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Song Y, Fothergill LJ, Lee KS, Liu BY, Koo A, Perelis M, Diwakarla S, Callaghan B, Huang J, Wykosky J, Furness JB, Yeo GW. Stratification of enterochromaffin cells by single-cell expression analysis. eLife 2025; 12:RP90596. [PMID: 40184163 PMCID: PMC11970908 DOI: 10.7554/elife.90596] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025] Open
Abstract
Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.
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Affiliation(s)
- Yan Song
- Department of Cellular and Molecular Medicine, University of California San DiegoLa JollaUnited States
- Stem Cell Program, University of California San DiegoLa JollaUnited States
- Institute for Genomic Medicine, University of California San DiegoLa JollaUnited States
| | - Linda J Fothergill
- Department of Anatomy & Physiology, University of MelbourneParkvilleAustralia
- Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
| | - Kari S Lee
- Department of Cellular and Molecular Medicine, University of California San DiegoLa JollaUnited States
- Stem Cell Program, University of California San DiegoLa JollaUnited States
- Institute for Genomic Medicine, University of California San DiegoLa JollaUnited States
| | - Brandon Y Liu
- Department of Cellular and Molecular Medicine, University of California San DiegoLa JollaUnited States
- Stem Cell Program, University of California San DiegoLa JollaUnited States
- Institute for Genomic Medicine, University of California San DiegoLa JollaUnited States
| | - Ada Koo
- Department of Anatomy & Physiology, University of MelbourneParkvilleAustralia
| | - Mark Perelis
- Department of Cellular and Molecular Medicine, University of California San DiegoLa JollaUnited States
- Stem Cell Program, University of California San DiegoLa JollaUnited States
- Institute for Genomic Medicine, University of California San DiegoLa JollaUnited States
| | - Shanti Diwakarla
- Department of Anatomy & Physiology, University of MelbourneParkvilleAustralia
| | - Brid Callaghan
- Department of Anatomy & Physiology, University of MelbourneParkvilleAustralia
| | - Jie Huang
- Takeda PharmaceuticalsSan DiegoUnited States
| | | | - John B Furness
- Department of Anatomy & Physiology, University of MelbourneParkvilleAustralia
- Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California San DiegoLa JollaUnited States
- Stem Cell Program, University of California San DiegoLa JollaUnited States
- Institute for Genomic Medicine, University of California San DiegoLa JollaUnited States
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2
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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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3
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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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4
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Song Y, Fothergill LJ, Lee KS, Liu BY, Koo A, Perelis M, Diwakarla S, Callaghan B, Huang J, Wykosky J, Furness JB, Yeo GW. Stratification of enterochromaffin cells by single-cell expression analysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.08.24.554649. [PMID: 37662229 PMCID: PMC10473706 DOI: 10.1101/2023.08.24.554649] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2 + population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated Piezo2 + ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.
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Affiliation(s)
- Yan Song
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, United States
- Stem Cell Program, University of California San Diego, La Jolla, CA 92093, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, United States
| | - Linda J. Fothergill
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
| | - Kari S. Lee
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, United States
- Stem Cell Program, University of California San Diego, La Jolla, CA 92093, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, United States
| | - Brandon Y. Liu
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, United States
- Stem Cell Program, University of California San Diego, La Jolla, CA 92093, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, United States
| | - Ada Koo
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Mark Perelis
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, United States
- Stem Cell Program, University of California San Diego, La Jolla, CA 92093, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, United States
| | - Shanti Diwakarla
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Brid Callaghan
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Jie Huang
- Takeda Pharmaceuticals, San Diego, CA 92121, United States
| | - Jill Wykosky
- Takeda Pharmaceuticals, San Diego, CA 92121, United States
| | - John B. Furness
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
| | - Gene W. Yeo
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, United States
- Stem Cell Program, University of California San Diego, La Jolla, CA 92093, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, United States
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Gong HS, Pan JP, Guo F, Wu MM, Dong L, Li Y, Rong WF. Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice. Acta Pharmacol Sin 2024; 45:1821-1831. [PMID: 38702501 PMCID: PMC11335854 DOI: 10.1038/s41401-024-01293-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 04/15/2024] [Indexed: 05/06/2024]
Abstract
Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.
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Affiliation(s)
- Hua-Shan Gong
- Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jing-Pei Pan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fei Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Mei-Mei Wu
- Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Li Dong
- Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yang Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Wei-Fang Rong
- Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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6
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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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Spencer NJ, Kyloh MA, Travis L, Hibberd TJ. Mechanisms underlying the gut-brain communication: How enterochromaffin (EC) cells activate vagal afferent nerve endings in the small intestine. J Comp Neurol 2024; 532:e25613. [PMID: 38625817 DOI: 10.1002/cne.25613] [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: 12/13/2023] [Revised: 03/02/2024] [Accepted: 03/24/2024] [Indexed: 04/18/2024]
Abstract
How the gastrointestinal tract communicates with the brain, via sensory nerves, is of significant interest for our understanding of human health and disease. Enterochromaffin (EC) cells in the gut mucosa release a variety of neurochemicals, including the largest quantity of 5-hydroxytryptamine (5-HT) in the body. How 5-HT and other substances released from EC cells activate sensory nerve endings in the gut wall remains a major unresolved mystery. We used in vivo anterograde tracing from nodose ganglia to determine the spatial relationship between 5-HT synthesizing and peptide-YY (PYY)-synthesizing EC cells and their proximity to vagal afferent nerve endings that project to the mucosa of mouse small intestine. The shortest mean distances between single 5-HT- and PYY-synthesizing EC cells and the nearest vagal afferent nerve endings in the mucosa were 33.1 ± 14.4 µm (n = 56; N = 6) and 70.3 ± 32.3 µm (n = 16; N = 6). No morphological evidence was found to suggest that 5-HT- or PYY-containing EC cells form close morphological associations with vagal afferents endings, or varicose axons of passage. The large distances between EC cells and vagal afferent endings are many hundreds of times greater than those known to underlie synaptic transmission in the nervous system (typically 10-15 nm). Taken together, the findings lead to the inescapable conclusion that communication between 5-HT-containing EC cells and vagal afferent nerve endings in the mucosa of the mouse small intestinal occurs in a paracrine fashion, via diffusion. New and Noteworthy None of the findings here are consistent with a view that close physical contacts occur between 5-HT-containing EC cells and vagal afferent nerve endings in mouse small intestine. Rather, the findings suggest that gut-brain communication between EC cells and vagal afferent endings occurs via passive diffusion. The morphological data presented do not support the view that EC cells are physically close enough to vagal afferent endings to communicate via fast synaptic transmission.
