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Overton E, Emelyanova A, Bunik VI. Thiamine, gastrointestinal beriberi and acetylcholine signaling. Front Nutr 2025; 12:1541054. [PMID: 40271433 PMCID: PMC12014454 DOI: 10.3389/fnut.2025.1541054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/20/2025] [Indexed: 04/25/2025] Open
Abstract
Research has highlighted numerous detrimental consequences of thiamine deficiency on digestive function. These range from impaired gastric and intestinal motility to aberrant changes in pancreatic exocrine function, gastric acidity and disturbances in gut barrier integrity and inflammation. Thiamine and its pharmacological forms, as a primary or adjunctive therapy, have been shown to improve symptoms such as nausea, constipation, dysphagia and intestinal dysmotility, in both humans and animals. This review aims to explore molecular mechanisms underlying the therapeutic action of thiamine in gastrointestinal dysfunction. Our analysis demonstrates that thiamine insufficiency restricted to the gastrointestinal system, i.e., lacking well-known symptoms of dry and wet beriberi, may arise through (i) a disbalance between the nutrient influx and efflux in the gastrointestinal system due to increased demands of thiamine by the organism; (ii) direct exposure of the gastrointestinal system to oral drugs and gut microbiome, targeting thiamine-dependent metabolism in the gastrointestinal system in the first line; (iii) the involvement of thiamine in acetylcholine (ACh) signaling and cholinergic activity in the enteric nervous system and non-neuronal cells of the gut and pancreas, employing both the coenzyme and non-coenzyme actions of thiamine. The coenzyme action relies on the requirement of the thiamine coenzyme form - thiamine diphosphate - for the production of energy and acetylcholine (ACh). The non-coenzyme action involves participation of thiamine and/or derivatives, including thiamine triphosphate, in the regulation of ACh synaptic function, consistent with the early data on thiamine as a co-mediator of ACh in neuromuscular synapses, and in allosteric action on metabolic enzymes. By examining the available evidence with a focus on the gastrointestinal system, we deepen the understanding of thiamine's contribution to overall gastrointestinal health, highlighting important implications of thiamine-dependent mechanisms in functional gastrointestinal disorders.
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Affiliation(s)
| | - Alina Emelyanova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Victoria I. Bunik
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
- Department of Biochemistry, Sechenov University, Moscow, Russia
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Zhao M, Lei Y, Wang M, Chen Y, Hou S, Dai X, Gao D, Liu Y, Mazet B, Sha L. Carbon monoxide produced by HO-1 upregulation is the main factor behind the abnormal motility seen in experimental ulcerative colitis in mice. Am J Physiol Gastrointest Liver Physiol 2025; 328:G311-G322. [PMID: 39925143 DOI: 10.1152/ajpgi.00179.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/11/2023] [Accepted: 01/15/2025] [Indexed: 02/11/2025]
Abstract
The colonic motility is altered in patients with ulcerative colitis (UC), but the mechanism is not clear. Carbon monoxide (CO) is the molecule regulating the resting membrane potential (RMP) gradient across colonic smooth muscle wall. Changes in RMP will affect the contractility of smooth muscle. In this study, we investigated the altered colonic motility in dextran sodium sulfate-induced UC mice and the role of CO. The results showed that in the UC group, the frequency of spontaneous colonic contractions was increased while the AUC was decreased compared with the control group. HO-1-, but not HO-2-, positive cells were increased in the colonic smooth muscle wall of the UC group. These HO-1-positive cells were mainly in the myenteric plexus and PGP9.5 positive, suggesting neuronal overproduction of CO. The RMP of circular smooth muscle cells (SMCs) in the colon of UC group was hyperpolarized compared with that of control group. In control group, application of CORM-3, a CO donor, altered colonic spontaneous contractions by increasing their frequency and decreasing amplitude. In the UC group, ZnPPIX, a HO-1 inhibitor, reduced the frequency and increased the amplitude. CORM-3 hyperpolarized the RMP of colonic SMCs and abolished its gradient in the control group, while ZnPPIX depolarized the RMP of colonic SMCs and restored its gradient in the UC group. CO produced by HO-1 upregulation is the main factor behind the altered colonic motility seen in UC mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility.NEW & NOTEWORTHY Carbon monoxide (CO) produced by HO-1 upregulation in myenteric plexus is the main factor that abolishes the RMP gradient across colonic muscle wall causing the altered colonic motility seen in experimental ulcerative colitis (UC) mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility.
