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Nikolla E, Grandberry A, Jamerson D, Flynn CR, Sundaresan S. The Enteric Neuronal Circuitry: A Key Ignored Player in Nutrient Sensing Along the Gut-Brain Axis. FASEB J 2025; 39:e70586. [PMID: 40318068 PMCID: PMC12048873 DOI: 10.1096/fj.202500220rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/06/2025] [Accepted: 04/18/2025] [Indexed: 05/07/2025]
Abstract
The role of the gut-to-brain axis in the regulation of nutrient sensing has been studied extensively for decades. Research has mainly centered on vagal afferent and efferent neurotransmission along the gastrointestinal tract, followed by the integration of luminal information in the nodose ganglia and transmission to vagal integral sites in the brain. The physiological and cellular mechanisms of nutrient sensing by enterocytes and enteroendocrine cells have been well established; however, the roles of the enteric nervous system (ENS) remain elusive. Recent advances in targeting specific neuronal subpopulations and imaging techniques unravel the plausible roles of the ENS in nutrient sensing. In this review, we highlight physiological, cellular, and molecular insights that direct toward direct and indirect roles of the ENS in luminal nutrient sensing and vagal neurotransmission along the gut-brain axis and discuss functional maladaptations observed during metabolic insults, as observed during obesity and associated comorbidities, including type 2 diabetes.
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Affiliation(s)
- Ester Nikolla
- Department of Physiology, College of Graduate StudiesMidwestern UniversityDowners GroveIllinoisUSA
| | - Ava Grandberry
- Department of Biomedical Sciences, College of Graduate StudiesMidwestern UniversityDowners GroveIllinoisUSA
| | - Destiné Jamerson
- Department of Biomedical Sciences, College of Graduate StudiesMidwestern UniversityDowners GroveIllinoisUSA
| | - Charles Robb Flynn
- Department of SurgeryVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Sinju Sundaresan
- Department of Physiology, College of Graduate StudiesMidwestern UniversityDowners GroveIllinoisUSA
- Chicago College of Osteopathic MedicineMidwestern UniversityDowners GroveIllinoisUSA
- Chicago College of OptometryMidwestern UniversityDowners GroveIllinoisUSA
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2
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Tarasiuk-Zawadzka A, Fichna J. Interaction between nutritional factors and the enteric nervous system in inflammatory bowel diseases. J Nutr Biochem 2025:109959. [PMID: 40354831 DOI: 10.1016/j.jnutbio.2025.109959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 01/30/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The enteric nervous system (ENS) is a highly conserved, yet complicated network of neurons and glial cells located throughout the gut wall that controls digestive processes and gastrointestinal (GI) homeostasis. The intestinal epithelium, the immune system, and the gut microbiota are just a few examples of the cellular networks that the ENS interacts with on a variety of levels to maintain GI function. The presence or absence of nutrients in the intestinal lumen may cause short- and/or long-term changes in neurotransmitter expression, excitability, and neuronal survival, which ultimately affect gut motility, secretion, and permeability. Hence, the ENS should be identified as a key factor in initiating coordinated responses to nutrients. In this review we summarize current knowledge on nutrient-dependent ENS activity and how ENS secondary to nutrition may affect likelihood of developing inflammatory bowel disease. Our findings highlight that nutrients interact with enteroendocrine cells in the gut, triggering hormone secretion that plays a crucial role in signaling food-related information to the brain and regulating metabolic processes such as feeding behavior, insulin secretion, and energy balance; however, the complex interactions between nutrients, the ENS, and the immune system require further research to understand their contributions to GI disorders and potential therapeutic applications in treating obesity and metabolic diseases. Lay Summary: The enteric nervous system (ENS) controls digestion and interacts with nutrients in the gut to regulate processes like gut movement and hormone release, affecting metabolism and overall gut health. This review highlights the need for further research on how nutrient-ENS interactions contribute to conditions like inflammatory bowel disease, obesity, and metabolic disorders.
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Affiliation(s)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland
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3
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Bohl B, Lei Y, Bewick GA, Hashemi P. Measurement of Real-Time Serotonin Dynamics from Human-Derived Gut Organoids. Anal Chem 2025; 97:5057-5065. [PMID: 40007472 PMCID: PMC11912129 DOI: 10.1021/acs.analchem.4c06033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/30/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025]
Abstract
The importance of the gut in regulating the brain-body immune axis is becoming increasingly evident. Interestingly, the brain and gut share many common signaling molecules, with serotonin being one of the most notable. In fact, the gut is the primary source of serotonin in the body. However, studying serotonin dynamics in a human-specific context remains a challenge. Human stem cell-derived models provide a promising avenue for studying signal transmission in well-controlled, in vitro environments. In this study, we report the first fast-scan cyclic voltammetry (FSCV) measurements of serotonin signaling in a newly developed enterochromaffin cell (ECC)-enriched gut organoid model. First, we characterize the stem cell-derived gut organoids and confirm they are enriched with ECCs, the key cell type responsible for producing and releasing serotonin in the gut. We then optimize an in vitro buffer that maintains cell viability while supporting FSCV measurements. Using this system, we detect spontaneous release events, which increase in frequency and amplitude following stimulation with forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX). Finally, we confirm the identity of the signal as serotonin using a selective serotonin reuptake inhibitor (SSRI), which significantly delayed the reuptake profile. Our study introduces the first real-time measurement of serotonin signaling in a human-derived gut model. We believe this system will be essential for future research on serotonin's role in the gut and for potential novel drug target identification.
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Affiliation(s)
- Bettina Bohl
- Department
of Bioengineering, Imperial College London, South Kensington, London SW72AZ, United Kingdom
| | - Yuxian Lei
- Diabetes
and Obesity Theme, School of Cardiovascular and Metabolic Medicine
and Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
| | - Gavin A. Bewick
- Diabetes
and Obesity Theme, School of Cardiovascular and Metabolic Medicine
and Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Diabetes
Endocrinology and Obesity Clinical academic Partnership Kings Health
Partners, London SE1 9RT, United Kingdom
| | - Parastoo Hashemi
- Department
of Bioengineering, Imperial College London, South Kensington, London SW72AZ, United Kingdom
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Chao J, Coleman RA, Keating DJ, Martin AM. Gut Microbiome Regulation of Gut Hormone Secretion. Endocrinology 2025; 166:bqaf004. [PMID: 40037297 PMCID: PMC11879239 DOI: 10.1210/endocr/bqaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Indexed: 03/06/2025]
Abstract
The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, is one of the largest microbial ecosystems in the human body and plays a crucial role in various physiological processes. This review explores the interaction between the gut microbiome and enteroendocrine cells (EECs), specialized hormone-secreting cells within the intestinal epithelium. EECs, which constitute less than 1% of intestinal epithelial cells, are key regulators of gut-brain communication, energy metabolism, gut motility, and satiety. Recent evidence shows that gut microbiota directly influence EEC function, maturation, and hormone secretion. For instance, commensal bacteria regulate the production of hormones like glucagon-like peptide 1 and peptide YY by modulating gene expression and vesicle cycling in EE cells. Additionally, metabolites such as short-chain fatty acids, derived from microbial fermentation, play a central role in regulating EEC signaling pathways that affect metabolism, gut motility, and immune responses. Furthermore, the interplay between gut microbiota, EECs, and metabolic diseases, such as obesity and diabetes, is examined, emphasizing the microbiome's dual role in promoting health and contributing to disease states. This intricate relationship between the gut microbiome and EECs offers new insights into potential therapeutic strategies for metabolic and gut disorders.
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Affiliation(s)
- Jessica Chao
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Rosemary A Coleman
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Damien J Keating
- Gut Sensory Systems Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Alyce M Martin
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
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5
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Spencer NJ, Keating DJ. Role of 5-HT in the enteric nervous system and enteroendocrine cells. Br J Pharmacol 2025; 182:471-483. [PMID: 35861711 DOI: 10.1111/bph.15930] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/29/2022] Open
Abstract
Since the 1950s, considerable circumstantial evidence had been presented that endogenous 5-HT (serotonin) synthesized from within the wall of the gastrointestinal (GI) tract played an important role in GI motility and transit. However, identifying the precise functional role of gut-derived 5-HT has been difficult to ascertain, for a number of reasons. Over the past decade, as recording techniques have advanced significantly and access to new genetically modified animals improved, there have been major new insights and major changes in our understanding of the functional role of endogenous 5-HT in the GI tract. Data from many different laboratories have shown that major patterns of GI motility and transit still occur with minor or no, change when all endogenous 5-HT is pharmacologically or genetically ablated from the gut. Furthermore, antagonists of 5-HT3 receptors are equally, or more potent at inhibiting GI motility in segments of intestine that are completely depleted of endogenous 5-HT. Here, the most recent findings are discussed with regard to the functional role of endogenous 5-HT in enterochromaffin cells and enteric neurons in gut motility and more broadly in some major homeostatic pathways.