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Affiliation(s)
- Nick J Spencer
- Visceral Neurophysiology Laboratory, Flinders Health and Medical Research Institute & College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia
| | - Melinda A Kyloh
- Visceral Neurophysiology Laboratory, Flinders Health and Medical Research Institute & College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia
| | - Lee Travis
- Visceral Neurophysiology Laboratory, Flinders Health and Medical Research Institute & College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia
| | - Timothy J Hibberd
- Visceral Neurophysiology Laboratory, Flinders Health and Medical Research Institute & College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia, Australia
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Fan C, Xu J, Tong H, Fang Y, Chen Y, Lin Y, Chen R, Chen F, Wu G. Gut-brain communication mediates the impact of dietary lipids on cognitive capacity. Food Funct 2024; 15:1803-1824. [PMID: 38314832 DOI: 10.1039/d3fo05288e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Cognitive impairment, as a prevalent symptom of nervous system disorders, poses one of the most challenging aspects in the management of brain diseases. Lipids present in the cell membranes of all neurons within the brain and dietary lipids can regulate the cognition and memory function. In recent years, the advancements in gut microbiome research have enabled the exploration of dietary lipids targeting the gut-brain axis as a strategy for regulating cognition. This present review provides an in-depth overview of how lipids modulate cognition via the gut-brain axis depending on metabolic, immune, neural and endocrine pathways. It also comprehensively analyzes the effects of diverse lipids on the gut microbiota and intestinal barrier function, thereby affecting the central nervous system and cognitive capacity. Moreover, comparative analysis of the positive and negative effects is presented between beneficial and detrimental lipids. The former encompass monounsaturated fatty acids, short-chain fatty acids, omega-3 polyunsaturated fatty acids, phospholipids, phytosterols, fungal sterols and bioactive lipid-soluble vitamins, as well as lipid-derived gut metabolites, whereas the latter (detrimental lipids) include medium- or long-chain fatty acids, excessive proportions of n-6 polyunsaturated fatty acids, industrial trans fatty acids, and zoosterols. To sum up, the focus of this review is on how gut-brain communication mediates the impact of dietary lipids on cognitive capacity, providing a novel theoretical foundation for promoting brain cognitive health and scientific lipid consumption patterns.
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Affiliation(s)
- Chenhan Fan
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Jingxuan Xu
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Haoxiang Tong
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Yucheng Fang
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Yiming Chen
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Yangzhuo Lin
- School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Rui Chen
- School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Fuhao Chen
- School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Guoqing Wu
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
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Ramzy A, Saber N, Bruin JE, Thompson DM, Kim PTW, Warnock GL, Kieffer TJ. Thyroid Hormone Levels Correlate With the Maturation of Implanted Pancreatic Endoderm Cells in Patients With Type 1 Diabetes. J Clin Endocrinol Metab 2024; 109:413-423. [PMID: 37671625 PMCID: PMC10795919 DOI: 10.1210/clinem/dgad499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 08/09/2023] [Accepted: 08/22/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Macroencapsulated pancreatic endoderm cells (PECs) can reverse diabetes in rodents and preclinical studies revealed that thyroid hormones in vitro and in vivo bias PECs to differentiate into insulin-producing cells. In an ongoing clinical trial, PECs implanted in macroencapsulation devices into patients with type 1 diabetes were safe but yielded heterogeneous outcomes. Though most patients developed meal responsive C-peptide, levels were heterogeneous and explanted grafts had variable numbers of surviving cells with variable distribution of endocrine cells. METHODS We measured circulating triiodothyronine and thyroxine levels in all patients treated at 1 of the 7 sites of the ongoing clinical trial and determined if thyroid hormone levels were associated with the C-peptide or glucagon levels and cell fate of implanted PECs. RESULTS Both triiodothyronine and thyroxine levels were significantly associated with the proportion of cells that adopted an insulin-producing fate with a mature phenotype. Thyroid hormone levels were inversely correlated to circulating glucagon levels after implantation, suggesting that thyroid hormones lead PECs to favor an insulin-producing fate over a glucagon-producing fate. In mice, hyperthyroidism led to more rapid maturation of PECs into insulin-producing cells similar in phenotype to PECs in euthyroid mice. CONCLUSION These data highlight the relevance of thyroid hormones in the context of PEC therapy in patients with type 1 diabetes and suggest that a thyroid hormone adjuvant therapy may optimize cell outcomes in some PEC recipients.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Nelly Saber
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Jennifer E Bruin
- Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada
| | - David M Thompson
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Peter T W Kim
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Garth L Warnock
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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10
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Singh SV, Ganguly R, Jaiswal K, Yadav AK, Kumar R, Pandey AK. Molecular signalling during cross talk between gut brain axis regulation and progression of irritable bowel syndrome: A comprehensive review. World J Clin Cases 2023; 11:4458-4476. [PMID: 37469740 PMCID: PMC10353503 DOI: 10.12998/wjcc.v11.i19.4458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 05/09/2023] [Accepted: 06/06/2023] [Indexed: 06/30/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder which alters gastrointestinal (GI) functions, thus leading to compromised health status. Pathophysiology of IBS is not fully understood, whereas abnormal gut brain axis (GBA) has been identified as a major etiological factor. Recent studies are suggestive for visceral hyper-sensitivity, altered gut motility and dysfunctional autonomous nervous system as the main clinical abnormalities in IBS patients. Bidirectional signalling interactions among these abnormalities are derived through various exogenous and endogenous factors, such as microbiota population and diversity, microbial metabolites, dietary uptake, and psychological abnormalities. Strategic efforts focused to study these interactions including probiotics, antibiotics and fecal transplantations in normal and germ-free animals are clearly suggestive for the pivotal role of gut microbiota in IBS etiology. Additionally, neurotransmitters act as communication tools between enteric microbiota and brain functions, where serotonin (5-hydroxytryptamine) plays a key role in pathophysiology of IBS. It regulates GI motility, pain sense and inflammatory responses particular to mucosal and brain activity. In the absence of a better understanding of various interconnected crosstalks in GBA, more scientific efforts are required in the search of novel and targeted therapies for the management of IBS. In this review, we have summarized the gut microbial composition, interconnected signalling pathways and their regulators, available therapeutics, and the gaps needed to fill for a better management of IBS.
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Affiliation(s)
- Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Risha Ganguly
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Kritika Jaiswal
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Aditya Kumar Yadav
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
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11
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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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12
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Czigle S, Bittner Fialová S, Tóth J, Mučaji P, Nagy M, on behalf of the OEMONOM. Treatment of Gastrointestinal Disorders-Plants and Potential Mechanisms of Action of Their Constituents. Molecules 2022; 27:2881. [PMID: 35566230 PMCID: PMC9105531 DOI: 10.3390/molecules27092881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/19/2022] [Accepted: 04/26/2022] [Indexed: 11/16/2022] Open
Abstract
The worldwide prevalence of gastrointestinal diseases is about 40%, with standard pharmacotherapy being long-lasting and economically challenging. Of the dozens of diseases listed by the Rome IV Foundation criteria, for five of them (heartburn, dyspepsia, nausea and vomiting disorder, constipation, and diarrhoea), treatment with herbals is an official alternative, legislatively supported by the European Medicines Agency (EMA). However, for most plants, the Directive does not require a description of the mechanisms of action, which should be related to the therapeutic effect of the European plant in question. This review article, therefore, summarizes the basic pharmacological knowledge of synthetic drugs used in selected functional gastrointestinal disorders (FGIDs) and correlates them with the constituents of medicinal plants. Therefore, the information presented here is intended as a starting point to support the claim that both empirical folk medicine and current and decades-old treatments with official herbal remedies have a rational basis in modern pharmacology.
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Affiliation(s)
- Szilvia Czigle
- Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia; (S.B.F.); (J.T.); (P.M.); (M.N.)
