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Aguilera-Lizarraga J, Lopez-Lopez C, Jaramillo-Polanco J, Florens MV, Yu Y, Tsang QK, Chakraborty A, De Gand S, Pia F, Quan R, Cuende-Estévez M, Van Remoortel S, Strid J, Lomax AE, Berin MC, Craig AW, Kaufmann E, Ormiston ML, Vanner SJ, Hussein H, Boeckxstaens GE, Reed DE. Psychological Stress-Induced Local Immune Response to Food Antigens Increases Pain Signaling Across the Gut in Mice. Gastroenterology 2025:S0016-5085(25)00371-3. [PMID: 39978560 DOI: 10.1053/j.gastro.2025.01.246] [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: 05/27/2024] [Revised: 12/29/2024] [Accepted: 01/15/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND AND AIMS We recently showed that a bacterial infection can break oral tolerance to food and lead to immunoglobulin E (IgE)-dependent mast cell activation and food-induced abdominal pain, which could constitute an important pathogenic mechanism in postinfectious irritable bowel syndrome (IBS). Here, we investigated whether similar immune mechanisms in response to psychological stress lead to food-evoked pain signaling, and thus potentially explain the pathophysiology in a larger group of patients with IBS. METHODS Mice were exposed to ovalbumin (OVA) during water avoidance stress (WAS) and re-exposed to OVA 5 weeks later. Nociception was evaluated by visceromotor responses and afferent nerve recordings to intestinal distension, and patch-clamp recordings of sensory neurons incubated with intestinal supernatants. The role of IgE and type 2 immunity was evaluated using pharmacologic and genetic approaches. RESULTS Re-exposure to OVA increased pain signaling in the colon and small intestine only in mice exposed to OVA during WAS, in the absence of systemic allergy. OVA-induced increases in pain responses depended on mast cells, IgE, and signal transducer and activator of transcription 6 signaling. Notably, incubation of sensory neurons with ileum and colon supernatants from WAS/OVA+OVA mice lowered their threshold of excitability. Finally, treatment with histamine receptor H1 antagonist pyrilamine blocked the increased sensory neuron excitability, and reduced ileal afferent nerve firing to distension in WAS/OVA+OVA mice. CONCLUSIONS Psychological stress induces a type 2 immune response to food antigens, with IgE-mediated mast cell activation and increased pain signaling in the small intestine and colon in response to food. These findings may explain the potential role of psychological stress in food-induced symptoms in IBS.
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Affiliation(s)
- Javier Aguilera-Lizarraga
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Cintya Lopez-Lopez
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Josue Jaramillo-Polanco
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Morgane V Florens
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Yang Yu
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Quentin K Tsang
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Ananya Chakraborty
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Sofie De Gand
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Fedrica Pia
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Runze Quan
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - María Cuende-Estévez
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Samuel Van Remoortel
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Jessica Strid
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - M Cecilia Berin
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Andrew W Craig
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Eva Kaufmann
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Mark L Ormiston
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Stephen J Vanner
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - Hind Hussein
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Center of Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada.
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Karaivazoglou K, Aggeletopoulou I, Triantos C. Interoceptive Processing in Functional Gastrointestinal Disorders. Int J Mol Sci 2024; 25:7633. [PMID: 39062876 PMCID: PMC11277500 DOI: 10.3390/ijms25147633] [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: 06/12/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Functional gastrointestinal disorders (FGIDs) are characterized by chronic gastrointestinal symptoms in the absence of overt pathology and affect a significant percentage of the worldwide population. They are commonly accompanied by co-morbid psychiatric symptomatology and are associated with significant suffering and great healthcare services utilization. There is growing evidence that dysregulation of the gut-brain axis and disturbances in the processing of afferent interoceptive signals lie at the heart of these disorders. In this context, the aim of the current review was to detect and critically review original articles focusing on the role of interoception in the pathophysiology of FGIDs. Our search yielded 38 relevant studies. FGID patients displayed increased visceral sensitivity, enhanced attention to gastrointestinal interoceptive cues, and greater emotional arousal when coping with gut-derived sensations. Neuroimaging studies have shown significant structural and functional changes in regions of the interoceptive network, while molecular and genetic studies have revealed significant associations between interoceptive signaling and deficits in excitatory neurotransmission, altered endocrine and immune physiological pathways, and aberrant expression of transient receptor potential channel genes. Finally, there were emerging data suggesting that interoception-based interventions may reduce physical symptoms and improve quality of life and should be integrated into FGID clinical management practices.