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Affiliation(s)
- Nick J Spencer
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia
| | - Damien J Keating
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia
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Winzenried ET, Neyens DM, Calkins R, Appleyard SM. CCK-expressing neurons in the NTS are directly activated by CCK-sensitive C-type vagal afferents. Am J Physiol Regul Integr Comp Physiol 2025; 328:R121-R132. [PMID: 39509587 DOI: 10.1152/ajpregu.00280.2023] [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: 12/12/2023] [Revised: 08/27/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024]
Abstract
Vagal sensory afferents carrying information from the gastrointestinal tract (GI) terminate in the nucleus of the solitary tract (NTS). Different subpopulations of NTS neurons then relay this information throughout the brain. Cholecystokinin (CCK) is a satiety peptide that activates vagal afferents in the GI. However, CCK is also expressed by neurons in the NTS, and activation of these neurons decreases food intake. What is less clear is how these NTS CCK neurons are activated by vagal afferents and what type of information they integrate about meal size and content. To address this, we identified NTS-CCK neurons by crossing CCK-IRES-Cre mice with floxed-Rosa-tdtomato mice and made a horizontal brain slice containing vagal afferents in the solitary tract (ST). Voltage clamp recordings of NTS-CCK neurons show that activation of the ST evokes excitatory postsynaptic currents (EPSCs) mediated by both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Analysis of these EPSCs revealed that 80% of NTS-CCK neurons receive direct, monosynaptic inputs, with many also receiving indirect, or polysynaptic, inputs. NTS-CCK neurons are sensitive to the transient receptor potential vanilloid type 1 agonist capsaicin, suggesting that they are downstream of C-fibers. In addition, both CCK and a 5 hydroxytryptamine 3 receptor (5-HT3R) agonist increased spontaneous EPSC (sEPSC) frequency in NTS-CCK neurons, with 69% of NTS-CCK neurons sensitive to CCK and 42% to the 5-HT3 receptor agonist, as well as 45% sensitive to both and 10% to neither. Taken together with previous studies, this suggests that NTS-CCK neurons are driven primarily by vagal afferents that are sensitive to CCK and are only weakly driven by those sensitive to serotonin.NEW & NOTEWORTHY Nucleus of the solitary tract (NTS) cholecystokinin (CCK) expressing neurons are directly activated by glutamate released from vagal afferents. They are downstream of primarily C-type CCK-sensitive afferents, with a small proportion also downstream of serotonin-sensitive afferents. These findings suggest that NTS-CCK neurons integrate signals from the gut about ingestion of fats and proteins as well as stretch of the stomach, which they then relay to other brain regions important for the control of food intake.
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Affiliation(s)
- Eric T Winzenried
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Drew M Neyens
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Rowan Calkins
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Suzanne M Appleyard
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
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7
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Alcaino C, Reimann F, Gribble FM. Incretin hormones and obesity. J Physiol 2024:10.1113/JP286293. [PMID: 39576749 PMCID: PMC7617301 DOI: 10.1113/jp286293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 10/31/2024] [Indexed: 11/24/2024] Open
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in co-ordinating postprandial metabolism, including modulation of insulin secretion and food intake. They are secreted from enteroendocrine cells in the intestinal epithelium following food ingestion, and act at multiple target sites including pancreatic islets and the brain. With the recent development of agonists targeting GLP-1 and GIP receptors for the treatment of type 2 diabetes and obesity, and the ongoing development of new incretin-based drugs with improved efficacy, there is great interest in understanding the physiology and pharmacology of these hormones.
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Affiliation(s)
- Constanza Alcaino
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
| | - Frank Reimann
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
| | - Fiona M Gribble
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
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8
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Sejbuk M, Siebieszuk A, Witkowska AM. The Role of Gut Microbiome in Sleep Quality and Health: Dietary Strategies for Microbiota Support. Nutrients 2024; 16:2259. [PMID: 39064702 PMCID: PMC11279861 DOI: 10.3390/nu16142259] [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: 06/03/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Dietary components, including dietary fiber, unsaturated fatty acids, and polyphenols, along with meal timing and spacing, significantly affect the microbiota's capacity to produce various metabolites essential for quality sleep and overall health. This review explores the role of gut microbiota in regulating sleep through various metabolites such as short-chain fatty acids, tryptophan, serotonin, melatonin, and gamma-aminobutyric acid. A balanced diet rich in plant-based foods enhances the production of these sleep-regulating metabolites, potentially benefiting overall health. This review aims to investigate how dietary habits affect gut microbiota composition, the metabolites it produces, and the subsequent impact on sleep quality and related health conditions.
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Affiliation(s)
- Monika Sejbuk
- Department of Food Biotechnology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland;
| | - Adam Siebieszuk
- Department of Physiology, Faculty of Medicine, Medical University of Bialystok, Mickiewicza 2C, 15-222 Białystok, Poland;
| | - Anna Maria Witkowska
- Department of Food Biotechnology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland;
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Jiang L, Han D, Hao Y, Song Z, Sun Z, Dai Z. Linking serotonin homeostasis to gut function: Nutrition, gut microbiota and beyond. Crit Rev Food Sci Nutr 2024; 64:7291-7310. [PMID: 36861222 DOI: 10.1080/10408398.2023.2183935] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
Abstract
Serotonin (5-HT) produced by enterochromaffin (EC) cells in the digestive tract is crucial for maintaining gut function and homeostasis. Nutritional and non-nutritional stimuli in the gut lumen can modulate the ability of EC cells to produce 5-HT in a temporal- and spatial-specific manner that toning gut physiology and immune response. Of particular interest, the interactions between dietary factors and the gut microbiota exert distinct impacts on gut 5-HT homeostasis and signaling in metabolism and the gut immune response. However, the underlying mechanisms need to be unraveled. This review aims to summarize and discuss the importance of gut 5-HT homeostasis and its regulation in maintaining gut metabolism and immune function in health and disease with special emphasis on different types of nutrients, dietary supplements, processing, and gut microbiota. Cutting-edge discoveries in this area will provide the basis for the development of new nutritional and pharmaceutical strategies for the prevention and treatment of serotonin homeostasis-related gut and systematic disorders and diseases.
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Affiliation(s)
- Lili Jiang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
| | - Dandan Han
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
| | - Youling Hao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
| | - Zhuan Song
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
| | - Zhiyuan Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P. R. China
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10
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Tian Y, Zi J, Hu Y, Zeng Y, Li H, Luo H, Xiong J. Shared and Unique Genetic Links between Neuroticism and Gastrointestinal Tract Diseases. Depress Anxiety 2024; 2024:5515448. [PMID: 40226707 PMCID: PMC11919111 DOI: 10.1155/2024/5515448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/02/2024] [Accepted: 06/10/2024] [Indexed: 04/15/2025] Open
Abstract
Objective Association between neuroticism and gastrointestinal tract (GIT) diseases may not be attributable to the genetic overlaps between neuroticism and psychiatric disorders. We aim to explore the genetic links and mechanisms of neuroticism and GIT diseases. Materials and Methods We obtained European genome-wide association data of neuroticism (n = 390,278) or subclusters (depressed, n = 357,957; worry, n = 348,219) and six GIT diseases: gastroesophageal reflux disease (GERD, n = 456,327), inflammatory bowel disease (IBD, n = 456,327), peptic ulcer disease (PUD, n = 456,327), irritable bowel syndrome (IBS, n = 486,601), Crohn's disease (CD, n = 20,883), and ulcerative colitis (UC, n = 21,895). We performed genetic correlation analysis (high-definition likelihood method and cross-trait linkage disequilibrium score regression), pairwise pleiotropic analysis, single nucleic acid polymorphism annotation, Bayesian colocalization, gene-level analysis, transcriptome-wide association analysis, and gene set enrichment analysis. Results Neuroticism and its subclusters are associated with most GIT diseases (15 of 18 trait-pairs). GERD and PUD were highly correlated with depressed affect. We identified pleiotropic loci 11q23.2 (mapped gene: NCAM1/DRD2) and 18q12.2 (mapped gene: CELF4) in neuroticism and IBS/GERD, supporting the genetic overlap between neuroticism and depression. We found that 16q12.1 (mapped gene: NKD1/ZNF423/NOD2) and 2q37.1 (mapped gene: ATG16L1/SP140) are only highlighted in depressed/neuroticism CD, revealing pleiotropic loci with dissimilarities between neuroticism and different GIT diseases. MR analysis suggested that genetic liability to neuroticism is associated with increased risks of IBS, PUD, and GERD. Conclusion Our findings document the genetic links between neuroticism and six GIT diseases, highlighting the genetic overlaps and heterogeneity between neuroticism and psychiatric disorders in the context of gastrointestinal disorders. Both the shared and unique pleiotropic loci identified between neuroticism and different GIT diseases could facilitate mechanistic understandings and may stimulate further translational implications.
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Affiliation(s)
- Ye Tian
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jing Zi
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yifan Hu
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yaxian Zeng
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Haoqi Li
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Hang Luo
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jingyuan Xiong
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu 610041, China
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Cai J, Cheung J, Cheung SWM, Chin KTC, Leung RWK, Lam RST, Sharma R, Yiu JHC, Woo CW. Butyrate acts as a positive allosteric modulator of the 5-HT transporter to decrease availability of 5-HT in the ileum. Br J Pharmacol 2024; 181:1654-1670. [PMID: 38129963 DOI: 10.1111/bph.16305] [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: 04/28/2023] [Revised: 10/23/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND AND PURPOSE Radiation therapy-induced gastrointestinal distress is partly associated with the elimination of gut microbiota. The effectiveness of 5-HT receptor antagonists to treat radiation therapy-induced emesis implies a pathophysiological role of 5-HT. Peripheral 5-HT is derived from intestinal epithelium. We have investigated the role of gut microbiota in regulating intestinal 5-HT availability. EXPERIMENTAL APPROACH A radiation therapy murine model accompanied by faecal microbiota transplantation from donors fed different diets was investigated, and mouse ileal organoids were used for mechanistic studies. The clinical relevance was validated by a small-scale human study. KEY RESULTS Short-term high-fat diet (HFD) induced gut bacteria to produce butyrate. Irradiated mice receiving HFD-induced microbiome had the lowest ileal levels of 5-HT, compared with other recipients. Treatment with butyrate increased 5-HT uptake in mouse ileal organoids, assayed by the real-time tracking of a fluorescent substrate for monoamine transporters. Silencing the 5-HT transporter (SERT) in the organoids abolished butyrate-stimulated 5-HT uptake. The competitive tests using different types of selective 5-HT reuptake inhibitors suggested that butyrate acted as a positive allosteric modulator of SERT. In human gut microbiota, butyrate production was associated with the interconversion between acetate and butyrate. Faecal contents of both acetate and butyrate were negatively associated with serum 5-HT, but only butyrate was positively correlated with body mass index in humans. CONCLUSION AND IMPLICATIONS Short-term HFD may be beneficial for alleviating gastrointestinal reactions by increasing butyrate to suppress local 5-HT levels and providing energy to cancer patients given radiation therapy.