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13
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Lyu D, Kou G, Li S, Li L, Li B, Zhou R, Yang X, Tian W, Li Y, Zuo X. Digital Spatial Profiling Reveals Functional Shift of Enterochromaffin Cell in Patients With Ulcerative Colitis. Front Cell Dev Biol 2022; 10:841090. [PMID: 35465329 PMCID: PMC9023741 DOI: 10.3389/fcell.2022.841090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/21/2022] [Indexed: 11/30/2022] Open
Abstract
As a major component of the enteroendocrine system, enterochromaffin (EC) cells play a key role in ulcerative colitis (UC). However, the scarcity of EC cells has limited the investigation of their function. In this study, we applied digital spatial profiling to acquire transcriptomic data for EC cells and other epithelial cells from colonoscopic biopsy samples from eight patients with UC and seven healthy controls. Differential expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were performed to identify differentially expressed genes and pathways and coexpression networks. Results were validated using an online dataset obtained by single-cell RNA sequencing, along with immunofluorescence staining and quantitative real-time PCR. In healthy participants, 10 genes were significantly enriched in EC cells, functionally concentrated in protein and bioamine synthesis. A coexpression network containing 17 hub genes, including TPH1, CHGA, and GCLC, was identified in EC cells. In patients with UC, EC cells gained increased capacity for protein synthesis, along with novel immunological functions such as antigen processing and presentation, whereas chemical sensation was downregulated. The specific expression of CHGB and RGS2 in EC cells was confirmed by immunofluorescence staining. Our results illuminate the transcriptional signatures of EC cells in the human colon. EC cells’ newly observed functional shift from sensation to secretion and immunity indicates their pivotal role in UC.
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Affiliation(s)
- Dongping Lyu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Guanjun Kou
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Shiyang Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Advanced Medical Research Institute, Shandong University, Jinan, China
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Shandong University, Jinan, China
| | - Bing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Ruchen Zhou
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Xiaoxiao Yang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Wenyu Tian
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Shandong University, Jinan, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Xiuli Zuo,
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14
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Shoubridge AP, Choo JM, Martin AM, Keating DJ, Wong ML, Licinio J, Rogers GB. The gut microbiome and mental health: advances in research and emerging priorities. Mol Psychiatry 2022; 27:1908-1919. [PMID: 35236957 DOI: 10.1038/s41380-022-01479-w] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/17/2022] [Accepted: 02/08/2022] [Indexed: 12/19/2022]
Abstract
The gut microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in the development of psychiatric conditions and in the efficacy of many common therapies. With the growing acceptance of the role played by the gut microbiome in mental health outcomes, the focus of research is now beginning to shift from identifying relationships between intestinal microbiology and pathophysiology, and towards using this newfound insight to improve clinical outcomes. Here, we review recent advances in our understanding of gut microbiome-brain interactions, the mechanistic underpinnings of these relationships, and the ongoing challenge of distinguishing association and causation. We set out an overarching model of the evolution of microbiome-CNS interaction and examine how a growing knowledge of these complex systems can be used to determine disease susceptibility and reduce risk in a targeted manner.
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Affiliation(s)
- Andrew P Shoubridge
- Microbiome and Host Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia.,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Jocelyn M Choo
- Microbiome and Host Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia.,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Alyce M Martin
- Neuroscience, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Damien J Keating
- Neuroscience, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Ma-Li Wong
- Department of Psychiatry and Behavioral Sciences and Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA
| | - Julio Licinio
- Department of Psychiatry and Behavioral Sciences and Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA.,Department of Psychiatry, Flinders University College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Geraint B Rogers
- Microbiome and Host Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia. .,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia.
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15
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Rezzani R, Franco C, Franceschetti L, Gianò M, Favero G. A Focus on Enterochromaffin Cells among the Enteroendocrine Cells: Localization, Morphology, and Role. Int J Mol Sci 2022; 23:ijms23073758. [PMID: 35409109 PMCID: PMC8998884 DOI: 10.3390/ijms23073758] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 12/11/2022] Open
Abstract
The intestinal epithelium plays a key role in managing the relationship with the environment, the internal and external inputs, and their changes. One percent of the gut epithelium is represented by the enteroendocrine cells. Among the enteroendocrine cells, a group of specific cells characterized by the presence of yellow granules, the enterochromaffin cells, has been identified. These granules contain many secretion products. Studies showed that these cells are involved in gastrointestinal inflammatory conditions and hyperalgesia; their number increases in these conditions both in affected and not-affected zones of the gut. Moreover, they are involved in the preservation and modulation of the intestinal function and motility, and they sense metabolic-nutritional alterations. Sometimes, they are confused or mixed with other enteroendocrine cells, and it is difficult to define their activity. However, it is known that they change their functions during diseases; they increased in number, but their involvement is related mainly to some secretion products (serotonin, melatonin, substance P). The mechanisms linked to these alterations are not well investigated. Herein, we provide an up-to-date highlight of the main findings about these cells, from their discovery to today. We emphasized their origin, morphology, and their link with diet to better evaluate their role for preventing or treating metabolic disorders considering that these diseases are currently a public health burden.
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Affiliation(s)
- Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.F.); (L.F.); (M.G.); (G.F.)
- Interdipartimental University Center of Research “Adaption and Regeneration of Tissues and Organs—(ARTO)”, University of Brescia, 25123 Brescia, Italy
- Italian Society of Orofacial Pain (SISDO), 25123 Brescia, Italy
- Correspondence: ; Tel.: +39-0303-717-483
| | - Caterina Franco
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.F.); (L.F.); (M.G.); (G.F.)
| | - Lorenzo Franceschetti
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.F.); (L.F.); (M.G.); (G.F.)
| | - Marzia Gianò
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.F.); (L.F.); (M.G.); (G.F.)
| | - Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.F.); (L.F.); (M.G.); (G.F.)
- Interdipartimental University Center of Research “Adaption and Regeneration of Tissues and Organs—(ARTO)”, University of Brescia, 25123 Brescia, Italy
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16
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Tao E, Zhu Z, Hu C, Long G, Chen B, Guo R, Fang M, Jiang M. Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome. Front Cell Neurosci 2022; 16:837166. [PMID: 35370559 PMCID: PMC8964523 DOI: 10.3389/fncel.2022.837166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/09/2022] [Indexed: 12/04/2022] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, also known as disorders of the gut–brain interaction; however, the pathophysiology of IBS remains unclear. Early life stress (ELS) is one of the most common risk factors for IBS development. However, the molecular mechanisms by which ELS induces IBS remain unclear. Enterochromaffin cells (ECs), as a prime source of peripheral serotonin (5-HT), play a pivotal role in intestinal motility, secretion, proinflammatory and anti-inflammatory effects, and visceral sensation. ECs can sense various stimuli and microbiota metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids. ECs can sense the luminal environment and transmit signals to the brain via exogenous vagal and spinal nerve afferents. Increasing evidence suggests that an ECs-5-HT signaling imbalance plays a crucial role in the pathogenesis of ELS-induced IBS. A recent study using a maternal separation (MS) animal model mimicking ELS showed that MS induced expansion of intestinal stem cells and their differentiation toward secretory lineages, including ECs, leading to ECs hyperplasia, increased 5-HT production, and visceral hyperalgesia. This suggests that ELS-induced IBS may be associated with increased ECs-5-HT signaling. Furthermore, ECs are closely related to corticotropin-releasing hormone, mast cells, neuron growth factor, bile acids, and SCFAs, all of which contribute to the pathogenesis of IBS. Collectively, ECs may play a role in the pathogenesis of ELS-induced IBS. Therefore, this review summarizes the physiological function of ECs and focuses on their potential role in the pathogenesis of IBS based on clinical and pre-clinical evidence.