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Affiliation(s)
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
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Vignali S, Buhner S, Greiter W, Daniel H, Frieling T, Schemann M, Annahazi A. Biopsy samples from patients with irritable bowel syndrome, but not from those with mastocytosis or unspecific gastrointestinal complaints reveal unique nerve activation in all gut regions independent of mast cell density, histamine content or specific gastrointestinal symptoms. Front Neurosci 2024; 18:1291554. [PMID: 39015376 PMCID: PMC11250647 DOI: 10.3389/fnins.2024.1291554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 05/29/2024] [Indexed: 07/18/2024] Open
Abstract
Introduction We previously showed enteric nerve activation after application of colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS). The question remains whether this is a region-specific or a generalized sensitization. We tested the nerve-activating properties of supernatants from large and small intestinal regions of IBS patients with diarrhea (IBS-D) in comparison to those from mastocytosis patients with diarrhea (MC-D) or non-IBS/non-MC patients with GI-complaints. MC-D patients were included to test samples from patients with an established, severe mast cell disorder, because mast cells are suggested to play a role in IBS. Methods Voltage-sensitive dye imaging was used to record the effects of mucosal biopsy supernatants from IBS-D, MC-D, and non-IBS/non-MC on guinea pig submucous neurons. Mast cell density and histamine concentrations were measured in all samples. Results The median neuroindex (spike frequency × % responding neurons in Hz × %) was significantly (all p < 0.001) increased for IBS-D (duodenum and colon, proximal and distal each, 49.3; 50.5; 63.7; 71.9, respectively) compared to non-IBS/non-MC (duodenum and colon, proximal and distal each, 8.7; 4.9; 6.9; 5.4, respectively) or MC-D supernatants (duodenum and colon, proximal and distal each, 9.4; 11.9; 0.0; 7.9, respectively). Nerve activation by MC-D and non-IBS/non-MC supernatants was comparable (p>0.05). Mast cell density or histamine concentrations were not different between IBS-D, MC-D, and non-IBS/non-MC samples. Discussion Nerve activation by biopsy supernatants is an IBS hallmark that occurs throughout the gut, unrelated to mast cell density or histamine concentration. At least as important is our finding that GI complaints per se were not associated with biopsy supernatant-induced nerve activation, which further stresses the relevance of altered nerve behavior in IBS.