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Affiliation(s)
- Jieling Cai
- State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jamie Cheung
- State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Samson W M Cheung
- State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Karie T C Chin
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ricky W K Leung
- Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ronald S T Lam
- Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Rakesh Sharma
- Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jensen H C Yiu
- State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Connie W Woo
- State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Micon Analytics, Toronto, Canada
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12
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Liikonen V, Gomez-Gallego C, Kolehmainen M. The effects of whole grain cereals on tryptophan metabolism and intestinal barrier function: underlying factors of health impact. Proc Nutr Soc 2024; 83:42-54. [PMID: 37843435 DOI: 10.1017/s0029665123003671] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
This review aims to investigate the relationship between the health impact of whole grains mediated via the interaction with intestinal microbiota and intestinal barrier function with special interest on tryptophan metabolism, focusing on the role of the intestinal microbiota and their impact on barrier function. Consuming various types of whole grains can lead to the growth of different microbiota species, which in turn leads to the production of diverse metabolites, including those derived from tryptophan metabolism, although the impact of whole grains on intestinal microbiota composition results remains inconclusive and vary among different studies. Whole grains can exert an influence on tryptophan metabolism through interactions with the intestinal microbiota, and the presence of fibre in whole grains plays a notable role in establishing this connection. The impact of whole grains on intestinal barrier function is closely related to their effects on the composition and activity of intestinal microbiota, and SCFA and tryptophan metabolites serve as potential links connecting whole grains, intestinal microbiota and the intestinal barrier function. Tryptophan metabolites affect various aspects of the intestinal barrier, such as immune balance, mucus and microbial barrier, tight junction complexes and the differentiation and proliferation of epithelial cells. Despite the encouraging discoveries in this area of research, the evidence regarding the effects of whole grain consumption on intestine-related activity remains limited. Hence, we can conclude that we are just starting to understand the actual complexity of the intestinal factors mediating in part the health impacts of whole grain cereals.
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Affiliation(s)
- Vilma Liikonen
- Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O.Box 1627, 70211 Kuopio, Finland
| | - Carlos Gomez-Gallego
- Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O.Box 1627, 70211 Kuopio, Finland
| | - Marjukka Kolehmainen
- Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O.Box 1627, 70211 Kuopio, Finland
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13
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Salazar V, Bolaños P, del Castillo JR. Enteric Nervous System: Identification of a Novel Neuronal Sensory Network in the Duodenal Epithelium. J Histochem Cytochem 2023; 71:601-630. [PMID: 37791513 PMCID: PMC10617440 DOI: 10.1369/00221554231203038] [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: 07/29/2023] [Accepted: 08/30/2023] [Indexed: 10/05/2023] Open
Abstract
The communication between the intestinal epithelium and the enteric nervous system has been considered indirect. Mechanical or chemical stimuli activate enteroendocrine cells inducing hormone secretion, which act on sub-epithelial nerve ends, activating the enteric nervous system. However, we identified an epithelial cell that expresses NKAIN4, a neuronal protein associated with the β-subunit of Na+/K+-ATPase. This cell overexpresses Na+/K+-ATPase and ouabain-insensitive Na+-ATPase, enzymes involved in active sodium transport. NKAIN4-positive cells also express neuronal markers as NeuN, acetylcholine-esterase, acetylcholine-transferase, α3- and α7-subunits of ACh receptors, glutamic-decarboxylase, and serotonin-receptor-7, suggesting they are neurons. NKAIN4-positive cells show a polarized shape with an oval body, an apical process finished in a knob-like terminal in contact with the lumen, a basal cilia body at the base of the apical extension, and basal axon-like soma projections connecting sub-epithelial nerve terminals, lymphoid nodules, glial cells, and enterochromaffin cells, forming a network that reaches the epithelial surface. We also showed, using retrograde labeling and immunofluorescence, that these cells receive afferent signals from the enteric nervous system. Finally, we demonstrated that acetylcholine activates NKAIN4-positive cells inducing Ca2+ mobilization and probably serotonin secretion in enterochromaffin cells. NKAIN4-positive cells are neurons that would form a part of a duodenal sensory network for physiological or noxious luminal stimuli.
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Affiliation(s)
- Víctor Salazar
- Light Microscopy Service, Biophysics and Biochemistry Center, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela
| | - Pura Bolaños
- Laboratory of Cell Physiology, Biophysics and Biochemistry Center, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela
| | - Jesús R. del Castillo
- Laboratory of Molecular Physiology, Biophysics and Biochemistry Center, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela
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14
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Tough IR, Lund ML, Patel BA, Schwartz TW, Cox HM. Paracrine relationship between incretin hormones and endogenous 5-hydroxytryptamine in the small and large intestine. Neurogastroenterol Motil 2023; 35:e14589. [PMID: 37010838 PMCID: PMC10909488 DOI: 10.1111/nmo.14589] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 02/13/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT3 receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5-HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5-HT signaling, local 5-HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter-relationships between incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) and endogenous 5-HT in mucosal and motility assays. METHODS Adult mouse GI mucosae were mounted in Ussing chambers and area-specific studies were performed to establish the 5-HT3 and 5-HT4 pharmacology, the sidedness of responses, and the inter-relationships between incretins and endogenous 5-HT. Natural fecal pellet transit in vitro and full-length GI transit in vivo were also measured. KEY RESULTS We observed the greatest level of tonic and exogenous 5-HT-induced ion transport and highest levels of 5-HT in ascending colon mucosa. Here both 5-HT3 and 5-HT4 receptors were involved but elsewhere in the GI tract epithelial basolateral 5-HT4 receptors mediate 5-HT's prosecretory effect. Exendin-4 and GIP induced 5-HT release in the ascending colon, while L cell-derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit. CONCLUSIONS & INFERENCES We provide functional evidence for paracrine interplay between 5-HT, GLP-1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5-HT4 receptors mediated both 5-HT and incretin mucosal responses in healthy colon.
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Affiliation(s)
- Iain R. Tough
- Wolfson Centre for Age‐Related Diseases, Institute of Psychology, Psychiatry and NeuroscienceKing's College LondonHodgkin Building, Guy's CampusLondonSE1 1ULUK
| | - Mari L. Lund
- The Novo Nordisk Foundation Centre for Basic Metabolic Research, Section for Metabolic Receptology and EnteroendocrinologyUniversity of CopenhagenCopenhagenDK‐2200Denmark
- Present address:
Chr. Hansen A/S, Human Health ResearchHoersholmDK‐2970Denmark
| | - Bhavik A. Patel
- Centre for Stress and Age‐Related Diseases, School of Applied SciencesUniversity of BrightonBrightonUK
| | - Thue W. Schwartz
- The Novo Nordisk Foundation Centre for Basic Metabolic Research, Section for Metabolic Receptology and EnteroendocrinologyUniversity of CopenhagenCopenhagenDK‐2200Denmark
| | - Helen M. Cox
- Wolfson Centre for Age‐Related Diseases, Institute of Psychology, Psychiatry and NeuroscienceKing's College LondonHodgkin Building, Guy's CampusLondonSE1 1ULUK
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15
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Bagyánszki M, Bódi N. Key elements determining the intestinal region-specific environment of enteric neurons in type 1 diabetes. World J Gastroenterol 2023; 29:2704-2716. [PMID: 37274063 PMCID: PMC10237112 DOI: 10.3748/wjg.v29.i18.2704] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/28/2023] [Accepted: 04/17/2023] [Indexed: 05/11/2023] Open
Abstract
Diabetes, as a metabolic disorder, is accompanied with several gastrointestinal (GI) symptoms, like abdominal pain, gastroparesis, diarrhoea or constipation. Serious and complex enteric nervous system damage is confirmed in the background of these diabetic motility complaints. The anatomical length of the GI tract, as well as genetic, developmental, structural and functional differences between its segments contribute to the distinct, intestinal region-specific effects of hyperglycemia. These observations support and highlight the importance of a regional approach in diabetes-related enteric neuropathy. Intestinal large and microvessels are essential for the blood supply of enteric ganglia. Bidirectional morpho-functional linkage exists between enteric neurons and enteroglia, however, there is also a reciprocal communication between enteric neurons and immune cells on which intestinal microbial composition has crucial influence. From this point of view, it is more appropriate to say that enteric neurons partake in multidirectional communication and interact with these key players of the intestinal wall. These interplays may differ from segment to segment, thus, the microenvironment of enteric neurons could be considered strictly regional. The goal of this review is to summarize the main tissue components and molecular factors, such as enteric glia cells, interstitial cells of Cajal, gut vasculature, intestinal epithelium, gut microbiota, immune cells, enteroendocrine cells, pro-oxidants, antioxidant molecules and extracellular matrix, which create and determine a gut region-dependent neuronal environment in diabetes.
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Affiliation(s)
- Mária Bagyánszki
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged H-6726, Hungary
| | - Nikolett Bódi
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged H-6726, Hungary
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16
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Wang Y, Geng R, Zhao Y, Fang J, Li M, Kang SG, Huang K, Tong T. The gut odorant receptor and taste receptor make sense of dietary components: A focus on gut hormone secretion. Crit Rev Food Sci Nutr 2023; 64:6975-6989. [PMID: 36785901 DOI: 10.1080/10408398.2023.2177610] [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] [Indexed: 02/15/2023]
Abstract
Odorant receptors (ORs) and taste receptors (TRs) are expressed primarily in the nose and tongue in which they transduce electrical signals to the brain. Advances in deciphering the dietary component-sensing mechanisms in the nose and tongue prompted research on the role of gut chemosensory cells. Acting as the pivotal interface between the body and dietary cues, gut cells "smell" and "taste" dietary components and metabolites by taking advantage of chemoreceptors-ORs and TRs, to maintain physiological homeostasis. Here, we reviewed this novel field, highlighting the latest discoveries pertinent to gut ORs and TRs responding to dietary components, their impacts on gut hormone secretion, and the mechanisms involved. Recent studies indicate that gut cells sense dietary components including fatty acid, carbohydrate, and phytochemical by activating relevant ORs, thereby modulating GLP-1, PYY, CCK, and 5-HT secretion. Similarly, gut sweet, umami, and bitter receptors can regulate the gut hormone secretion and maintain homeostasis in response to dietary components. A deeper understanding of the favorable influence of dietary components on gut hormone secretion via gut ORs and TRs, coupled with the facts that gut hormones are involved in diverse physiological or pathophysiological phenomena, may ultimately lead to a promising treatment for various human diseases.