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MESH Headings
- Animals
- Colitis, Ulcerative/physiopathology
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/enzymology
- Carbon Monoxide/metabolism
- Gastrointestinal Motility/drug effects
- Gastrointestinal Motility/physiology
- Up-Regulation
- Colon/physiopathology
- Colon/drug effects
- Colon/metabolism
- Colon/innervation
- Mice
- Male
- Heme Oxygenase-1/metabolism
- Muscle, Smooth/metabolism
- Muscle, Smooth/physiopathology
- Muscle, Smooth/drug effects
- Dextran Sulfate
- Disease Models, Animal
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Mice, Inbred C57BL
- Muscle Contraction/drug effects
- Myenteric Plexus/metabolism
- Organometallic Compounds/pharmacology
- Membrane Proteins
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Affiliation(s)
- Mengchao Zhao
- Department of Pharmacy, General Hospital of Ningxia Medical University, Yinchuan, China
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Yaru Lei
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Mengyuan Wang
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Yixin Chen
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Shaozhang Hou
- Department of Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xinyuan Dai
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Di Gao
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Yudan Liu
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Bruno Mazet
- Institute of NeuroPhysiopathology (INP)-UMR CNRS 7051, Aix-Marseille University, Marseilles, France
| | - Lei Sha
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
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Wang Z, Liu C, Hu K, Zuo M, Tian Z, Wei Y, Zhou Q, Li Q. Postoperative delayed gastric emptying: may gut microbiota play a role? Front Cell Infect Microbiol 2024; 14:1449530. [PMID: 39193506 PMCID: PMC11347441 DOI: 10.3389/fcimb.2024.1449530] [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] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 07/22/2024] [Indexed: 08/29/2024] Open
Abstract
Postoperative delayed gastric emptying is a prevalent complication following surgical procedures, imposing heavy physical and financial burdens on patients. However, current treatment options remain suboptimal. In recent years, an increasing number of studies have highlighted that the gut microbiota and its metabolites are closely associated with postoperative complications. Various factors can disrupt the gut microbiome after surgery. This review discusses the potential mechanisms by which the gut microbiota and their metabolites may contribute to the pathogenesis of postoperative delayed gastric emptying. However, the current knowledge base is limited in terms of fully understanding the exact mechanisms involved. It is therefore evident that further research is required to fully elucidate the role of the gut microbiome in postoperative delayed gastric emptying, with the aim of uncovering new possibilities for preventive measures and therapeutic treatments.