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Affiliation(s)
- Sheila Vignali
- Chair of Human Biology, Technical University of Munich, Freising, Germany
| | - Sabine Buhner
- Chair of Human Biology, Technical University of Munich, Freising, Germany
- Chair of Zoology, Technical University of Munich, Freising, Germany
| | - Wolfgang Greiter
- Chair of Human Biology, Technical University of Munich, Freising, Germany
- Chair of Zoology, Technical University of Munich, Freising, Germany
| | - Hannelore Daniel
- Chair of Nutrition Physiology, Technical University of Munich, Freising, Germany
| | - Thomas Frieling
- Medical Clinic II, Helios Klinikum Krefeld, Krefeld, Germany
| | - Michael Schemann
- Chair of Human Biology, Technical University of Munich, Freising, Germany
| | - Anita Annahazi
- Chair of Human Biology, Technical University of Munich, Freising, Germany
- Chair of Zoology, Technical University of Munich, Freising, Germany
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Li ZY, Mao YQ, Hua Q, Sun YH, Wang HY, Ye XG, Hu JX, Wang YJ, Jiang M. Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome. World J Gastroenterol 2024; 30:1431-1449. [PMID: 38596485 PMCID: PMC11000090 DOI: 10.3748/wjg.v30.i10.1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 02/06/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Serotonin receptor 2B (5-HT2B receptor) plays a critical role in many chronic pain conditions. The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea (IBS-D) was investigated in the present study. AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D. METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls. The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores. The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint. Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1 (TRPV1) expression were examined following 5-HT2B receptor antagonist administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded. RESULTS Here, we observed greater expression of the 5-HT2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT2B receptor antagonist exhibited inhibited visceral hyperalgesia.Moreover, the percentage of 5-HT2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT2B receptor I+) and total 5-HT2B receptor IR cells (5-HT2B receptor IT) in IBS-D rats was significantly reduced by the administration of a 5-HT2B receptor antagonist. CONCLUSION Our finding that increased expression of the 5-HT2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.
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Affiliation(s)
- Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yu-Qing Mao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qian Hua
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yong-Hong Sun
- Department of Gastroenterology, Dalian Friendship Hospital, Dalian 116001, Liaoning Province, China
| | - Hai-Yan Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Xuan-Guang Ye
- Department of Pathology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Jing-Xian Hu
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ya-Jie Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Miao Jiang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
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Zhang X, Wang F, Su Y. TRPV: An emerging target in glaucoma and optic nerve damage. Exp Eye Res 2024; 239:109784. [PMID: 38199261 DOI: 10.1016/j.exer.2024.109784] [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: 08/23/2023] [Revised: 11/30/2023] [Accepted: 01/06/2024] [Indexed: 01/12/2024]
Abstract
Transient receptor potential vanilloid (TRPV) channels are members of the TRP channel superfamily, which are ion channels that sense mechanical and osmotic stimuli and participate in Ca2+ signalling across the cell membrane. TRPV channels play important roles in maintaining the normal functions of an organism, and defects or abnormalities in TRPV channel function cause a range of diseases, including cardiovascular, neurological and urological disorders. Glaucoma is a group of chronic progressive optic nerve diseases with pathological changes that can occur in the tissues of the anterior and posterior segments of the eye, including the ciliary body, trabecular meshwork, Schlemm's canal, and retina. TRPV channels are expressed in these tissues and play various roles in glaucoma. In this article, we review various aspects of the pathogenesis of glaucoma, the structure and function of TRPV channels, the relationship between TRPV channels and systemic diseases, and the relationship between TRPV channels and ocular diseases, especially glaucoma, and we suggest future research directions. This information will help to further our understanding of TRPV channels and provide new ideas and targets for the treatment of glaucoma and optic nerve damage.