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Affiliation(s)
- Enfu Tao
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- Wenling Maternal and Child Health Care Hospital, Wenling, China
| | - Zhenya Zhu
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Chenmin Hu
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Gao Long
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Bo Chen
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Rui Guo
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Marong Fang
- Institute of Neuroscience and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mizu Jiang
- Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- *Correspondence: Mizu Jiang,
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17
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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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18
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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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19
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Metzler-Zebeli BU, Klinsoda J, Vötterl J, Sharma S, Koger S, Sener-Aydemir A. Short-, medium-, and long-chain fatty acid profiles and signaling is responsive to dietary phytase and lactic acid treatment of cereals along the gastrointestinal tract of growing pigs. J Anim Sci 2021; 99:6231813. [PMID: 33864091 DOI: 10.1093/jas/skab117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/15/2021] [Indexed: 12/18/2022] Open
Abstract
Dietary and microbially derived fatty acids (FA) play important roles in gut mucosal inflammatory signaling, barrier function, and oxidative stress response. Nevertheless, little information is available about gastrointestinal FA profiles and receptor distribution in pigs, especially for long-chain FA (LCFA). Therefore, the present pilot study aimed to (1) investigate the gastrointestinal FA profiles; (2) link the luminal FA profiles to the mucosal expression of genes related to FA sensing and signaling; and (3) assess potential dietary effects on gut and systemic lipid metabolism in pigs. Gut, liver, and serum samples were obtained from barrows (13.1 ± 2.3 kg) fed diets containing either phytase (500 phytase units/kg diet) or cereals treated with 2.5% lactic acid (LA; n = 8/diet) for 18 d. Results showed gut regional and diet-related differences in luminal FA profiles and mucosal receptor expression, whereas diet little affected hepatic expression levels and serum lipids. Short-chain fatty acids (SCFA) increased from stomach, jejunum, and ileum to the cecum (P < 0.05), whereas LCFA were higher in stomach, cecum, and colon than in jejunum and ileum (P < 0.05). LA-treated cereals enhanced cecal acetate and butyrate, whereas phytase and LA treated cereals decreased the LCFA by 35.9% and 14.4%, respectively (P < 0.05). Gut regional differences suggested stronger signaling via FFAR1 expression in the ileum, and via FFAR2, FFAR4, and HCAR1 expression in cecum and colon (P < 0.05). Expression of AMPK, FASN, PPARG, SREBP1, and SREBP2 was higher in the cecum and colon compared with the small intestine (P < 0.05), with stronger sensing via FASN and SREBP2. Phytase decreased expression of FFAR2 and FFAR4, whereas it increased that of FFAR3 and MCT1 in the cecum (P < 0.05). LA-treated cereals raised cecal expression of FFAR3 and HCAR1 (P < 0.05). Pearson's correlations (|r| > 0.35; P < 0.05) supported that FA receptor- and nuclear transcription factor-dependent pathways were involved in the mucosal regulation of gut incretin expression but differed across gut regions. In conclusion, results support regional differences in SCFA, lactate and LCFA sensing and absorption capacities in the small and large intestines of pigs. Effects of phytase and the LA-treated cereals on intestinal FA levels and signaling can be explained by differences in nutrient flows (e.g., phosphorus and carbohydrate fractions). This overview provides a solid basis for future intestinal FA sensing in pigs.
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Affiliation(s)
- Barbara U Metzler-Zebeli
- Unit Nutritional Physiology, Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Jutamat Klinsoda
- Unit Nutritional Physiology, Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.,Institute of Food Research and Product Development, University of Kasetsart, Bangkok, Thailand
| | - Julia Vötterl
- Unit Nutritional Physiology, Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Suchitra Sharma
- Institute of Animal Nutrition and Functional Plant Compounds, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Simone Koger
- Institute of Food Research and Product Development, University of Kasetsart, Bangkok, Thailand
| | - Arife Sener-Aydemir
- Institute of Food Research and Product Development, University of Kasetsart, Bangkok, Thailand
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20
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Wei L, Singh R, Ha SE, Martin AM, Jones LA, Jin B, Jorgensen BG, Zogg H, Chervo T, Gottfried-Blackmore A, Nguyen L, Habtezion A, Spencer NJ, Keating DJ, Sanders KM, Ro S. Serotonin Deficiency Is Associated With Delayed Gastric Emptying. Gastroenterology 2021; 160:2451-2466.e19. [PMID: 33662386 PMCID: PMC8532026 DOI: 10.1053/j.gastro.2021.02.060] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiologic roles of 5-HT deficiency in gastric motility in mice and humans. METHODS We developed an inducible, EC cell-specific Tph1CreERT2/+ mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG). RESULTS Tph1-tdTom mice showed EC cells that were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate. CONCLUSIONS The Tph1CreERT2/+ mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiologic mechanism of 5-HT deficiency in IG.
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Affiliation(s)
- Lai Wei
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Rajan Singh
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Se Eun Ha
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Alyce M Martin
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Lauren A Jones
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Byungchang Jin
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Brian G Jorgensen
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Hannah Zogg
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Tyler Chervo
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Andres Gottfried-Blackmore
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Linda Nguyen
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Nick J Spencer
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Damien J Keating
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Seungil Ro
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada.
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21
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Effect of Obesity on the Expression of Nutrient Receptors and Satiety Hormones in the Human Colon. Nutrients 2021; 13:nu13041271. [PMID: 33924402 PMCID: PMC8070384 DOI: 10.3390/nu13041271] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Receptors located on enteroendocrine cells (EECs) of the colon can detect nutrients in the lumen. These receptors regulate appetite through a variety of mechanisms, including hormonal and neuronal signals. We assessed the effect of obesity on the expression of these G-protein coupled receptors (GPCRs) and hormones at both mRNA and protein level. Methods: qPCR and immunohistochemistry were used to examine colonic tissue from cohorts of patients from the Netherlands (proximal and sigmoid tissue) and the United Kingdom (tissue from across the colon) and patients were grouped by body mass index (BMI) value (BMI < 25 and BMI ≥ 25). Results: The mRNA expression of the hormones/signaling molecules serotonin, glucagon, peptide YY (PYY), CCK and somatostatin were not significantly different between BMI groups. GPR40 mRNA expression was significantly increased in sigmoid colon samples in the BMI ≥ 25 group, but not proximal colon. GPR41, GPR109a, GPR43, GPR120, GPRC6A, and CaSR mRNA expression were unaltered between low and high BMI. At the protein level, serotonin and PYY containing cell numbers were similar in high and low BMI groups. Enterochromaffin cells (EC) showed high degree of co-expression with amino acid sensing receptor, CaSR while co-expression with PYY containing L-cells was limited, regardless of BMI. Conclusions: While expression of medium/long chain fatty acid receptor GPR40 was increased in the sigmoid colon of the high BMI group, expression of other nutrient sensing GPCRs, and expression profiles of EECs involved in peripheral mechanisms of appetite regulation were unchanged. Collectively, these data suggest that in human colonic tissue, EEC and nutrient-sensing receptor expression profiles are not affected despite changes to BMI.