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Affiliation(s)
- Zhiyi Wang
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
- Department of Oncology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chuanbo Liu
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Kaiwen Hu
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Minghuan Zuo
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Zhen Tian
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Yue Wei
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Qin Zhou
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Quanwang Li
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
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Jeffrey MP, Saleem L, MacPherson CW, Tompkins TA, Clarke ST, Green-Johnson JM. A Lacticaseibacillus rhamnosus secretome induces immunoregulatory transcriptional, functional and immunometabolic signatures in human THP-1 monocytes. Sci Rep 2024; 14:8379. [PMID: 38600116 PMCID: PMC11006683 DOI: 10.1038/s41598-024-56420-8] [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: 12/22/2023] [Accepted: 03/06/2024] [Indexed: 04/12/2024] Open
Abstract
Macrophage responses to activation are fluid and dynamic in their ability to respond appropriately to challenges, a role integral to host defence. While bacteria can influence macrophage differentiation and polarization into pro-inflammatory and alternatively activated phenotypes through direct interactions, many questions surround indirect communication mechanisms mediated through secretomes derived from gut bacteria, such as lactobacilli. We examined effects of secretome-mediated conditioning on THP-1 human monocytes, focusing on the ability of the Lacticaseibacillus rhamnosus R0011 secretome (LrS) to drive macrophage differentiation and polarization and prime immune responses to subsequent challenge with lipopolysaccharide (LPS). Genome-wide transcriptional profiling revealed increased M2-associated gene transcription in response to LrS conditioning in THP-1 cells. Cytokine and chemokine profiling confirmed these results, indicating increased M2-associated chemokine and cytokine production (IL-1Ra, IL-10). These cells had increased cell-surface marker expression of CD11b, CD86, and CX3CR1, coupled with reduced expression of the M1 macrophage-associated marker CD64. Mitochondrial substrate utilization assays indicated diminished reliance on glycolytic substrates, coupled with increased utilization of citric acid cycle intermediates, characteristics of functional M2 activity. LPS challenge of LrS-conditioned THP-1s revealed heightened responsiveness, indicative of innate immune priming. Resting stage THP-1 macrophages co-conditioned with LrS and retinoic acid also displayed an immunoregulatory phenotype with expression of CD83, CD11c and CD103 and production of regulatory cytokines. Secretome-mediated conditioning of macrophages into an immunoregulatory phenotype is an uncharacterized and potentially important route through which lactic acid bacteria and the gut microbiota may train and shape innate immunity at the gut-mucosal interface.
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Affiliation(s)
- Michael P Jeffrey
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Tech University, Oshawa, ON, L1G 0C5, Canada
| | - Lin Saleem
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Tech University, Oshawa, ON, L1G 0C5, Canada
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, N1G 5C9, Canada
| | - Chad W MacPherson
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada
| | | | - Sandra T Clarke
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Tech University, Oshawa, ON, L1G 0C5, Canada
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, N1G 5C9, Canada
| | - Julia M Green-Johnson
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Tech University, Oshawa, ON, L1G 0C5, Canada.
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Selvakumar B, Sekar P, Samsudin AR. Intestinal macrophages in pathogenesis and treatment of gut leakage: current strategies and future perspectives. J Leukoc Biol 2024; 115:607-619. [PMID: 38198217 DOI: 10.1093/jleuko/qiad165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 11/13/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024] Open
Abstract
Macrophages play key roles in tissue homeostasis, defense, disease, and repair. Macrophages are highly plastic and exhibit distinct functional phenotypes based on micro-environmental stimuli. In spite of several advancements in understanding macrophage biology and their different functional phenotypes in various physiological and pathological conditions, currently available treatment strategies targeting macrophages are limited. Macrophages' high plasticity and diverse functional roles-including tissue injury and wound healing mechanisms-mark them as potential targets to mine for efficient therapeutics to treat diseases. Despite mounting evidence on association of gut leakage with several extraintestinal diseases, there is no targeted standard therapy to treat gut leakage. Therefore, there is an urgent need to develop therapeutic strategies to treat this condition. Macrophages are the cells that play the largest role in interacting with the gut microbiota in the intestinal compartment and exert their intended functions in injury and repair mechanisms. In this review, we have summarized the current knowledge on the origins and phenotypes of macrophages. The specific role of macrophages in intestinal barrier function, their role in tissue repair mechanisms, and their association with gut microbiota are discussed. In addition, currently available therapies and the putative tissue repair mediators of macrophages for treating microbiota dysbiosis induced gut leakage are also discussed. The overall aim of this review is to convey the intense need to screen for microbiota induced macrophage-released prorepair mediators, which could lead to the identification of potential candidates that could be developed for treating the leaky gut and associated diseases.