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Affiliation(s)
- Yanan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Ruixuan Geng
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yuhan Zhao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Jingjing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Mengjie Li
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Seong-Gook Kang
- Department of Food Engineering, Mokpo National University, Muangun, Korea
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
| | - Tao Tong
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
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17
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Tavares G, Rosendo-Silva D, Simões F, Eickhoff H, Marques D, Sacramento JF, Capucho AM, Seiça R, Conde SV, Matafome P. Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue. Int J Mol Sci 2023; 24:ijms24032464. [PMID: 36768789 PMCID: PMC9916853 DOI: 10.3390/ijms24032464] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.
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Affiliation(s)
- Gabriela Tavares
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical-Academic Center of Coimbra, 3004-531 Coimbra, Portugal
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Daniela Rosendo-Silva
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical-Academic Center of Coimbra, 3004-531 Coimbra, Portugal
| | - Flávia Simões
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Hans Eickhoff
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Daniela Marques
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Joana F. Sacramento
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Adriana M. Capucho
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Raquel Seiça
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical-Academic Center of Coimbra, 3004-531 Coimbra, Portugal
| | - Sílvia V. Conde
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
| | - Paulo Matafome
- Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical-Academic Center of Coimbra, 3004-531 Coimbra, Portugal
- Instituto Politécnico de Coimbra, Coimbra Health School, 3046-854 Coimbra, Portugal
- Correspondence:
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18
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Knutson KR, Whiteman ST, Alcaino C, Mercado-Perez A, Finholm I, Serlin HK, Bellampalli SS, Linden DR, Farrugia G, Beyder A. Intestinal enteroendocrine cells rely on ryanodine and IP 3 calcium store receptors for mechanotransduction. J Physiol 2023; 601:287-305. [PMID: 36428286 PMCID: PMC9840706 DOI: 10.1113/jp283383] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/24/2022] [Indexed: 11/27/2022] Open
Abstract
Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release of signalling molecules such as serotonin (5-HT). For mechanosensitive EECs, force activates Piezo2 channels, which generate a very rapidly activating and inactivating (∼10 ms) cationic (Na+ , K+ , Ca2+ ) receptor current. Piezo2 receptor currents lead to a large and persistent increase in intracellular calcium (Ca2+ ) that lasts many seconds to sometimes minutes, suggesting signal amplification. However, intracellular calcium dynamics in EEC mechanotransduction remain poorly understood. The aim of this study was to determine the role of Ca2+ stores in EEC mechanotransduction. Mechanical stimulation of a human EEC cell model (QGP-1) resulted in a rapid increase in cytoplasmic Ca2+ and a slower decrease in ER stores Ca2+ , suggesting the involvement of intracellular Ca2+ stores. Comparing murine primary colonic EECs with colonocytes showed expression of intercellular Ca2+ store receptors, a similar expression of IP3 receptors, but a >30-fold enriched expression of Ryr3 in EECs. In mechanically stimulated primary EECs, Ca2+ responses decreased dramatically by emptying stores and pharmacologically blocking IP3 and RyR1/3 receptors. RyR3 genetic knockdown by siRNA led to a significant decrease in mechanosensitive Ca2+ responses and 5-HT release. In tissue, pressure-induced increase in the Ussing short circuit current was significantly decreased by ryanodine receptor blockade. Our data show that mechanosensitive EECs use intracellular Ca2+ stores to amplify mechanically induced Ca2+ entry, with RyR3 receptors selectively expressed in EECs and involved in Ca2+ signalling, 5-HT release and epithelial secretion. KEY POINTS: A population of enteroendocrine cells (EECs) are specialized mechanosensors of the gastrointestinal (GI) epithelium that respond to mechanical stimulation with the release of important signalling molecules such as serotonin. Mechanical activation of these EECs leads to an increase in intracellular calcium (Ca2+ ) with a longer duration than the stimulus, suggesting intracellular Ca2+ signal amplification. In this study, we profiled the expression of intracellular Ca2+ store receptors and found an enriched expression of the intracellular Ca2+ receptor Ryr3, which contributed to the mechanically evoked increases in intracellular calcium, 5-HT release and epithelial secretion. Our data suggest that mechanosensitive EECs rely on intracellular Ca2+ stores and are selective in their use of Ryr3 for amplification of intracellular Ca2+ . This work advances our understanding of EEC mechanotransduction and may provide novel diagnostic and therapeutic targets for GI motility disorders.
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Affiliation(s)
- Kaitlyn R. Knutson
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Sara T. Whiteman
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Constanza Alcaino
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Arnaldo Mercado-Perez
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
- Medical Scientist Training Program (MSTP), Mayo Clinic, Rochester, Minnesota
| | - Isabelle Finholm
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Hannah K. Serlin
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Shreya S. Bellampalli
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
- Medical Scientist Training Program (MSTP), Mayo Clinic, Rochester, Minnesota
| | - David R. Linden
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Gianrico Farrugia
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Division of Gastroenterology &Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Arthur Beyder
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, Minnesota
- Division of Gastroenterology &Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
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19
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O'Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, Morley SJ, Clarke G, Schellekens H, Cryan JF. Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol Cell Endocrinol 2022; 546:111572. [PMID: 35066114 DOI: 10.1016/j.mce.2022.111572] [Citation(s) in RCA: 216] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 02/08/2023]
Abstract
The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate. Ongoing research is focused on the entry of SCFAs into systemic circulation from the gut lumen, their migration to cerebral circulation and across the blood brain barrier, and their potential to exert acute and chronic effects on brain structure and function. This review aims to discuss our current mechanistic understanding of the direct and indirect influence that SCFAs have on brain function, behaviour and physiology, which will inform future microbiota-targeted interventions for brain disorders.
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Affiliation(s)
| | - Michael K Collins
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - Gerard M Moloney
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - Emily G Knox
- APC Microbiome Ireland, University College Cork, Ireland; School of Pharmacy, University College Cork, Ireland
| | - María R Aburto
- APC Microbiome Ireland, University College Cork, Ireland
| | | | - Shane J Morley
- APC Microbiome Ireland, University College Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Harriët Schellekens
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland.
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20
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Stucky C, Johnson MA. Improved Serotonin Measurement with Fast-Scan Cyclic Voltammetry: Mitigating Fouling by SSRIs. JOURNAL OF THE ELECTROCHEMICAL SOCIETY 2022; 169:045501. [PMID: 36157165 PMCID: PMC9491377 DOI: 10.1149/1945-7111/ac5ec3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Selective serotonin reuptake inhibitors (SSRIs) have been used for decades to treat disorders linked to serotonin dysregulation in the brain. Moreover, SSRIs are often used in studies aimed at measuring serotonin with fast-scan cyclic voltammetry (FSCV) in living tissues. Here, we show that three different SSRIs - fluoxetine, escitalopram, and sertraline - significantly diminish the faradaic oxidation current of serotonin when employing the commonly used Jackson waveform. Coating carbon-fiber microelectrodes (CFMs) with Nafion resulted in further degradation of peak current, increased response times, and decreased background charging currents compared to bare CFMs. To decrease fouling, we employed a recently published extended serotonin waveform, which scans to a maximum positive potential of +1.3 V, rather than +1.0 V used in the Jackson waveform. Use of this waveform with bare CFMs alleviated the decrease in faradaic current, indicating decreased electrode fouling. Collectively, our results suggest that fouling considerations are important when designing FSCV experiments that employ SSRIs and that they can be overcome by using the appropriate waveform.
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Affiliation(s)
| | - Michael A. Johnson
- Corresponding author: Michael A. Johnson, 2030 Becker Drive, Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047 USA,
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21
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The Role of Serotonin Neurotransmission in Gastrointestinal Tract and Pharmacotherapy. Molecules 2022; 27:molecules27051680. [PMID: 35268781 PMCID: PMC8911970 DOI: 10.3390/molecules27051680] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/01/2022] [Indexed: 02/06/2023] Open
Abstract
5-Hydroxytryptamine (5-HT, serotonin) is a neurotransmitter in both the central nervous system and peripheral structures, acting also as a hormone in platelets. Although its concentration in the gut covers >90% of all organism resources, serotonin is mainly known as a neurotransmitter that takes part in the pathology of mental diseases. Serotonin modulates not only CNS neurons, but also pain transmission and platelet aggregation. In the periphery, 5-HT influences muscle motility in the gut, bronchi, uterus, and vessels directly and through neurons. Serotonin synthesis starts from hydroxylation of orally delivered tryptophan, followed by decarboxylation. Serotonin acts via numerous types of receptors and clinically plays a role in several neural, mental, and other chronic disorders, such as migraine, carcinoid syndrome, and some dysfunctions of the alimentary system. 5-HT acts as a paracrine hormone and growth factor. 5-HT receptors in both the brain and gut are targets for drugs modifying serotonin neurotransmission. The aim of the present article is to review the 5-HT receptors in the gastrointestinal (GI) tract to determine the role of serotonin in GI physiology and pathology, including known GI diseases and the role of serotonin in GI pharmacotherapy.