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22
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Obermanns J, Krawczyk E, Juckel G, Emons B. Analysis of cytokine levels, T regulatory cells and serotonin content in patients with depression. Eur J Neurosci 2021; 53:3476-3489. [PMID: 33768559 DOI: 10.1111/ejn.15205] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 02/22/2021] [Accepted: 03/18/2021] [Indexed: 12/27/2022]
Abstract
Alterations in peripheral serotonin concentrations and an imbalanced immune system have been reported in patients with depression. Cytokines and T regulatory (Treg) cells may play an important role in the development of depression. This study investigates the levels of cytokines and Treg cells, as well as the concentration of serotonin (5-HT) in the blood of 89 patients suffering from depression and 89 healthy participants between two acquisitions. We investigated the state of health before (T1) and after (T2) psychological and pharmacological therapy. Both cytokine (IL-6, IL-10, TNF-α, and INF-γ) and 5-HT levels in the blood were measured by enzyme-linked immunosorbent assays. The levels of CD4+ CD25+ Treg cells were determined by flow cytometric analysis. Patients with depression showed significantly higher serum levels of IL-6 and INF-γ, no altered serum levels of IL-10 and TNF-α, and decreased platelet and serum 5-HT levels compared with healthy participants at the first acquisition. In addition, the symptoms of depression and anxiety, the TNF-α level, and the amount of CD4+ CD25+ cells in the blood were decreased from the first to the second acquisition. Further, a correlation between IL-6 and platelet 5-HT has been observed in patients. An imbalance of the immune system in patients with depression and an association of the serotonergic system and cytokines were observed. These results indicate that the development of depression might be related to several interacting proteins, including cytokines and 5-HT, and the treatment affects imbalances of these factors.
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Affiliation(s)
- Jasmin Obermanns
- Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
| | - Elena Krawczyk
- Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
| | - Georg Juckel
- Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
| | - Barbara Emons
- Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
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23
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The Intestinal Fatty Acid-Enteroendocrine Interplay, Emerging Roles for Olfactory Signaling and Serotonin Conjugates. Molecules 2021; 26:molecules26051416. [PMID: 33807994 PMCID: PMC7961910 DOI: 10.3390/molecules26051416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/19/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal enteroendocrine cells (EECs) respond to fatty acids from dietary and microbial origin by releasing neurotransmitters and hormones with various paracrine and endocrine functions. Much has become known about the underlying signaling mechanisms, including the involvement of G-protein coupled receptors (GPCRs), like free fatty acids receptors (FFARs). This review focusses on two more recently emerging research lines: the roles of odorant receptors (ORs), and those of fatty acid conjugates in gut. Odorant receptors belong to a large family of GPCRs with functional roles that only lately have shown to reach beyond the nasal-oral cavity. In the intestinal tract, ORs are expressed on serotonin (5-HT) and glucagon-like-peptide-1 (GLP-1) producing enterochromaffin and enteroendocrine L cells, respectively. There, they appear to function as chemosensors of microbiologically produced short-, and branched-chain fatty acids. Another mechanism of fatty acid signaling in the intestine occurs via their conjugates. Among them, conjugates of unsaturated long chain fatty acids and acetate with 5-HT, N-acyl serotonins have recently emerged as mediators with immune-modulatory effects. In this review, novel findings in mechanisms and molecular players involved in intestinal fatty acid biology are highlighted and their potential relevance for EEC-mediated signaling to the pancreas, immune system, and brain is discussed.
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24
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Kuramoto H, Koo A, Fothergill LJ, Hunne B, Yoshimura R, Kadowaki M, Furness JB. Morphologies and distributions of 5-HT containing enteroendocrine cells in the mouse large intestine. Cell Tissue Res 2021; 384:275-286. [PMID: 33547947 DOI: 10.1007/s00441-020-03322-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/12/2020] [Indexed: 12/18/2022]
Abstract
Serotonin (5-HT)-containing gastrointestinal endocrine cells contribute to regulation of numerous bodily functions, but whether these functions are related to differences in cell shape is not known. The current study identified morphologies and localization of subtypes of 5-HT-containing enteroendocrine cells in the mouse large intestine. 5-HT cells were most frequent in the proximal colon compared with cecum and distal colon. The large intestine harbored both open (O) cells, with apical processes that reached the lumen, and closed (C) cells, not contacting the lumen, classified into O1, O2, and O3 and C1, C2, and C3 cells, by the lengths of their basal processes. O1 and C1 cells, with basal processes sometimes longer that 100 µm, were most common in the distal colon. Their long basal processes ran against the inner surfaces of the mucosal epithelial cells and were strongly immunoreactive for 5-HT; these processes are ideally placed to communicate with the epithelium and to react to mechanical forces. O2 and C2 cells that had similar but shorter basal processes were also most common in the distal colon. O3 and C3 cells had no or very short basal processes. The O3 open type 5-HT cells were abundant in the proximal colon, particularly at the luminal surface, where they could release 5-HT into the lumen to act on luminal 5-HT receptors. Numerous O3 type 5-HT cells occurred in the lower (submucosal) region of the crypts in all segments and might release 5-HT to influence cell renewal in the crypt proliferative zones.
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Affiliation(s)
- Hirofumi Kuramoto
- Department of Applied Biology, Kyoto Institute of Technology, Kyoto, 606-8585, Japan
| | - Ada Koo
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Linda J Fothergill
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia
| | - Billie Hunne
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Ryoichi Yoshimura
- Department of Applied Biology, Kyoto Institute of Technology, Kyoto, 606-8585, Japan
| | - Makoto Kadowaki
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, 930-0194, Japan
| | - John B Furness
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia.
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25
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Nunez-Salces M, Li H, Feinle-Bisset C, Young RL, Page AJ. Nutrient-sensing components of the mouse stomach and the gastric ghrelin cell. Neurogastroenterol Motil 2020; 32:e13944. [PMID: 32666613 DOI: 10.1111/nmo.13944] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/22/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND The ability of the gut to detect nutrients is critical to the regulation of gut hormone secretion, food intake, and postprandial blood glucose control. Ingested nutrients are detected by specific gut chemosensors. However, knowledge of these chemosensors has primarily been derived from the intestine, while available information on gastric chemosensors is limited. This study aimed to investigate the nutrient-sensing repertoire of the mouse stomach with particular emphasis on ghrelin cells. METHODS Quantitative RT-PCR was used to determine mRNA levels of nutrient chemosensors (protein: G protein-coupled receptor 93 [GPR93], calcium-sensing receptor [CaSR], metabotropic glutamate receptor type 4 [mGluR4]; fatty acids: CD36, FFAR2&4; sweet/umami taste: T1R3), taste transduction components (TRPM5, GNAT2&3), and ghrelin and ghrelin-processing enzymes (PC1/3, ghrelin O-acyltransferase [GOAT]) in the gastric corpus and antrum of adult male C57BL/6 mice. Immunohistochemistry was performed to assess protein expression of chemosensors (GPR93, T1R3, CD36, and FFAR4) and their co-localization with ghrelin. KEY RESULTS Most nutrient chemosensors had higher mRNA levels in the antrum compared to the corpus, except for CD36, GNAT2, ghrelin, and GOAT. Similar regional distribution was observed at the protein level. At least 60% of ghrelin-positive cells expressed T1R3 and FFAR4, and over 80% expressed GPR93 and CD36. CONCLUSIONS AND INFERENCES The cellular mechanisms for the detection of nutrients are expressed in a region-specific manner in the mouse stomach and gastric ghrelin cells. These gastric nutrient chemosensors may play a role modulating gastrointestinal responses, such as the inhibition of ghrelin secretion following food intake.