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Affiliation(s)
- Balachandar Selvakumar
- Department of Microbiota, Research Institute for Medical and Health Sciences, College of Medicine, University of Sharjah, University City Road, Sharjah, 27272, United Arab Emirates
| | - Priyadharshini Sekar
- Department of Microbiota, Research Institute for Medical and Health Sciences, College of Medicine, University of Sharjah, University City Road, Sharjah, 27272, United Arab Emirates
| | - A Rani Samsudin
- Department of Microbiota, Research Institute for Medical and Health Sciences, College of Medicine, University of Sharjah, University City Road, Sharjah, 27272, United Arab Emirates
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, University City Road, Sharjah, 27272, United Arab Emirates
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Uppaluri S, Jain MA, Ali H, Shingala J, Amin D, Ajwani T, Fatima I, Patel N, Kaka N, Sethi Y, Kapoor N. Pathogenesis and management of diabetic gastroparesis: An updated clinically oriented review. Diabetes Metab Syndr 2024; 18:102994. [PMID: 38579489 DOI: 10.1016/j.dsx.2024.102994] [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: 09/27/2023] [Revised: 02/25/2024] [Accepted: 03/20/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND AND AIMS Diabetic gastroparesis (DGp) is a common and preventable complication of uncontrolled diabetes mellitus (D.M.) and significantly affects the Quality of Life of patients. Diagnosis and management present as a clinical challenge due to the disease's complexity and limited effective therapeutic options. This review aims to comprehensively outline the pathogenesis, diagnosis, and management of diabetic gastroparesis, evaluating evolving approaches to guide clinicians and provide future recommendations. METHODS A literature review was conducted on scholarly databases of PubMed, Google Scholar, Scopus and Web of Science encompassing published articles, gray literature and relevant clinical guidelines. Data were synthesized and analyzed to provide a comprehensive overview of diabetic gastroparesis, focusing on pathogenesis, diagnosis, and management. RESULTS The review intricately explores the pathogenesis contributing to diabetic gastroparesis, emphasizing autonomic neuropathy, oxidative stress, inflammation, hormonal dysregulation, microbiota alterations, and gastrointestinal neuropathy. Primary management strategies are underscored, including lifestyle modifications, symptom relief, and glycemic control. The discussion encompasses pharmacological and surgical options, highlighting the importance of a multidisciplinary approach involving various healthcare professionals for comprehensive patient care. CONCLUSION This review offers a thorough understanding of pathogenesis, diagnosis, and management of diabetic gastroparesis, underlining evolving approaches for clinicians. A multidisciplinary approach is crucial to address both the physical and mental health aspects of diabetes and its complications.
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Affiliation(s)
- Srikar Uppaluri
- Kamineni Academy of Medical Sciences and Research Center, Hyderabad, India; PearResearch, Dehradun, India.
| | - Manisha Ashok Jain
- PearResearch, Dehradun, India; Shri Bhausaheb Hire Govt. Medical College, Dhule, Maharashtra, India.
| | - Hira Ali
- PearResearch, Dehradun, India; Chifeng University Medical College, China.
| | - Jay Shingala
- PearResearch, Dehradun, India; B.J. Medical College, Ahmedabad, India.
| | - Dhruti Amin
- PearResearch, Dehradun, India; GMERS Medical College and Hospital, Gotri, Vadodara, India.
| | - Trisha Ajwani
- PearResearch, Dehradun, India; Baroda Medical College, Gujarat, India.
| | - Irum Fatima
- PearResearch, Dehradun, India; Osmania Medical College, Hyderabad, India.
| | - Neil Patel
- PearResearch, Dehradun, India; GMERS Medical College, Himmatnagar, Gujarat, India.
| | - Nirja Kaka
- PearResearch, Dehradun, India; GMERS Medical College, Himmatnagar, Gujarat, India.
| | - Yashendra Sethi
- PearResearch, Dehradun, India; Government Doon Medical College, Dehradun, India.