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22
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Fung C, Cools B, Malagola S, Martens T, Tack J, Kazwiny Y, Vanden Berghe P. Luminal short-chain fatty acids and 5-HT acutely activate myenteric neurons in the mouse proximal colon. Neurogastroenterol Motil 2021; 33:e14186. [PMID: 34121274 DOI: 10.1111/nmo.14186] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 04/03/2021] [Accepted: 05/04/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Gastrointestinal (GI) function is critically dependent on the control of the enteric nervous system (ENS), which is situated within the gut wall and organized into two ganglionated nerve plexuses: the submucosal and myenteric plexus. The ENS is optimally positioned and together with the intestinal epithelium, is well-equipped to monitor the luminal contents such as microbial metabolites and to coordinate appropriate responses accordingly. Despite the heightened interest in the gut microbiota and its influence on intestinal physiology and pathophysiology, how they interact with the host ENS remains unclear. METHODS Using full-thickness proximal colon preparations from transgenic Villin-CreERT2;R26R-GCaMP3 and Wnt1-Cre;R26R-GCaMP3 mice, which express a fluorescent Ca2+ indicator in their intestinal epithelium or in their ENS, respectively, we examined the effects of key luminal microbial metabolites (SCFAs and 5-HT) on the mucosa and underlying enteric neurons. KEY RESULTS We show that the SCFAs acetate, propionate, and butyrate, as well as 5-HT can, to varying extents, acutely elicit epithelial and neuronal Ca2+ responses. Furthermore, SCFAs exert differential effects on submucosal and myenteric neurons. Additionally, we found that submucosal ganglia are predominantly aligned along the striations of the transverse mucosal folds in the proximal colon. CONCLUSIONS & INFERENCES Taken together, our study demonstrates that different microbial metabolites, including SCFAs and 5-HT, can acutely stimulate Ca2+ signaling in the mucosal epithelium and in enteric neurons.
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Affiliation(s)
- Candice Fung
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Bert Cools
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Sergio Malagola
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Tobias Martens
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Youcef Kazwiny
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Pieter Vanden Berghe
- Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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Nunez-Salces M, Li H, Young RL, Page AJ. The secretion of total and acyl ghrelin from the mouse gastric mucosa: Role of nutrients and the lipid chemosensors FFAR4 and CD36. Peptides 2021; 146:170673. [PMID: 34627956 DOI: 10.1016/j.peptides.2021.170673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 10/20/2022]
Abstract
AIMS This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. METHODS Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. RESULTS TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. CONCLUSION Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.
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Affiliation(s)
- Maria Nunez-Salces
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Hui Li
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Richard L Young
- Intestinal Nutrient Sensing Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
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24
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Cookson TA. Bacterial-Induced Blood Pressure Reduction: Mechanisms for the Treatment of Hypertension via the Gut. Front Cardiovasc Med 2021; 8:721393. [PMID: 34485420 PMCID: PMC8414577 DOI: 10.3389/fcvm.2021.721393] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/16/2021] [Indexed: 01/08/2023] Open
Abstract
Hypertension is a major risk factor for the development of cardiovascular disease. As more research into the gut microbiome emerges, we are finding increasing evidence to support that these microbes may have significant positive and negative effects on blood pressure and associated disorders. The bacterial-derived metabolites that are produced in the gut are capable of widespread effects to several tissue types and organs in the body. It is clear that the extensive metabolic function that is lost with gut dysbiosis is unlikely to be replenished with a single metabolite or bacterial strain. Instead, combinations of bacteria and concomitant therapies will provide a more well-rounded solution to manage hypertension. The bioactive molecules that are recognized in this review will inform on ideal characteristics of candidate bacteria and provide direction for future research on the gut microbiome in hypertension.
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25
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Liu N, Sun S, Wang P, Sun Y, Hu Q, Wang X. The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine. Int J Mol Sci 2021; 22:ijms22157931. [PMID: 34360695 PMCID: PMC8347425 DOI: 10.3390/ijms22157931] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/16/2021] [Accepted: 06/19/2021] [Indexed: 12/17/2022] Open
Abstract
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.
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Affiliation(s)
- Ning Liu
- Key Laboratory of Precision Nutrition and Food Quality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (P.W.); (Y.S.); (Q.H.)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China
| | - Shiqiang Sun
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713ZG Groningen, The Netherlands;
- Department of Genetics, University Medical Center Groningen, University of Groningen, 9713ZG Groningen, The Netherlands
| | - Pengjie Wang
- Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (P.W.); (Y.S.); (Q.H.)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China
| | - Yanan Sun
- Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (P.W.); (Y.S.); (Q.H.)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China
| | - Qingjuan Hu
- Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (P.W.); (Y.S.); (Q.H.)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China
| | - Xiaoyu Wang
- Key Laboratory of Precision Nutrition and Food Quality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Correspondence: ; Tel.: +86-10-6273-8589
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26
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Han H, Yi B, Zhong R, Wang M, Zhang S, Ma J, Yin Y, Yin J, Chen L, Zhang H. From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators. MICROBIOME 2021; 9:162. [PMID: 34284827 PMCID: PMC8293578 DOI: 10.1186/s40168-021-01093-y] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/11/2021] [Indexed: 05/25/2023]
Abstract
Feelings of hunger and satiety are the key determinants for maintaining the life of humans and animals. Disturbed appetite control may disrupt the metabolic health of the host and cause various metabolic disorders. A variety of factors have been implicated in appetite control, including gut microbiota, which develop the intricate interactions to manipulate the metabolic requirements and hedonic feelings. Gut microbial metabolites and components act as appetite-related signaling molecules to regulate appetite-related hormone secretion and the immune system, or act directly on hypothalamic neurons. Herein, we summarize the effects of gut microbiota on host appetite and consider the potential molecular mechanisms. Furthermore, we propose that the manipulation of gut microbiota represents a clinical therapeutic potential for lessening the development and consequence of appetite-related disorders. Video abstract.
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Affiliation(s)
- Hui Han
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
- Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Passage de Déportés 2, 5030, Gembloux, Belgium
| | - Bao Yi
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Mengyu Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Shunfen Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Jie Ma
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China
| | - Yulong Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, 410125, China
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China.
| | - Liang Chen
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China.
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Rosendo-Silva D, Matafome P. Gut-adipose tissue crosstalk: A bridge to novel therapeutic targets in metabolic syndrome? Obes Rev 2021; 22:e13130. [PMID: 32815267 DOI: 10.1111/obr.13130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/13/2022]
Abstract
The gut is one of the main endocrine organs in our body, producing hormones acknowledged to play determinant roles in controlling appetite, energy balance and glucose homeostasis. One of the targets of such hormones is the adipose tissue, a major energetic reservoir, which governs overall metabolism through the secretion of adipokines. Disturbances either in nutrient and metabolic sensing and consequent miscommunication between these organs constitute a key driver to the metabolic complications clustered in metabolic syndrome. Thus, it is essential to understand how the disruption of this crosstalk might trigger adipose tissue dysfunction, a strong characteristic of obesity and insulin resistance. The beneficial effects of metabolic surgery in the amelioration of glucose homeostasis and body weight reduction allowed to understand the potential of gut signals modulation as a treatment for metabolic syndrome-related obesity and type 2 diabetes. In this review, we cover the effects of gut hormones in the modulation of adipose tissue metabolic and endocrine functions, as well as their impact in tissue plasticity. Furthermore, we discuss how the modulation of gut secretome, either through surgical procedures or pharmacological approaches, might improve adipose tissue function in obesity and metabolic syndrome.
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Affiliation(s)
- Daniela Rosendo-Silva
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine and Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Paulo Matafome
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine and Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.,Department of Complementary Sciences, Instituto Politécnico de Coimbra, Coimbra Health School (ESTeSC), Coimbra, Portugal
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28
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Jastrzębski M, Przybyłkowski A. Biogenic amines in the colon. POSTEP HIG MED DOSW 2021; 75:183-190. [DOI: 10.5604/01.3001.0014.7954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025] Open
Abstract
Summary
The gastrointestinal (GI) tract contains the highest concentration of biogenic amines in the human body. Neurons located in the GI tract, modulated by biogenic amines and various peptide and non-peptide transmitters, are called Enteric Nervous System (ENS). That explains why many medications used in neurology and psychiatry present side effects from the gut. Serotonin (5-hyroxytrypatamine, 5-HT), 95% of which is synthesized in the gut, is the most important amine (beside epinephrine and norepinephrine) colon functionality but another substances such as histamine, dopamine and melatonin are also potent in modulating intestine’s actions. Over 30 receptors for 5-HT were described in the human body, and 5-HT3, 5-HT4 and 5-HT7 are known to have the highest influence on motility and are a potent target for the drugs for treatment GI disorders, such as Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Diseases (IBD). Histamine is a key biogenic amine for pathogenesis of allergy also in the colon. Alteration in histaminergic system is found in patients with diarrhea and allergic enteropathy. Dopamine affects functions of the large intestine but its modulating actions are more presented in the upper part of GI tract. Melatonin is best known for regulating circadian circle, but may also be a potent anti-inflammatory agent within the gut. Despite many years of research, it seems that more studies are needed to fully understand human colon neurochemistry.
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Affiliation(s)
- Miłosz Jastrzębski
- Department of Gastroenterology and Internal Medicine , Medical University of Warsaw , Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine , Medical University of Warsaw , Poland
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29
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Mahfud M, Ernawati E, Mahmud NRA, Budipitojo T, Wijayanto H. An immunohistochemical study of endocrine cells in the digestive tract of Varanus salvator (Reptile: Varanidae). Vet World 2020; 13:1737-1742. [PMID: 33132583 PMCID: PMC7566259 DOI: 10.14202/vetworld.2020.1737-1742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/10/2020] [Indexed: 11/16/2022] Open
Abstract
Aim: The aim of the study was to identify the distribution pattern and frequency of endocrine cell types in the digestive tract of Varanus salvator. Materials and Methods: The presence of endocrine cells (glucagon, somatostatin, and serotonin) in the digestive tract (esophagus, stomach, and intestine) was detected using the avidin-biotin complex (ABC) method. Results: Three types of endocrine cells immunoreactive to antisera glucagon, serotonin, and somatostatin were found in the caudal portion of the small and large intestines but were not observed in the esophagus, stomach, and caput and medial sections of the small intestine. Endocrine cells distributed in the digestive tract of V. salvator vary in color intensity, from weak to sharp, in response to the primer antibody. Conclusion: Endocrine cells in the digestive tract that is immunoreactive to glucagon, somatostatin, and serotonin are those found in the caudal portion of the small and large intestines. They are varied in distribution pattern, frequency, and color intensity.