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Affiliation(s)
- Maria Nunez-Salces
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Hui Li
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Christine Feinle-Bisset
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Richard L Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.,Intestinal Nutrient Sensing Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
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26
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Lin L, Feng B, Zhou R, Liu Y, Li L, Wang K, Yu Y, Liu C, Long X, Gu X, Li B, Wang X, Yang X, Cong Y, Zuo X, Li Y. Acute stress disrupts intestinal homeostasis via GDNF-RET. Cell Prolif 2020; 53:e12889. [PMID: 32808420 PMCID: PMC7574880 DOI: 10.1111/cpr.12889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/11/2020] [Accepted: 07/26/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D). MATERIALS AND METHODS GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro. RESULTS GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner. CONCLUSIONS We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.
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Affiliation(s)
- Lin Lin
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Bingcheng Feng
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Ruchen Zhou
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yi Liu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Lixiang Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Kairuo Wang
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yanbo Yu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Chao Liu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xin Long
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xiang Gu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Bing Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xiaojie Wang
- Department of dermatologyPeking University People’s HospitalBeijingChina
| | - Xiaoyun Yang
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yingzi Cong
- Department of Microbiology and ImmunologyUniversity of Texas Medical BranchGalvestonTexasUSA
| | - Xiuli Zuo
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yanqing Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
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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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28
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Engevik MA, Luck B, Visuthranukul C, Ihekweazu FD, Engevik AC, Shi Z, Danhof HA, Chang-Graham AL, Hall A, Endres BT, Haidacher SJ, Horvath TD, Haag AM, Devaraj S, Garey KW, Britton RA, Hyser JM, Shroyer NF, Versalovic J. Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut-Brain Axis. Cell Mol Gastroenterol Hepatol 2020; 11:221-248. [PMID: 32795610 PMCID: PMC7683275 DOI: 10.1016/j.jcmgh.2020.08.002] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. METHODS Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT-receptor expression in the brain, and 5-HT-receptor-dependent behavior was evaluated using the marble burying test. RESULTS B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium-secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT-receptor 2a in B dentium-treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT-receptor 2a. CONCLUSIONS These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior.
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Affiliation(s)
- Melinda A Engevik
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Berkley Luck
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Chonnikant Visuthranukul
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas; Department of Pediatrics, Pediatric Nutrition Special Task Force for Activating Research (STAR), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Faith D Ihekweazu
- Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Amy C Engevik
- Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville Tennessee
| | - Zhongcheng Shi
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Heather A Danhof
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | | | - Anne Hall
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas; Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Bradley T Endres
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas
| | - Sigmund J Haidacher
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Thomas D Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Anthony M Haag
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Sridevi Devaraj
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas
| | - Kevin W Garey
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas
| | - Robert A Britton
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Joseph M Hyser
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Noah F Shroyer
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - James Versalovic
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas.
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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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30
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Kumar J, Rani K, Datt C. Molecular link between dietary fibre, gut microbiota and health. Mol Biol Rep 2020; 47:6229-6237. [PMID: 32623619 DOI: 10.1007/s11033-020-05611-3] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/20/2020] [Indexed: 12/17/2022]
Abstract
Natural polysaccharides cellulose, hemicelluloses, inulin etc., galactooligosaccharides (GOS), and fructooligosaccharides (FOS) play a significant role in the improvement of gut microbiota balance and human health. These polysaccharides prevent pathogen adhesion that stimulates the immune system and gut barrier function by servicing as fermentable substrates for the gut microbiota. The gut microbiota plays a key role in the fermentation of non-digestible carbohydrates (NDCs) fibres. Moreover, the gut microbiota is responsible for the production of short-chain fatty acids (SCFAs) like acetate, propionate and butyrate. Acetate is the most abundant and it is used by many gut commensals to produce propionate and butyrate in a growth-promoting cross-feeding process. The dietary fibres affect the gut microbiome and play vital roles in signaling pathways. The SCFAs, acetate, butyrate, and propionate have been reported to affect on metabolic activities at the molecular level. Acetate affects the metabolic pathway through the G protein-coupled receptor (GPCR) and free fatty acid receptor 2 (FFAR2/GPR43) while butyrate and propionate transactivate the peroxisome proliferator-activated receptorsγ (PPARγ/NR1C3) and regulate the PPARγ target gene Angptl4 in colonic cells of the gut. The FFAR2 signaling pathway regulates the insulin-stimulated lipid accumulation in adipocytes and inflammation, however peptide tyrosine-tyrosine (PPY) and glucagon-like peptide 1 regulates appetite. The NDCs via gut microbiota dependent pathway regulate glucose homeostasis, gut integrity and hormone by GPCR, NF-kB, and AMPK-dependent processes.
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Affiliation(s)
- Jitendra Kumar
- ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India.
| | - Kavita Rani
- ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Chander Datt
- Division of Animal Nutrition, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
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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: 128] [Impact Index Per Article: 25.6] [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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Hao MM, Fung C, Boesmans W, Lowette K, Tack J, Vanden Berghe P. Development of the intrinsic innervation of the small bowel mucosa and villi. Am J Physiol Gastrointest Liver Physiol 2020; 318:G53-G65. [PMID: 31682159 DOI: 10.1152/ajpgi.00264.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Detection of nutritional and noxious food components in the gut is a crucial component of gastrointestinal function. Contents in the gut lumen interact with enteroendocrine cells dispersed throughout the gut epithelium. Enteroendocrine cells release many different hormones, neuropeptides, and neurotransmitters that communicate either directly or indirectly with the central nervous system and the enteric nervous system, a network of neurons and glia located within the gut wall. Several populations of enteric neurons extend processes that innervate the gastrointestinal lamina propria; however, how these processes develop and begin to transmit information from the mucosa is not fully understood. In this study, we found that Tuj1-immunoreactive neurites begin to project out of the myenteric plexus at embryonic day (E)13.5 in the mouse small intestine, even before the formation of villi. Using live calcium imaging, we discovered that neurites were capable of transmitting electrical information from stimulated villi to the plexus by E15.5. In unpeeled gut preparations where all layers were left intact, we also mimicked the basolateral release of 5-HT from enteroendocrine cells, which triggered responses in myenteric cell bodies at postnatal day (P)0. Altogether, our results show that enteric neurons extend neurites out of the myenteric plexus early during mouse enteric nervous system development, innervating the gastrointestinal mucosa, even before villus formation in mice of either sex. Neurites are already able to conduct electrical information at E15.5, and responses to 5-HT develop postnatally.NEW & NOTEWORTHY How enteric neurons project into the gut mucosa and begin to communicate with the epithelium during development is not known. Our study shows that enteric neurites project into the lamina propria as early as E13.5 in the mouse, before development of the submucous plexus and before formation of intestinal villi. These neurites are capable of transmitting electrical signals back to their cell bodies by E15.5 and respond to serotonin applied to neurite terminals by birth.