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Affiliation(s)
- Xiaotong Zhang
- Department of Ophthalmology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Feng Wang
- Department of Ophthalmology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
| | - Ying Su
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
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Zogg H, Singh R, Ha SE, Wang Z, Jin B, Ha M, Dafinone M, Batalon T, Hoberg N, Poudrier S, Nguyen L, Yan W, Layden BT, Dugas LR, Sanders KM, Ro S. miR-10b-5p rescues leaky gut linked with gastrointestinal dysmotility and diabetes. United European Gastroenterol J 2023; 11:750-766. [PMID: 37723933 PMCID: PMC10576606 DOI: 10.1002/ueg2.12463] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 07/31/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND/AIM Diabetes has substantive co-occurrence with disorders of gut-brain interactions (DGBIs). The pathophysiological and molecular mechanisms linking diabetes and DGBIs are unclear. MicroRNAs (miRNAs) are key regulators of diabetes and gut dysmotility. We investigated whether impaired gut barrier function is regulated by a key miRNA, miR-10b-5p, linking diabetes and gut dysmotility. METHODS We created a new mouse line using the Mb3Cas12a/Mb3Cpf1 endonuclease to delete mir-10b globally. Loss of function studies in the mir-10b knockout (KO) mice were conducted to characterize diabetes, gut dysmotility, and gut barrier dysfunction phenotypes in these mice. Gain of function studies were conducted by injecting these mir-10b KO mice with a miR-10b-5p mimic. Further, we performed miRNA-sequencing analysis from colonic mucosa from mir-10b KO, wild type, and miR-10b-5p mimic injected mice to confirm (1) deficiency of miR-10b-5p in KO mice, and (2) restoration of miR-10b-5p after the mimic injection. RESULTS Congenital loss of mir-10b in mice led to the development of hyperglycemia, gut dysmotility, and gut barrier dysfunction. Gut permeability was increased, but expression of the tight junction protein Zonula occludens-1 was reduced in the colon of mir-10b KO mice. Patients with diabetes or constipation- predominant irritable bowel syndrome, a known DGBI that is linked to leaky gut, had significantly reduced miR-10b-5p expression. Injection of a miR-10b-5p mimic in mir-10b KO mice rescued these molecular alterations and phenotypes. CONCLUSIONS Our study uncovered a potential pathophysiologic mechanism of gut barrier dysfunction that links both the diabetes and gut dysmotility phenotypes in mice lacking miR-10b-5p. Treatment with a miR-10b-5p mimic reversed the leaky gut, diabetic, and gut dysmotility phenotypes, highlighting the translational potential of the miR-10b-5p mimic.
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Affiliation(s)
- Hannah Zogg
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Rajan Singh
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Se Eun Ha
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Zhuqing Wang
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Byungchang Jin
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Mariah Ha
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Mirabel Dafinone
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Tylar Batalon
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Nicholas Hoberg
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Sandra Poudrier
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Linda Nguyen
- Division of Gastroenterology & HepatologyStanford University School of MedicineStanfordCaliforniaUSA
| | - Wei Yan
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and MetabolismDepartment of MedicineThe University of Illinois at ChicagoChicagoIllinoisUSA
- Jesse Brown Veterans Affairs Medical CenterChicagoIllinoisUSA
| | - Lara R. Dugas
- Loyola University ChicagoPublic Health SciencesMaywoodIllinoisUSA
- Division of Epidemiology & BiostatisticsSchool of Public HealthFaculty of Health SciencesUniversity of Cape TownCape TownSouth Africa
| | - Kenton M. Sanders
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
| | - Seungil Ro
- Department of Physiology and Cell BiologySchool of MedicineUniversity of NevadaRenoNevadaUSA
- RosVivo TherapeuticsApplied Research FacilityRenoNevadaUSA
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Ran Y, Wu K, Hu C, Liang R, Zhang L, Xiao J, Peng Y, Sun W. Downregulated APOD and FCGR2A correlates with immune infiltration and lipid-induced symptoms of irritable bowel syndrome. Sci Rep 2023; 13:14211. [PMID: 37648784 PMCID: PMC10469184 DOI: 10.1038/s41598-023-41004-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 08/20/2023] [Indexed: 09/01/2023] Open
Abstract
Fat intake is among the most significant triggers for symptom development in patients with irritable bowel syndrome (IBS). Nevertheless, long-term restriction in fatty foods ingestion may lead to nutritional inadequacies. This study aimed to identify the crucial genes involved in lipid-induced gastrointestinal symptoms, contributing to helping IBS patients regulate fat. The clinical characteristics of the subjects were collected by questionnaire investigation and analyzed using multivariate logistic regression. Differentially expressed genes (DEG) and signaling pathways were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. ImmuInfiltration and CIBERSORT packages evaluated small intestine immune cell infiltration. Random forest and SVM-RFE algorithms were used to select hub genes. A receiver operating characteristic curve was used to access the diagnostic significance of each hub gene. Gene Set Enrichment Analysis (GSEA) was performed to identify hub genes' molecular processes in IBS development after lipid infusion. IBS patients' risk, severity, and quality of life