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Affiliation(s)
- Mahfud Mahfud
- Department of Biology Education, University of Muhammadiyah Kupang, East of Nusa Tenggara Province, Indonesia
| | - Ernawati Ernawati
- Department of Biology Education, University of Muhammadiyah Kupang, East of Nusa Tenggara Province, Indonesia
| | - Nur R Adawiyah Mahmud
- Department of Biology Education, University of Muhammadiyah Kupang, East of Nusa Tenggara Province, Indonesia
| | - Teguh Budipitojo
- Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Gajah Mada University, Yogyakarta, Indonesia
| | - Hery Wijayanto
- Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Gajah Mada University, Yogyakarta, Indonesia
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30
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Martin AM, Jones LA, Jessup CF, Sun EW, Keating DJ. Diet differentially regulates enterochromaffin cell serotonin content, density and nutrient sensitivity in the mouse small and large intestine. Neurogastroenterol Motil 2020; 32:e13869. [PMID: 32378785 DOI: 10.1111/nmo.13869] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Enterochromaffin (EC) cells are specialized enteroendocrine cells lining the gastrointestinal (GI) tract and the source of almost all serotonin (5-hydroxytryptamine; 5-HT) in the body. Gut-derived 5-HT has a plethora of physiological roles, including regulation of gastrointestinal motility, and has been implicated as a driver of obesity and metabolic disease. This is due to 5-HT influencing key metabolic processes, such as hepatic gluconeogenesis, adipose tissue lipolysis and hindering thermogenic capacity. Increased circulating 5-HT occurs in humans with obesity and type 2 diabetes. However, despite the known metabolic roles of gut-derived 5-HT, the mechanisms underlying the cellular-level change in EC cells under obesogenic conditions remains unknown. METHODS We use a mouse model of diet-induced obesity (DIO) to identify the regional changes that occur in primary EC cells from the duodenum and colon. Transcriptional changes in the nutrient sensing profile of primary EC cells were assessed, and responses to nutrient stimuli in culture were determined by 5-HT ELISA. KEY RESULTS We find that obesogenic conditions affect EC cells in a region-dependent manner. Duodenal EC cells from DIO mice have impaired sugar sensing even in the presence of increased 5-HT content per cell, while colonic EC cell numbers are significantly increased, but have unaltered nutrient sensing capacity. CONCLUSIONS & INFERENCES Our findings from this study add novel insights into the mechanisms by which functional changes to EC cells occur at a cellular level, which may contribute to the altered circulating 5-HT seen with obesity and metabolic disease, and associated gastrointestinal disorders.
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Affiliation(s)
- Alyce M Martin
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Lauren A Jones
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Claire F Jessup
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Emily W Sun
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Damien J Keating
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, Australia
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31
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The ever-changing roles of serotonin. Int J Biochem Cell Biol 2020; 125:105776. [PMID: 32479926 DOI: 10.1016/j.biocel.2020.105776] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/25/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022]
Abstract
Serotonin (5-HT) has traditional roles as a key neurotransmitter in the central nervous system and as a regulatory hormone controlling a broad range of physiological functions. Perhaps the most classically-defined functions of 5-HT are centrally in the control of mood, sleep and anxiety and peripherally in the modulation of gastrointestinal motility. A more recently appreciated role for 5-HT has emerged, however, as an important metabolic hormone contributing to glucose homeostasis and adiposity, with a causal relationship existing between circulating 5-HT levels and metabolic diseases. Almost all peripheral 5-HT is derived from specialised enteroendocrine cells, called enterochromaffin (EC) cells, located throughout the length of the lining of the gastrointestinal tract. EC cells are important luminal sensory cells that can detect and respond to an array of ingested nutrients, as well as luminal gut microbiota and their associated metabolites. Intriguingly, the interaction between gut microbiota and EC cells is dynamic in nature and has strong implications for host physiology. In this review, we discuss the traditional and modern functions of 5-HT and highlight an emerging pathway by which gut microbiota influences host health. Serotonin, also known as 5-hydroxytryptamine (5-HT), is an important neurotransmitter, growth factor and hormone that mediates a range of physiological functions. In mammals, serotonin is synthesized from the essential amino acid tryptophan by the rate-limiting enzyme tryptophan hydroxylase (TPH), for which there are two isoforms expressed in distinct cell types throughout the body. Tph1 is mainly expressed by specialized gut endocrine cells known as enterochromaffin (EC) cells and by other non-neuronal cell types such as adipocytes (Walther et al., 2003). Tph2 is primarily expressed in neurons of the raphe nuclei of the brain stem and a subset of neurons in the enteric nervous system (ENS) (Yabut et al., 2019). As 5-HT cannot readily cross the blood-brain barrier, the central and peripheral pools of 5-HT are anatomically separated and as such, act in their own distinct manners (Martin et al., 2017c). In this review we discuss the peripheral roles of serotonin, with particular focus on the interaction of gut-derived serotonin with the gut microbiota, and address emerging evidence linking this relationship with host homeostasis.
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32
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Bioavailability of Melatonin from Lentil Sprouts and Its Role in the Plasmatic Antioxidant Status in Rats. Foods 2020; 9:foods9030330. [PMID: 32178261 PMCID: PMC7143261 DOI: 10.3390/foods9030330] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/26/2020] [Accepted: 03/10/2020] [Indexed: 12/29/2022] Open
Abstract
Melatonin is a multifunctional antioxidant neurohormone found in plant foods such as lentil sprouts. We aim to evaluate the effect of lentil sprout intake on the plasmatic levels of melatonin and metabolically related compounds (plasmatic serotonin and urinary 6-sulfatoxymelatonin), total phenolic compounds, and plasmatic antioxidant status, and compare it with synthetic melatonin. The germination of lentils increases the content of melatonin. However, the phenolic content diminished due to the loss of phenolic acids and flavan-3-ols. The flavonol content remained unaltered, being the main phenolic family in lentil sprouts, primarily composed of kaempferol glycosides. Sprague Dawley rats were used to investigate the pharmacokinetic profile of melatonin after oral administration of a lentil sprout extract and to evaluate plasma and urine melatonin and related biomarkers and antioxidant capacity. Melatonin showed maximum concentration (45.4 pg/mL) 90 min after lentil sprout administration. The plasmatic melatonin levels increased after lentil sprout intake (70%, p < 0.05) with respect to the control, 1.2-fold more than after synthetic melatonin ingestion. These increments correlated with urinary 6-sulfatoxymelatonin content (p < 0.05), a key biomarker of plasmatic melatonin. Nonetheless, the phenolic compound content did not exhibit any significant variation. Plasmatic antioxidant status increased in the antioxidant capacity upon both lentil sprout and synthetic melatonin administration. For the first time, we investigated the bioavailability of melatonin from lentil sprouts and its role in plasmatic antioxidant status. We concluded that their intake could increase melatonin plasmatic concentration and attenuate plasmatic oxidative stress.
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33
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Tan W, Lee G, Chen JH, Huizinga JD. Relationships Between Distention-, Butyrate- and Pellet-Induced Stimulation of Peristalsis in the Mouse Colon. Front Physiol 2020; 11:109. [PMID: 32132933 PMCID: PMC7040375 DOI: 10.3389/fphys.2020.00109] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Luminal factors such as short-chain fatty acids are increasingly recognized for playing a regulatory role in peristaltic activity. Our objective was to understand the roles of butyrate and propionate in regulating peristaltic activity in relation to distention-induced activities. Methods Butyrate and propionate were perfused intraluminally under varying intraluminal pressures in murine colons bathed in Krebs solution. We used video recording and spatiotemporal maps to examine peristalsis induced by the intrinsic rhythmic colonic motor complex (CMC) as well as pellet-induced peristaltic reflex movements. Results The CMC showed several configurations at different levels of excitation, culminating in long distance contractions (LDCs) which possess a triangular shape in murine colon spatiotemporal maps. Butyrate increased the frequency of CMCs but was a much weaker stimulus than distention and only contributed to significant changes under low distention. Propionate inhibited CMCs by decreasing either their amplitudes or frequencies, but only in low distention conditions. Butyrate did not consistently counteract propionate-induced inhibition likely due to the multiple and distinct mechanisms of action for these signaling molecules in the lumen. Pellet movement occurred through ongoing CMCs as well as pellet induced peristaltic reflex movements and butyrate augmented both types of peristaltic motor patterns to decrease the amount of time required to expel each pellet. Conclusions Butyrate is effective in promoting peristalsis, but only when the level of colonic activity is low such as under conditions of low intraluminal pressure. This suggests that it may play a significant role in patients with poor fiber intake, where there is low mechanical stimulation in the lumen.
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Affiliation(s)
- Wei Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Medicine, Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Grace Lee
- Department of Medicine, Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Ji-Hong Chen
- Department of Medicine, Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jan D Huizinga
- Department of Medicine, Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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34
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Merino B, Fernández-Díaz CM, Cózar-Castellano I, Perdomo G. Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients 2019; 12:E94. [PMID: 31905727 PMCID: PMC7019254 DOI: 10.3390/nu12010094] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/26/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.
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Affiliation(s)
- Beatriz Merino
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Cristina M. Fernández-Díaz
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain
| | - German Perdomo
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos 09001, Spain
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35
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Martin AM, Sun EW, Keating DJ. Mechanisms controlling hormone secretion in human gut and its relevance to metabolism. J Endocrinol 2019; 244:R1-R15. [PMID: 31751295 PMCID: PMC6892457 DOI: 10.1530/joe-19-0399] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 11/18/2019] [Indexed: 12/16/2022]
Abstract
The homoeostatic regulation of metabolism is highly complex and involves multiple inputs from both the nervous and endocrine systems. The gut is the largest endocrine organ in our body and synthesises and secretes over 20 different hormones from enteroendocrine cells that are dispersed throughout the gut epithelium. These hormones include GLP-1, PYY, GIP, serotonin, and CCK, each of whom play pivotal roles in maintaining energy balance and glucose homeostasis. Some are now the basis of several clinically used glucose-lowering and weight loss therapies. The environment in which these enteroendocrine cells exist is also complex, as they are exposed to numerous physiological inputs including ingested nutrients, circulating factors and metabolites produced from neighbouring gut microbiome. In this review, we examine the diverse means by which gut-derived hormones carry out their metabolic functions through their interactions with different metabolically important organs including the liver, pancreas, adipose tissue and brain. Furthermore, we discuss how nutrients and microbial metabolites affect gut hormone secretion and the mechanisms underlying these interactions.