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Affiliation(s)
- Marlene M Hao
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium.,Department of Anatomy and Neuroscience, the University of Melbourne, Australia
| | - Candice Fung
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
| | - Werend Boesmans
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium.,Department of Pathology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands.,Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - Katrien Lowette
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
| | - Jan Tack
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
| | - Pieter Vanden Berghe
- Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
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33
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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: 62] [Impact Index Per Article: 10.3] [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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Mucosal Monosaccharide Transporter Expression in Newborns With Jejunoileal Atresia and Along the Adult Intestine. J Pediatr Gastroenterol Nutr 2019; 69:611-618. [PMID: 31261244 DOI: 10.1097/mpg.0000000000002425] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVES In newborn rodents, intestinal maturation involves delayed fructose transporter GLUT5 expression until weaning. In jejunoileal atresia (JIA), distal intestinal segments lack exposure to amniotic fluid-containing carbohydrates. We assessed in human newborns, the impact of intestinal maturation and obstruction on mucosal monosaccharide transporter expression. METHODS Samples were obtained from 10 newborns operated for small intestinal atresia and from 17 adults undergoing gastroduodenoscopy and/or ileocolonoscopy. mRNA expression of the transporters SGLT1, GLUT1, GLUT2, GLUT5, and GLUT7 was measured in neonate samples proximal and distal of the atresia as well as in adult duodenum, ileum, and colon. Protein expression and localization was assessed using immunofluorescence. RESULTS Although mRNA expression of monosaccharide transporters did not significantly differ between newborn and adult samples, luminal fructose transporter GLUT5 protein was absent in 0- to 4-day-old neonates, but expressed in adults. The mRNA expression of the 5 tested monosaccharide transporters was unchanged distal from the JIA relative to proximal. Similarly, luminal sodium-dependent glucose transporter SGLT1 and basolateral GLUT2 were expressed proximal and distal to JIA as visualized by immunofluorescence staining. With the exception of glucose transporter GLUT1 that showed highest expression levels in colon, all investigated hexose transporters showed strongest expression in duodenum, lower levels in ileum and lowest in colon. CONCLUSIONS Human newborns lack small intestinal fructose transporter GLUT5 protein expression and small intestinal atresia does not affect the expression of hexose transporters.
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35
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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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36
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Abstract
The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin.
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37
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Use of a microelectrode array to record extracellular pacemaker potentials from the gastrointestinal tracts of the ICR mouse and house musk shrew (Suncus murinus). Cell Calcium 2019; 80:175-188. [DOI: 10.1016/j.ceca.2019.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/23/2019] [Accepted: 05/08/2019] [Indexed: 12/17/2022]
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38
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Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JHR, Harb G, Poh YC, Sintov E, Gürtler M, Pagliuca FW, Peterson QP, Melton DA. Charting cellular identity during human in vitro β-cell differentiation. Nature 2019; 569:368-373. [PMID: 31068696 DOI: 10.1038/s41586-019-1168-5] [Citation(s) in RCA: 355] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 04/02/2019] [Indexed: 02/08/2023]
Abstract
In vitro differentiation of human stem cells can produce pancreatic β-cells; the loss of this insulin-secreting cell type underlies type 1 diabetes. Here, as a step towards understanding this differentiation process, we report the transcriptional profiling of more than 100,000 human cells undergoing in vitro β-cell differentiation, and describe the cells that emerged. We resolve populations that correspond to β-cells, α-like poly-hormonal cells, non-endocrine cells that resemble pancreatic exocrine cells and a previously unreported population that resembles enterochromaffin cells. We show that endocrine cells maintain their identity in culture in the absence of exogenous growth factors, and that changes in gene expression associated with in vivo β-cell maturation are recapitulated in vitro. We implement a scalable re-aggregation technique to deplete non-endocrine cells and identify CD49a (also known as ITGA1) as a surface marker of the β-cell population, which allows magnetic sorting to a purity of 80%. Finally, we use a high-resolution sequencing time course to characterize gene-expression dynamics during the induction of human pancreatic endocrine cells, from which we develop a lineage model of in vitro β-cell differentiation. This study provides a perspective on human stem-cell differentiation, and will guide future endeavours that focus on the differentiation of pancreatic islet cells, and their applications in regenerative medicine.
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Affiliation(s)
- Adrian Veres
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.,Harvard Systems Biology PhD Program, Harvard University, Cambridge, MA, USA
| | - Aubrey L Faust
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Henry L Bushnell
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Elise N Engquist
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | | | | | | | - Elad Sintov
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | | | | | - Quinn P Peterson
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Douglas A Melton
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. .,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. .,Howard Hughes Medical Institute, Chevy Chase, MD, USA.
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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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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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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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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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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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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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45
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Tough IR, Forbes S, Cox HM. Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate. Neurogastroenterol Motil 2018; 30:e13454. [PMID: 30136343 PMCID: PMC6282569 DOI: 10.1111/nmo.13454] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/20/2018] [Accepted: 07/25/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Propionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein-coupled receptors (GPCRs) are expressed by enteroendocrine L cells that contain anorectic peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal responses utilizing selective ligands including an FFA3 antagonist, in mouse and human colonic mucosa. METHODS Vectorial ion transport was measured in native colonic preparations from normal mouse and human colon with intact submucosal innervation. Endogenous fecal pellet propulsion was monitored in colons isolated from wild-type (WT) and PYY-/- mice. KEY RESULTS FFA2 and FFA3 signaling differed significantly. FFA2 agonism involved endogenous L cell-derived PYY and was glucose dependent, while FFA3 agonism was independent of PYY and glucose, but required submucosal enteric neurons for activity. Tonic FFA3 activity was observed in mouse and human colon mucosa. Apical propionate responses were a combination of FFA2-PYY mediation and FFA3 neuronal GLP-1- and CGRP-dependent signaling in mouse ascending colon mucosa. Propionate also slowed WT and PYY-/- colonic transit, and this effect was blocked by a GLP-1 receptor antagonist. CONCLUSIONS & INFERENCES We conclude that luminal propionate costimulates FFA2 and FFA3 pathways, reducing anion secretion and slowing colonic motility; FFA2 via PYY mediation and FFA3 signaling by activation of enteric sensory neurons.
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Affiliation(s)
- Iain R. Tough
- King's College LondonWolfson Centre for Age‐Related Diseases, Institute of Psychiatry, Psychology & NeuroscienceLondonUK
| | - Sarah Forbes
- King's College LondonWolfson Centre for Age‐Related Diseases, Institute of Psychiatry, Psychology & NeuroscienceLondonUK
| | - Helen M. Cox
- King's College LondonWolfson Centre for Age‐Related Diseases, Institute of Psychiatry, Psychology & NeuroscienceLondonUK
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Fothergill LJ, Furness JB. Diversity of enteroendocrine cells investigated at cellular and subcellular levels: the need for a new classification scheme. Histochem Cell Biol 2018; 150:693-702. [PMID: 30357510 DOI: 10.1007/s00418-018-1746-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2018] [Indexed: 02/07/2023]
Abstract
Enteroendocrine cells were historically classified by a letter code, each linked to a single hormone, deduced to be the only hormone produced by the cell. One type, the L cell, was recognised to store and secrete two products, peptide YY (PYY) and glucagon-related peptides. Many other exceptions to the one-cell one-hormone classifications have been reported over the last 40 years or so, and yet the one-hormone dogma has persisted. In the last 6 years, a plethora of data has appeared that makes the concept unviable. Here, we describe the evidence that multiple hormone transcripts and their products reside in single cells and evidence that the hormones are often, but not always, processed into separate storage vesicles. It has become clear that most enteroendocrine cells contain multiple hormones. For example, most secretin cells contain 5-hydroxytryptamine (5-HT), and in mouse many of these also contain cholecystokinin (CCK). Furthermore, CCK cells also commonly store ghrelin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), neurotensin, and PYY. Several hormones, for example, secretin and 5-HT, are in separate storage vesicles at a subcellular level. Hormone patterns can differ considerably between species. Another complication is that relative levels of expression vary substantially. This means that data are significantly influenced by the sensitivities of detection techniques. For example, a hormone that can be detected in storage vesicles by super-resolution microscopy may not be above threshold for detection by conventional fluorescence microscopy. New nomenclature for cell clusters with common attributes will need to be devised and old classifications abandoned.