increased with fat intake. In total, 116 robust DEGs were identified in IBS patients after lipid infusion using the GSE166869 dataset and were mainly clustered in the immune and inflammatory pathways. IBS patients had greater Neutrophils, CD4+ T cells, and M1 Macrophages than healthy controls. Furthermore, infiltration levels of Neutrophils and resting memory CD4+ T cells were inversely related to the expression of hub genes (IGKV1D-43, IGKV1-12, APOD, FCGR2A and IGKV2-29). After lipid infusion, GSEA results of each hub gene indicated the relevance of proinflammatory pathways in IBS pathogenesis. After verification, only APOD and FCGR2A were stably downregulated in small intestinal mucosa and plasma of IBS patients. The area under the curve of APOD combined with FCGR2A expression was 0.9. APOD and FCGR2A may be promising biomarkers for IBS diagnosis and lipid-sensitive IBS patients. Their potential roles in the immune microenvironment of the small intestinal mucosa may provide a vital clue to IBS precision therapy.
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Affiliation(s)
- Yamei Ran
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Kangqi Wu
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Chenglin Hu
- Department of Standardization Training Management, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Renzheng Liang
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Li Zhang
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Juan Xiao
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Yongmei Peng
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China
| | - Wenjing Sun
- Department of Gastroenterology and Hepatology, Thirteenth People's Hospital of Chongqing (Chongqing Geriatric Hospital), Chongqing, 400053, China.
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Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F. The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. Int J Mol Sci 2023; 24:11074. [PMID: 37446251 DOI: 10.3390/ijms241311074] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing. In this review, we describe the correlation status between channelopathies and FGIDs. Different findings are available. Among others, mutations in the ABCC7/CFTR gene have been described as a cause of constipation and diarrhea. Mutations of the SCN5A gene are instead associated with irritable bowel syndrome. In contrast, mutations of the TRPV1 and TRPA genes of the transient receptor potential (TRP) superfamily manifest hypersensitivity and visceral pain in sensory nerves. Recently, mice and humans affected by Cantu syndrome (CS), which is associated with the mutations of the KCNJ8 and ABCC9 genes encoding for the Kir6.1 and SUR2 subunits, showed dysfunction of contractility throughout the intestine and death in the mice after the weaning on solid food. The discovery of a correlation between channelopathies and FIGD opens new avenues for discovering new direct drug targets for specific channelopathies, leading to significant implications for diagnosing and treating functional GI diseases.
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Affiliation(s)
- Fatima Maqoud
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
| | - Domenico Tricarico
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy
| | - Rosanna Mallamaci
- Department of Biosciences, Biotechnologies and Environment University of Bari Aldo Moro, 70125 Bari, Italy
| | - Antonella Orlando
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
| | - Francesco Russo
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
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9
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Vanuytsel T, Bercik P, Boeckxstaens G. Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders. Gut 2023; 72:787-798. [PMID: 36657961 PMCID: PMC10086308 DOI: 10.1136/gutjnl-2020-320633] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023]
Abstract
Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.
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Affiliation(s)
- Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium.,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Premysl Bercik
- Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Guy Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium .,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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10
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Colomier E, Algera JP, Van den Houte K, Simrén M, Tack J. Mechanisms underlying food-related symptoms in disorders of gut-brain interaction: Course ahead in research and clinical practice. Best Pract Res Clin Gastroenterol 2023; 62-63:101824. [PMID: 37094907 DOI: 10.1016/j.bpg.2023.101824] [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: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 04/26/2023]
Abstract
A subgroup of patients with a disorder of gut-brain interaction (DGBI) report symptoms such as abdominal pain, gas-related symptoms, dyspeptic symptoms and loose stool or urgency after meal intake. Therefore, the effect of several dietary therapies including fibre-rich or restrictive diets have already been studied in patients with irritable bowel syndrome, functional abdominal bloating or distention, and functional dyspepsia. However, there is a paucity of studies in the literature on the mechanisms underlying food-related symptoms. Therefore, this review focuses on these potential mechanisms and explains the role of nutrient sensing and tasting, physical considerations, malabsorption or allergy-like reaction to food and its interaction with microbiota. In addition, it emphasizes the importance of future research and clinical practice regarding food-related symptoms in patients with a DGBI.