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Affiliation(s)
- Alyce M Martin
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Emily W Sun
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Damien J Keating
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Correspondence should be addressed to D J Keating:
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36
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Tian L, Qian W, Qian Q, Zhang W, Cai X. Gingerol inhibits cisplatin-induced acute and delayed emesis in rats and minks by regulating the central and peripheral 5-HT, SP, and DA systems. J Nat Med 2019; 74:353-370. [PMID: 31768887 PMCID: PMC7044144 DOI: 10.1007/s11418-019-01372-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022]
Abstract
Abstract Gingerol, a biologically active component in ginger, has shown antiemetic properties. Our study aimed to explore the underlying mechanisms of gingerol on protecting rats and minks from chemotherapy-induced nausea and vomiting. The preventive impact of gingerol was evaluated in the pica model of rats and the vomiting model of minks induced by cisplatin at every 6 h continuously for a duration of 72 h. Animals were arbitrarily separated into blank control group, simple gingerol control group, cisplatin control group, cisplatin + metoclopramide group, cisplatin + three different doses gingerol group (low-dose; middle-dose; high-dose). The area postrema as well as ileum damage were assessed using H&E stain. The levels of 5-TH, 5-HT3 receptor, TPH, SERT, SP, NK1 receptor, PPT, NEP, DA, D2R, TH, and DAT were determined using immunohistochemistry or qRT-PCR in rats and minks. All indicators were measured in the area postrema along with ileum. The kaolin intake by rats and the incidence of CINV of minks were significantly decreased after pretreatment with gingerol in a dosage-dependent way for the duration of 0–24-h and 24–72-h. Gingerol markedly decreased the levels of 5-TH, 5-HT3 receptor, TPH, SP, NK1 receptor, PPT, DA, D2R, TH, alleviated area postrema as well as ileum damage, and increased the accumulation of SERT, NEP, DAT in the area postrema along with ileum of rats and minks. Gingerol alleviates cisplatin-induced kaolin intake of rats and emesis of minks possibly by regulating central and peripheral 5-HT system, SP system and DA system. Graphic abstract ![]()
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Affiliation(s)
- Li Tian
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People's Republic of China
| | - Weibin Qian
- Postdoctoral Mobile Station, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People's Republic of China.,Department of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, Shandong, People's Republic of China
| | - Qiuhai Qian
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People's Republic of China
| | - Wei Zhang
- Department of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, Shandong, People's Republic of China.
| | - Xinrui Cai
- Department of Traditional Chinese Medicine, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 17 Yuxing Road, Central District, Jinan, Shandong, People's Republic of China.
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37
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Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99:1877-2013. [PMID: 31460832 DOI: 10.1152/physrev.00018.2018] [Citation(s) in RCA: 2665] [Impact Index Per Article: 444.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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Affiliation(s)
- John F. Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kenneth J. O'Riordan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitlin S. M. Cowan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kiran V. Sandhu
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Thomaz F. S. Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcus Boehme
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Martin G. Codagnone
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Sofia Cussotto
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Christine Fulling
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Anna V. Golubeva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Katherine E. Guzzetta
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Minal Jaggar
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitriona M. Long-Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joshua M. Lyte
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Jason A. Martin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Alicia Molinero-Perez
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emanuela Morelli
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Enrique Morillas
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Rory O'Connor
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joana S. Cruz-Pereira
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Veronica L. Peterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Nathaniel L. Ritz
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Eoin Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Simon Spichak
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emily M. Teichman
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcel van de Wouw
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Ana Paula Ventura-Silva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Shauna E. Wallace-Fitzsimons
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Niall Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
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38
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Shokrollahi M, Chen JH, Huizinga JD. Intraluminal prucalopride increases propulsive motor activities via luminal 5-HT 4 receptors in the rabbit colon. Neurogastroenterol Motil 2019; 31:e13598. [PMID: 31012538 DOI: 10.1111/nmo.13598] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/13/2019] [Accepted: 03/28/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Activating luminal 5-HT4 receptors results in the release of 5-HT from enterochromaffin cells into the lamina propria to modulate colonic motility. Our aim was to evaluate characteristics of colonic motor patterns involved in the prokinetic effects of intraluminal prucalopride in the rabbit colon. METHODS Colonic motor patterns were studied ex vivo using simultaneous spatiotemporal diameter mapping and pressure sensing. KEY RESULTS Intraluminal prucalopride and intraluminal exogenous 5-HT strongly evoked or enhanced the colonic motor complex at all levels of excitation beginning with generation of clusters of fast propagating contractions (FPCs), then development of long-distance contractions (LDCs) within the clusters, and finally forceful LDCs as the highest level of excitation. Intraluminal prucalopride and intraluminal exogenous 5-HT stimulated propulsive motor activity in a dose-dependent and antagonist-sensitive manner by increasing the contraction amplitude, intraluminal pressure, frequency, velocity, and degree of propagation of the colonic motor complex. CONCLUSIONS AND INFERENCES Activating mucosal 5-HT4 receptors via intraluminal prucalopride or 5-HT increases propulsive motor activity in a graded manner; that is, depending on starting conditions, amplitudes or frequencies of an activity may increase or a new pattern may be initiated. Our data support further studies into delivering 5-HT4 receptor agonists via colon-targeted drug delivery systems and studies into the role of luminal 5-HT as an essential requirement for normal colon motor pattern generation.
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Affiliation(s)
- Mitra Shokrollahi
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Ji-Hong Chen
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Jan D Huizinga
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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39
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Yabut JM, Crane JD, Green AE, Keating DJ, Khan WI, Steinberg GR. Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule. Endocr Rev 2019; 40:1092-1107. [PMID: 30901029 PMCID: PMC6624793 DOI: 10.1210/er.2018-00283] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 03/18/2019] [Indexed: 12/12/2022]
Abstract
Serotonin is a phylogenetically ancient biogenic amine that has played an integral role in maintaining energy homeostasis for billions of years. In mammals, serotonin produced within the central nervous system regulates behavior, suppresses appetite, and promotes energy expenditure by increasing sympathetic drive to brown adipose tissue. In addition to these central circuits, emerging evidence also suggests an important role for peripheral serotonin as a factor that enhances nutrient absorption and storage. Specifically, glucose and fatty acids stimulate the release of serotonin from the duodenum, promoting gut peristalsis and nutrient absorption. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue, while reducing lipolysis and the metabolic activity of brown and beige adipose tissue. Collectively, peripheral serotonin acts as an endocrine factor to promote the efficient storage of energy by upregulating lipid anabolism. Pharmacological inhibition of serotonin synthesis or signaling in key metabolic tissues are potential drug targets for obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Julian M Yabut
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.,Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Justin D Crane
- Department of Biology, Northeastern University, Boston, Massachusetts
| | - Alexander E Green
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.,Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Damien J Keating
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
| | - Waliul I Khan
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.,Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.,Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.,Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
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40
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Keski-Rahkonen P, Kolehmainen M, Lappi J, Micard V, Jokkala J, Rosa-Sibakov N, Pihlajamäki J, Kirjavainen PV, Mykkänen H, Poutanen K, Gunter MJ, Scalbert A, Hanhineva K. Decreased plasma serotonin and other metabolite changes in healthy adults after consumption of wholegrain rye: an untargeted metabolomics study. Am J Clin Nutr 2019; 109:1630-1639. [PMID: 31136658 DOI: 10.1093/ajcn/nqy394] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 12/31/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Wholegrain consumption has been associated with beneficial health effects including reduction of diabetes and cancer risk; however, the underlying mechanisms are not fully understood. OBJECTIVE The aim of this study was to characterize the effects of wholegrain rye intake on circulating metabolites in a human intervention study using untargeted metabolomics. METHODS The intervention consisted of 2 successive 4-wk periods in a randomized crossover design, where 15 adults consumed wholegrain rye bread (WGR) or white wheat bread enriched with fermented rye bran (WW+RB), following a 4-wk rye-free period with white wheat bread (WW). Fasting plasma samples were collected at the end of each period and analyzed using liquid chromatography-mass spectrometry. Metabolic profiles were compared to identify compounds discriminating WGR from the WW+RB and WW periods. Because peripheral serotonin is produced mainly in the gut, a hypothesis of its altered biosynthesis as a response to increased cereal fiber intake was tested by measuring intestinal serotonin of mice fed for 9 wk on a high-fat diet supplemented with different sources of fiber (rye bran flour, ground wheat aleurone, or powdered cellulose). RESULTS Five endogenous metabolites and 15 rye phytochemicals associated with WGR intake were identified. Plasma concentrations of serotonin, taurine, and glycerophosphocholine were significantly lower after the WGR than WW period (Q < 0.05). Concentrations of 2 phosphatidylethanolamine plasmalogens, PE(18:2/P-18:0) and PE(18:2/P-16:0), were lower after the WGR period than the WW+RB period (Q < 0.05). The concentration of serotonin was significantly lower in the colonic tissue of mice that consumed rye bran or wheat aleurone compared with cellulose (P < 0.001). CONCLUSIONS Wholegrain rye intake decreases plasma serotonin in healthy adults when compared with refined wheat. Intake of rye bran and wheat aleurone decreases colonic serotonin in mice. These results suggest that peripheral serotonin could be a potential link between wholegrain consumption and its associated health effects.Data used in the study were derived from a trial registered at www.clinicaltrials.gov as NCT03550365.
