and stricture in approximately 30% to 50% of patients over time. The pathogenesis of fibrostenotic disease is multifactorial involving the activation of mesenchymal cells by cytokines, growth factors, and other mediators released by immune cells, epithelial cells, and mesenchymal cells. Transforming growth factor β, a key activator of mesenchymal cells, is central to the process of fibrosis and regulates numerous genes involved in the disordered wound healing including collagens, and other extracellular matrix proteins, connective tissue growth factor, and insulin-like growth factors. The activated mesenchymal compartment is expanded by recruitment of new mesenchymal cells through epithelial to mesenchymal transition, endothelial to mesenchymal transition, and invasion of circulating fibrocytes. Cellular hyperplasia and increased extracellular matrix production, particularly collagens, from fibroblasts, myofibroblasts, and smooth muscle cells add to the disturbed architecture and scarring on the intestine. Extracellular matrix homeostasis is further disrupted by alterations in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in the gut. Among the 163 susceptibility genes identified that contribute to susceptibility in inflammatory bowel disease mutations in NOD2/CARD15, innate immune system components and autophagy jointly contribute to the activation of mesenchymal cells and pathogenesis of fibrosis in this polygenic disorder. Numerous growth factors cytokines and other mediators also contribute to development of fibrosis in the susceptible patient. This review focuses on the molecular mechanisms that regulate mesenchymal cell function, particularly smooth muscle cells, the largest compartment of mesenchyme in the intestine, that lead to fibrosis in Crohn's disease.
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Abstract
Dyspepsia is a complex disorder with several distinct pathophysiologic mechanisms that are still poorly understood. Patients who experience dyspepsia have a high burden of disease, with significant personal and economic costs. Although serious pathology presenting as dyspepsia is rare, clinicians need to be aware of alarm features that should trigger prompt referral for subspecialty care. Those without alarm features can be managed in a rational way with either empiric antisecretory therapy, test-and-treat for H pylori eradication, antidepressants, and psychotherapy, or a combination of these. Given the heterogeneity of symptoms and large variability in response to different treatments, more research into specific pathophysiologic mechanisms will likely help guide diagnosis and treatment choices in the future.
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Affiliation(s)
- Maryann Katherine Overland
- Division of General Internal Medicine, Primary Care Clinic, VA Puget Sound Health Care System, University of Washington, 1660 South Columbian Way, Seattle, WA 98108, USA.
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Wilder-Smith CH, Li X, Shen L, Cao Y, Ho KY, Wong RK. Dysfunctional endogenous pain modulation in patients with functional dyspepsia. Neurogastroenterol Motil 2014; 26:489-98. [PMID: 24351013 DOI: 10.1111/nmo.12291] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 11/23/2013] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- C H Wilder-Smith
- Brain-Gut Research Group, Bern, Switzerland; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Wilder-Smith CH, Materna A, Wermelinger C, Schuler J. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther 2013; 37:1074-83. [PMID: 23574302 PMCID: PMC3672687 DOI: 10.1111/apt.12306] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 01/22/2013] [Accepted: 03/20/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND The association of fructose and lactose intolerance and malabsorption with the symptoms of different functional gastrointestinal disorders (FGID) remains unclear. AIM To investigate the prevalence of fructose and lactose intolerance (symptom induction) and malabsorption and their association with clinical gastrointestinal (GI) as well as non-GI symptoms in FGID and the outcome of dietary intervention. METHODS Fructose and lactose intolerance (defined by positive symptom index) and malabsorption (defined by increased hydrogen/methane) were determined in 1372 FGID patients in a single centre using breath testing. Results were correlated with clinical symptoms in different FGID Rome III subgroups. The effectiveness of a targeted saccharide-reduced diet was assessed after 6-8 weeks. RESULTS Intolerance prevalence across all FGIDs was 60% to fructose, 51% to lactose and 33% to both. Malabsorption occurred in 45%, 32% and 16% respectively. There were no differences in intolerance or malabsorption prevalence between FGID subgroups. FGID symptoms correlated with symptoms evoked during testing (r = 0.35-0.61. P < 0.0001), but not with malabsorption. Non-GI symptoms occurred more commonly in patients with intolerances. Methane breath levels were not associated with constipation using several cut-off thresholds. Adequate symptom relief was achieved in >80% of intolerant patients, irrespective of malabsorption. CONCLUSIONS Fructose and lactose intolerances are common in FGID and associated with increased non-GI symptoms, but not with specific FGID subtypes. Symptoms experienced during breath testing, but not malabsorption, correlate with FGID symptoms. Effective symptom relief with dietary adaptation is not associated with malabsorption. Mechanisms relating to the generation of GI and non-GI symptoms due to lactose and fructose in FGID need to be explored further.
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Affiliation(s)
- C H Wilder-Smith
- Gastroenterology Group Practice, Brain-Gut Research Group, Bern, Switzerland.
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