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Affiliation(s)
- Esther Colomier
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Joost P Algera
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karen Van den Houte
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Center for Functional GI and Motility Disorders, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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11
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Maalouf E, Grover M. Editorial: repurposed linaclotide and the quest for abdominal pain management in irritable bowel syndrome. Aliment Pharmacol Ther 2023; 57:261-262. [PMID: 36565004 DOI: 10.1111/apt.17304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Elisia Maalouf
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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12
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Shin A, Kashyap PC. Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead. Gut Microbes 2023; 15:2195792. [PMID: 37009874 PMCID: PMC10072066 DOI: 10.1080/19490976.2023.2195792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/23/2023] [Indexed: 04/04/2023] Open
Abstract
Reliable biomarkers for common disorders of gut-brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.
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Affiliation(s)
- Andrea Shin
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Purna C. Kashyap
- Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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13
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Camilleri M, Magnus Y, Carlson P, Wang XJ, Chedid V, Maselli D, Taylor A, McKinzie S, Kengunte Nagaraj N, Busciglio I, Nair A. Differential mRNA expression in ileal and colonic biopsies in irritable bowel syndrome with diarrhea or constipation. Am J Physiol Gastrointest Liver Physiol 2022; 323:G88-G101. [PMID: 35502856 PMCID: PMC9291427 DOI: 10.1152/ajpgi.00063.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Altered mucosal functions are documented in jejunal or colorectal mucosa from patients with irritable bowel syndrome (IBS). Our aim was to quantify ileal, ascending, and rectosigmoid colon mucosal expression of genes in IBS-diarrhea (D) and IBS-constipation (C). Forty-four patients with IBS-D, 30 with IBS-C, and 30 healthy volunteers underwent colonoscopic ileal, ascending, and rectosigmoid colon biopsies. Biopsies were stored in RNAlater at -80 °C, purified with on-column DNase, cDNA libraries prepared from 100-200 ng of total RNA, sequenced on Illumina NovaSeq 6000, and analyzed on Illumina's RTA version 3.4.4. Normalized mRNA expression was obtained using MAP-RSeq bioinformatics pipeline. Differential expressions in the groups (Log2-fold change) were measured using the bioinformatics package edgeR 2.6.2, corrected for false discovery rate (PADJ <0.05). There were 30 females with IBS-C and 31 females and 13 males with IBS-D. In IBS-D and IBS-C groups, there were differential expressions of 181 genes in ascending colon and 199 genes in rectosigmoid colon. The majority were gene upregulations in IBS-D with functions reflecting activation of inflammation genes, TRPV1 (visceral hypersensitivity) and neurotransmitters/receptors (specifically purinergic, GABA, and cannabinoid). Although gene differential expressions in the ascending and rectosigmoid colon mucosa of the two groups were different, the diverse upregulated genes involved immune functions, receptors, transmitters, ion channels, and transporters. Conversely, there was reduced expression of PI15 and PI16 genes that inhibit proteases. In patients with IBS-D and IBS-C, differential expressions of genes related to immune, transmitter, nociceptive, protease inhibition, channel, and transporter functions suggest opportunities to reverse the pathobiology and treat patients with IBS.NEW & NOTEWORTHY This study compares gene expression in mucosa of the terminal ileum, right colon, and left colon in patients with diarrhea- or constipation-predominant irritable bowel syndrome (IBS) and contrasts expression between these two disease entities and also between each entity and mucosa from healthy controls. The study shows there is differential expression of genes related to immune, transmitter, nociceptive, ion channel, and transporter functions, as well as reduced serine protease inhibition, in patients with IBS.