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Affiliation(s)
- Linda J Fothergill
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia.
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Lu VB, Gribble FM, Reimann F. Free Fatty Acid Receptors in Enteroendocrine Cells. Endocrinology 2018; 159:2826-2835. [PMID: 29688303 DOI: 10.1210/en.2018-00261] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 04/17/2018] [Indexed: 02/02/2023]
Abstract
Free fatty acid receptors (FFAs) are highly enriched in enteroendocrine cells providing pathways to link dietary fats and microbially generated short-chain fatty acids (SCFAs) to the secretion of a variety of gut hormones. FFA1 and FFA4 are receptors for long-chain fatty acids that have been linked to the elevation of plasma gut hormones after fat ingestion. FFA2 and FFA3 are receptors for SCFA, which are generated at high concentrations by microbial fermentation of dietary fiber and have also been implicated in enhancement of gut hormone secretion. FFAs are candidate drug targets for increasing the secretion of intestinal hormones such as glucagon-like peptide-1 and peptide YY as potential new treatments for type 2 diabetes and obesity. This review will examine aspects of intestinal physiology and pharmacology related to the function of FFAs in enteroendocrine cells.
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Affiliation(s)
- Van B Lu
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Fiona M Gribble
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Frank Reimann
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
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48
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Lund ML, Egerod KL, Engelstoft MS, Dmytriyeva O, Theodorsson E, Patel BA, Schwartz TW. Enterochromaffin 5-HT cells - A major target for GLP-1 and gut microbial metabolites. Mol Metab 2018; 11:70-83. [PMID: 29576437 PMCID: PMC6001397 DOI: 10.1016/j.molmet.2018.03.004] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 02/23/2018] [Accepted: 03/06/2018] [Indexed: 12/28/2022] Open
Abstract
Objectives 5-HT storing enterochromaffin (EC) cells are believed to respond to nutrient and gut microbial components, and 5-HT receptor-expressing afferent vagal neurons have been described to be the major sensors of nutrients in the GI-tract. However, the molecular mechanism through which EC cells sense nutrients and gut microbiota is still unclear. Methods and results TPH1, the 5-HT generating enzyme, and chromogranin A, an acidic protein responsible for secretory granule storage of 5-HT, were highly enriched in FACS-purified EC cells from both small intestine and colon using a 5-HT antibody-based method. Surprisingly, EC cells from the small intestine did not express GPCR sensors for lipid and protein metabolites, such as FFAR1, GPR119, GPBAR1 (TGR5), CaSR, and GPR142, in contrast to the neighboring GLP-1 storing enteroendocrine cell. However, the GLP-1 receptor was particularly highly expressed and enriched in EC cells as judged both by qPCR and by immunohistochemistry using a receptor antibody. GLP-1 receptor agonists robustly stimulated 5-HT secretion from intestinal preparations using both HPLC and a specific amperometric method. Colonic EC cells expressed many different types of known and potential GPCR sensors of microbial metabolites including three receptors for SCFAs, i.e. FFAR2, OLF78, and OLF558 and receptors for aromatic acids, GPR35; secondary bile acids GPBAR1; and acyl-amides and lactate, GPR132. Conclusion Nutrient metabolites apparently do not stimulate EC cells of the small intestine directly but through a paracrine mechanism involving GLP-1 secreted from neighboring enteroendocrine cells. In contrast, colonic EC cells are able to sense a multitude of different metabolites generated by the gut microbiota as well as gut hormones, including GLP-1.
Pure intestinal 5-HT cells are obtained through antibody-based FACS sorting. Small intestinal 5-HT cells do not express sensors for nutrient metabolites. Colonic 5-HT cells express multiple types of receptors for gut microbial metabolites. GLP-1 stimulates 5-HT release from ex vivo intestinal preparations. GLP-1 and 5-HT act in series and synergy to control GI-tract and metabolism.
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Affiliation(s)
- Mari L Lund
- Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark
| | - Kristoffer L Egerod
- Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark
| | - Maja S Engelstoft
- Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark
| | - Oksana Dmytriyeva
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Laboratory of Neural Plasticity, Institute of Neuroscience, University of Copenhagen, Copenhagen, Denmark
| | - Elvar Theodorsson
- Department of Clinical and Experimental Medicine, Linköping University, Sweden
| | - Bhavik A Patel
- School of Pharmacy and Biomolecular Sciences, University of Brighton, UK
| | - Thue W Schwartz
- Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department for Biomedical Research, Faculty of Health Sciences, University of Copenhagen, Denmark.
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Martin AM, Lumsden AL, Young RL, Jessup CF, Spencer NJ, Keating DJ. Regional differences in nutrient-induced secretion of gut serotonin. Physiol Rep 2017; 5:5/6/e13199. [PMID: 28320893 PMCID: PMC5371566 DOI: 10.14814/phy2.13199] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/15/2017] [Accepted: 02/16/2017] [Indexed: 12/17/2022] Open
Abstract
Enterochromaffin (EC) cells located in the gastrointestinal (GI) tract provide the vast majority of serotonin (5-HT) in the body and constitute half of all enteroendocrine cells. EC cells respond to an array of stimuli, including various ingested nutrients. Ensuing 5-HT release from these cells plays a diverse role in regulating gut motility as well as other important responses to nutrient ingestion such as glucose absorption and fluid balance. Recent data also highlight the role of peripheral 5-HT in various pathways related to metabolic control. Details related to the manner by which EC cells respond to ingested nutrients are scarce and as that the nutrient environment changes along the length of the gut, it is unknown whether the response of EC cells to nutrients is dependent on their GI location. The aim of the present study was to identify whether regional differences in nutrient sensing capability exist in mouse EC cells. We isolated mouse EC cells from duodenum and colon to demonstrate differential responses to sugars depending on location. Measurements of intracellular calcium concentration and 5-HT secretion demonstrated that colonic EC cells are more sensitive to glucose, while duodenal EC cells are more sensitive to fructose and sucrose. Short-chain fatty acids (SCFAs), which are predominantly synthesized by intestinal bacteria, have been previously associated with an increase in circulating 5-HT; however, we find that SCFAs do not acutely stimulate EC cell 5-HT release. Thus, we highlight that EC cell physiology is dictated by regional location within the GI tract, and identify differences in the regional responsiveness of EC cells to dietary sugars.
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Affiliation(s)
- Alyce M Martin
- Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, Australia
| | - Amanda L Lumsden
- Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, Australia
| | - Richard L Young
- South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Claire F Jessup
- Department of Anatomy and Histology and Centre for Neuroscience, Flinders University, Adelaide, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Nick J Spencer
- Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, Australia
| | - Damien J Keating
- Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, Australia .,South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
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50
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Diwakarla S, Fothergill LJ, Fakhry J, Callaghan B, Furness JB. Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 2017; 29:10.1111/nmo.13101. [PMID: 28485065 PMCID: PMC5475263 DOI: 10.1111/nmo.13101] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 04/04/2017] [Indexed: 12/20/2022]
Abstract
Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells was due to their content of the reactive aromatic amine, 5-hydroxytryptamine (5-HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5-HT, cholecystokinin and 5-HT, and all three of secretin, cholecystokinin, and 5-HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5-HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles.
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Affiliation(s)
- Shanti Diwakarla
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Linda J Fothergill
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
| | - Josiane Fakhry
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
| | - Brid Callaghan
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
| | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia
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