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Affiliation(s)
| | - Marjukka Kolehmainen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Jenni Lappi
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Valerie Micard
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Montpellier SupAgro-INRA-University of Montpellier-CIRAD, Montpellier, France
| | - Jenna Jokkala
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Natalia Rosa-Sibakov
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Montpellier SupAgro-INRA-University of Montpellier-CIRAD, Montpellier, France
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - Pirkka V Kirjavainen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Environmental Health Unit, The National Institute for Health and Welfare, Kuopio, Finland
| | - Hannu Mykkänen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Kaisa Poutanen
- VTT Technical Research Centre of Finland, Espoo, Finland
| | - Marc J Gunter
- International Agency for Research on Cancer, Lyon, France
| | | | - Kati Hanhineva
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
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41
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Yang Y, Wang S, Kobayashi K, Hao Y, Kanda H, Kondo T, Kogure Y, Yamanaka H, Yamamoto S, Li J, Miwa H, Noguchi K, Dai Y. TRPA1-expressing lamina propria mesenchymal cells regulate colonic motility. JCI Insight 2019; 4:122402. [PMID: 31045572 DOI: 10.1172/jci.insight.122402] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 04/02/2019] [Indexed: 12/19/2022] Open
Abstract
The physiological process of defecation is directly controlled by colorectal motility. The transient receptor potential ankyrin 1 (TRPA1) channel is expressed in small intestine enterochromaffin cells and is involved in gastrointestinal motility via serotonin release. In the colorectum, however, enterochromaffin cell localization is largely distinct from that in the small intestine. Here, we investigated the role of lower gastrointestinal tract TRPA1 in modulating colorectal motility. We found that in colonic tissue, TRPA1 is predominantly expressed in mesenchymal cells of the lamina propria, which are clearly distinct from those in the small intestine. These cells coexpressed COX1 and microsomal prostaglandin E synthase-1. Intracolonic administration of TRPA1 agonists induced colonic contraction, which was suppressed by a prostaglandin E2 (PGE2) receptor 1 antagonist. TRPA1 activation induced calcium influx and PGE2 release from cultured human fibroblastic cells. In dextran sulfate sodium-treated animals, both TRPA1 and its endogenous agonist were dramatically increased in the colonic lamina propria, accompanied by abnormal colorectal contractions. Abnormal colorectal contractions were significantly prevented by pharmacological and genetic inhibition of TRPA1. In conclusion, in the lower gastrointestinal tract, mesenchymal TRPA1 activation results in PGE2 release and consequently promotes colorectal contraction, representing what we believe is a novel physiological and inflammatory bowel disease-associated mechanism of gastrointestinal motility.
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Affiliation(s)
- Yanjing Yang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Shenglan Wang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine (BUCM), Beijing, China
| | - Kimiko Kobayashi
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Yongbiao Hao
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Hirosato Kanda
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Takashi Kondo
- Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Yoko Kogure
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan
| | - Hiroki Yamanaka
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Satoshi Yamamoto
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan
| | - Junxiang Li
- Division of Gastroenterology, Department of Internal Medicine, Dongfang Hospital of BUCM, Beijing, China
| | - Hiroto Miwa
- Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Koichi Noguchi
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Yi Dai
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
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42
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Martin AM, Sun EW, Rogers GB, Keating DJ. The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release. Front Physiol 2019; 10:428. [PMID: 31057420 PMCID: PMC6477058 DOI: 10.3389/fphys.2019.00428] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/27/2019] [Indexed: 12/17/2022] Open
Abstract
The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release.
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Affiliation(s)
- Alyce M Martin
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Emily W Sun
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Geraint B Rogers
- Microbiome Research Laboratory, Flinders University, Adelaide, SA, Australia.,Infection and Immunity, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Damien J Keating
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.,Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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43
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Zhu MJ, Yang ZJ, Wang FF, Di ZS, Wang YX, Li LS, Xu JD. Enterochromaffin cells and gastrointestinal diseases. Shijie Huaren Xiaohua Zazhi 2019; 27:117-124. [DOI: 10.11569/wcjd.v27.i2.117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Enterochromaffin cells (ECs), known for their special histochemical characteristics, originate from enteroblasts. For their important role in physiological and pathophysiological conditions, ECs in the gut could synthesize and secrete about 95% of 5-hydroxytryptamine (5-HT) in the body, which is an important humoral factor. As a chemosensor, ECs can regulate nutrition absorption and satiety through the sensory neural pathways. In addition, ECs participate in immune regulation. What's more, ECs and 5-HT are closely related to many kinds of gastrointestinal diseases.
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Affiliation(s)
- Min-Jia Zhu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Ze-Jun Yang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Fei-Fei Wang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Zhi-Shan Di
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Yue-Xiu Wang
- International College, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
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44
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Sugar Responses of Human Enterochromaffin Cells Depend on Gut Region, Sex, and Body Mass. Nutrients 2019; 11:nu11020234. [PMID: 30678223 PMCID: PMC6412251 DOI: 10.3390/nu11020234] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 12/15/2018] [Accepted: 01/14/2019] [Indexed: 12/12/2022] Open
Abstract
Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p < 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p < 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.
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45
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Cheng X, Voss U, Ekblad E. A novel serotonin-containing tuft cell subpopulation in mouse intestine. Cell Tissue Res 2019; 376:189-197. [DOI: 10.1007/s00441-018-02988-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 12/22/2018] [Indexed: 01/12/2023]
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46
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Martin AM, Sun EW, Rogers GB, Keating DJ. The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release. Front Physiol 2019. [PMID: 31057420 DOI: 10.3389/fphys.2019.00428/bibtex] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023] Open
Abstract
The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release.
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Affiliation(s)
- Alyce M Martin
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Emily W Sun
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Geraint B Rogers
- Microbiome Research Laboratory, Flinders University, Adelaide, SA, Australia
- Infection and Immunity, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Damien J Keating
- Molecular and Cellular Physiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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47
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Kreuch D, Keating DJ, Wu T, Horowitz M, Rayner CK, Young RL. Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control. Front Endocrinol (Lausanne) 2018; 9:741. [PMID: 30564198 PMCID: PMC6288399 DOI: 10.3389/fendo.2018.00741] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [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: 11/22/2018] [Indexed: 12/25/2022] Open
Abstract
Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes.
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Affiliation(s)
- Denise Kreuch
- Faculty of Health and Medical Sciences & Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Damien J. Keating
- College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Tongzhi Wu
- Faculty of Health and Medical Sciences & Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Michael Horowitz
- Faculty of Health and Medical Sciences & Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Christopher K. Rayner
- Faculty of Health and Medical Sciences & Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Richard L. Young
- Faculty of Health and Medical Sciences & Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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48
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Goldspink DA, Reimann F, Gribble FM. Models and Tools for Studying Enteroendocrine Cells. Endocrinology 2018; 159:3874-3884. [PMID: 30239642 PMCID: PMC6215081 DOI: 10.1210/en.2018-00672] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/05/2018] [Indexed: 12/14/2022]
Abstract
Gut hormones produced by gastrointestinal enteroendocrine cells modulate key physiological processes including glucose homeostasis and food intake, making them potential therapeutic candidates to treat obesity and diabetes. Understanding the function of enteroendocrine cells and the molecular mechanisms driving hormone production is a key step toward mobilizing endogenous hormone reserves in the gut as a therapeutic strategy. In this review, we will discuss the variety of ex vivo and in vitro model systems driving this research and their contributions to our current understanding of nutrient-sensing mechanisms in enteroendocrine cells.
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Affiliation(s)
- Deborah A Goldspink
- Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
| | - Frank Reimann
- Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
| | - Fiona M Gribble
- Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
- Correspondence: Fiona M. Gribble, DPhil, BM, BCh, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom. E-mail:
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49
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Wilder-Smith CH, Olesen SS, Materna A, Drewes AM. Fermentable Sugar Ingestion, Gas Production, and Gastrointestinal and Central Nervous System Symptoms in Patients With Functional Disorders. Gastroenterology 2018; 155:1034-1044.e6. [PMID: 30009815 DOI: 10.1053/j.gastro.2018.07.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 06/03/2018] [Accepted: 07/03/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Functional gastrointestinal disorders (FGID) are defined by broad phenotypic descriptions and exclusion of recognizable disease. FGIDs cause multi-organ symptoms and abnormal results in a wide range of laboratory tests, indicating broad mechanisms of pathogenesis. Many patients with FGID develop symptoms following ingestion of fermentable sugars; we investigated the associations between symptoms and intestinal gas production following sugar provocation tests to elucidate mechanisms of FGID. METHODS We performed fructose and lactose breath tests in 2042 patients with a diagnosis of FGID (based on Rome III criteria), referred to a gastroenterology practice from January 2008 through December 2011. Medical and diet histories were collected from all subjects. Breath samples were collected before and each hour after, for 5 hours, subjects ingested fructose (35 g) and lactose (50 g) dissolved in 300 mL water. Hydrogen and methane gas concentrations were measured and GI and non-GI symptoms were registered for 5 hours following sugar ingestion. Symptom and gas time profiles were compared, treelet transforms were used to derive data-related symptom clusters, and the symptom severity of the clusters were analyzed for their association with breath gas characteristics. RESULTS We identified 11 GI and central nervous system (CNS) symptom profiles and hydrogen and methane breath concentrations that changed significantly with time following sugar ingestion. Treelet transform analysis identified 2 distinct clusters, based on GI and CNS symptoms. The severity scores for the GI and CNS symptoms correlated following ingestion of sugars (all, P < .0001). However, only the GI symptoms associated with hydrogen and methane gas production (all, P < .0001). CONCLUSIONS In an analysis of breath test results from more than 2000 patients with FGIDs, we identified clusters of GI and CNS symptoms in response to fructose of lactose ingestion. The association between specific symptoms and breath gas concentrations indicate distinct mechanisms of FGID pathogenesis, such as changes in the microbiome or mechanical and chemical sensitization. ClinicalTrials.gov ID: NCT02085889.
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Affiliation(s)
| | - Søren S Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Andrea Materna
- Brain-Gut Research Group, Gastroenterology Group Practice, Bern, Switzerland
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
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50
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Adriaenssens AE, Reimann F, Gribble FM. Distribution and Stimulus Secretion Coupling of Enteroendocrine Cells along the Intestinal Tract. Compr Physiol 2018; 8:1603-1638. [DOI: 10.1002/cphy.c170047] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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