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Affiliation(s)
- Michael Camilleri
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Yorick Magnus
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Paula Carlson
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Xiao Jing Wang
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Victor Chedid
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Daniel Maselli
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Ann Taylor
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Sanna McKinzie
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | | | - Irene Busciglio
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Asha Nair
- 2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
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14
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Ceulemans M, Jacobs I, Wauters L, Vanuytsel T. Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect. Front Neurosci 2022; 16:831761. [PMID: 35557605 PMCID: PMC9087267 DOI: 10.3389/fnins.2022.831761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.
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Affiliation(s)
- Matthias Ceulemans
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Inge Jacobs
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Lucas Wauters
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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15
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Burns GL, Talley NJ, Keely S. Immune responses in the irritable bowel syndromes: time to consider the small intestine. BMC Med 2022; 20:115. [PMID: 35354471 PMCID: PMC8969236 DOI: 10.1186/s12916-022-02301-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction (DGBI), presenting as chronic abdominal pain and altered defaecation. Symptoms are often food related. Much work in the field has focused on identifying physiological, immune and microbial abnormalities in the colon of patients; however, evidence of small intestinal immune activation and microbial imbalance has been reported in small studies. The significance of such findings has been largely underappreciated despite a growing body of work implicating small intestinal homeostatic imbalance in the pathogenesis of DGBIs. MAIN TEXT Small intestinal mechanosensation is a characteristic feature of IBS. Furthermore, altered small intestinal barrier functions have been demonstrated in IBS patients with the diarrhoea-predominant subtype. Small intestinal bacterial overgrowth and increased populations of small intestinal mast cells are frequently associated with IBS, implicating microbial imbalance and low-grade inflammation in the pathogenesis of IBS. Furthermore, reports of localised food hypersensitivity responses in IBS patients implicate the small intestine as the site of immune-microbial-food interactions. CONCLUSIONS Given the association of IBS symptoms with food intake in a large proportion of patients and the emerging evidence of immune activation in these patients, the current literature suggests the pathogenesis of IBS is not limited to the colon but rather may involve dysfunction of the entire intestinal tract. It remains unclear if regional variation in IBS pathology explains the various symptom phenotypes and further work should consider the intestinal tract as a whole to answer this question.
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Affiliation(s)
- Grace L Burns
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia.,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia.,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Nicholas J Talley
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia.,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia.,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Simon Keely
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia. .,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia. .,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
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16
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Chu F, Wan H, Xiao W, Dong H, Lü M. Ca 2+-Permeable Channels/Ca 2+ Signaling in the Regulation of Ileal Na +/Gln Co-Transport in Mice. Front Pharmacol 2022; 13:816133. [PMID: 35281933 PMCID: PMC8905502 DOI: 10.3389/fphar.2022.816133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
Oral glutamine (Gln) has been widely used in gastrointestinal (GI) clinical practice, but it is unclear if Ca2+ regulates intestinal Gln transport, although both of them are essential nutrients for mammals. Chambers were used to determine Gln (25 mM)-induced Isc through Na+/Gln co-transporters in the small intestine in the absence or the presence of selective activators or blockers of ion channels and transporters. Luminal but not serosal application of Gln induced marked intestinal Isc, especially in the distal ileum. Lowering luminal Na+ almost abolished the Gln-induced ileal Isc, in which the calcium-sensitive receptor (CaSR) activation were not involved. Ca2+ removal from both luminal and serosal sides of the ileum significantly reduced Gln- Isc. Blocking either luminal Ca2+ entry via the voltage-gated calcium channels (VGCC) or endoplasmic reticulum (ER) release via inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) attenuated the Gln-induced ileal Isc, Likewise, blocking serosal Ca2+ entry via the store-operated Ca2+ entry (SOCE), TRPV1/2 channels, and Na+/Ca2+ exchangers (NCX) attenuated the Gln-induced ileal Isc. In contrast, activating TRPV1/2 channels enhanced the Gln-induced ileal Isc. We concluded that Ca2+ signaling is critical for intestinal Gln transport, and multiple plasma membrane Ca2+-permeable channels and transporters play roles in this process. The Ca2+ regulation of ileal Na+/Gln transport expands our understanding of intestinal nutrient uptake and may be significant in GI health and disease.
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Affiliation(s)
- Fenglan Chu
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hanxing Wan
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Muhan Lü
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China
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17
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Singh R, Zogg H, Ghoshal UC, Ro S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front Pharmacol 2022; 13:808195. [PMID: 35145413 PMCID: PMC8822166 DOI: 10.3389/fphar.2022.808195] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) have been re-named as disorders of gut-brain interactions. These conditions are not only common in clinical practice, but also in the community. In reference to the Rome IV criteria, the most common FGIDs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific gastrointestinal motility disorders, such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The treatment options currently available include lifestyle modifications, dietary and gut microbiota manipulation interventions including fecal microbiota transplantation, prokinetics, antispasmodics, laxatives, and centrally and peripherally acting neuromodulators. However, treatment that targets the pathophysiological mechanisms underlying the symptoms are scanty. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying pathologies of these disorders might provide the best avenue for future pharmaceutical development. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and FGIDs. Furthermore, the fundamental challenges in treating these disorders should be defined; for instance, 1. Cause and effect cannot be disentangled between symptoms and pathophysiological mechanisms due to current therapies that entail the off-label use of medications to treat symptoms. 2. Despite the knowledge that the microbiota in our gut plays an essential part in maintaining gut health, their exact functions in gut homeostasis are still unclear. What constitutes a healthy microbiome and further, the precise definition of gut microbial dysbiosis is lacking. More comprehensive, large-scale, and longitudinal studies utilizing multi-omics data are needed to dissect the exact contribution of gut microbial alterations in disease pathogenesis. Accordingly, we review the current treatment options, clinical insight on pathophysiology, therapeutic modalities, current challenges, and therapeutic clues for the clinical care and management of functional dyspepsia, gastroparesis, irritable bowel syndrome, functional constipation, and functional diarrhea.
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Affiliation(s)
- Rajan Singh
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
- *Correspondence: Uday C Ghoshal, ; Seungil Ro,
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
- *Correspondence: Uday C Ghoshal, ; Seungil Ro,
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18
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Grover M, Berumen A, Peters S, Wei T, Breen-Lyles M, Harmsen WS, Busciglio I, Burton D, Vazquez Roque M, DeVault KR, Camilleri M, Wallace M, Dasari S, Neumann H, Houghton LA. Editorial: understanding IBS pathophysiology through "converging channels" of research-authors' reply. Aliment Pharmacol Ther 2021; 54:1215-1216. [PMID: 34637534 DOI: 10.1111/apt.16613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Antonio Berumen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Stephanie Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ting Wei
- Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | | | - William S Harmsen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Irene Busciglio
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Duane Burton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Maria Vazquez Roque
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Kenneth R DeVault
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Michael Wallace
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Helmut Neumann
- Department of Medicine I, University Medical Center, Mainz, Germany.,GastroZentrum Lippe, Bad Salzuflen, Germany
| | - Lesley A Houghton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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19
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Elwing JE, Sayuk GS. Editorial: understanding IBS pathophysiology through "converging channels" of research. Aliment Pharmacol Ther 2021; 54:1213-1214. [PMID: 34637533 DOI: 10.1111/apt.16603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Jill E Elwing
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA.,St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
| | - Gregory S Sayuk
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA.,St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA.,Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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