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India.
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7
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Zuo S, Jiang L, Chen L, Wang W, Gu J, Kuai J, Yang X, Ma Y, Han C, Wei W. Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets. Int J Mol Sci 2024; 25:690. [PMID: 38255764 PMCID: PMC10815613 DOI: 10.3390/ijms25020690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/21/2023] [Accepted: 12/30/2023] [Indexed: 01/24/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Chenchen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China; (S.Z.); (L.J.); (L.C.); (W.W.); (J.G.); (J.K.); (X.Y.); (Y.M.)
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China; (S.Z.); (L.J.); (L.C.); (W.W.); (J.G.); (J.K.); (X.Y.); (Y.M.)
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8
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Choi EL, Taheri N, Zhang Y, Matsumoto K, Hayashi Y. The critical role of muscularis macrophages in modulating the enteric nervous system function and gastrointestinal motility. J Smooth Muscle Res 2024; 60:1-9. [PMID: 38462479 PMCID: PMC10921093 DOI: 10.1540/jsmr.60.1] [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: 12/15/2023] [Accepted: 02/14/2024] [Indexed: 03/12/2024] Open
Abstract
Macrophages are the originators of inflammatory compounds, phagocytic purifiers in their local environment, and wound healing protectors in oxidative environments. They are molded by the tissue milieu they inhabit, with gastrointestinal (GI) muscularis macrophages (MMs) being a prime example. MMs are located in the muscular layer of the GI tract and contribute to muscle repair and maintenance of GI motility. MMs are often in close proximity to the enteric nervous system, specifically near the enteric neurons and interstitial cells of Cajal (ICCs). Consequently, the anti-inflammatory function of MMs corresponds to the development and maintenance of neural networks in the GI tract. The capacity of MMs to shift from anti-inflammatory to proinflammatory states may contribute to the inflammatory aspects of various GI diseases and disorders such as diabetic gastroparesis or postoperative ileus, functional disorders such as irritable bowel syndrome, and organic diseases such as inflammatory bowel disease. We reviewed the current knowledge of MMs and their influence on neighboring cells due to their important role in the GI tract.
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Affiliation(s)
- Egan L. Choi
- Graduate Research Education Program in the Department of
Physiology and Biomedical Engineering, Mayo Clinic Graduate School of Biomedical Sciences,
200 First Street SW, Rochester, MN 55905, USA
| | - Negar Taheri
- Research Fellow in the Department of Physiology and
Biomedical Engineering, Mayo Clinic School of Graduate Medical Education, 200 First Street
SW, Rochester, MN 55905, USA
| | - Yuebo Zhang
- Department of Physiology and Biomedical Engineering, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Kenjiro Matsumoto
- Laboratory of Pathophysiology, Faculty of Pharmaceutical
Sciences, Doshisha Woman’s College of Liberal Arts, Kodo, Kyotanabe City, Kyoto 610-0395,
Japan
| | - Yujiro Hayashi
- Department of Physiology and Biomedical Engineering, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Li Y, Chen Q, Wang L, Chen X, Wang B, Zhong W. The mechanisms of nerve injury caused by viral infection in the occurrence of gastrointestinal motility disorder-related diseases. Virol J 2023; 20:251. [PMID: 37915051 PMCID: PMC10621196 DOI: 10.1186/s12985-023-02185-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/14/2023] [Indexed: 11/03/2023] Open
Abstract
Gastrointestinal motility refers to the peristalsis and contractility of gastrointestinal muscles, including the force and frequency of gastrointestinal muscle contraction. Gastrointestinal motility maintains the normal digestive function of the human body and is a critical component of the physiological function of the digestive tract. At present, gastrointestinal motility disorder-related diseases are gradually affecting human production and life. In recent years, it has been consistently reported that the enteric nervous system has a coordinating and controlling role in gastrointestinal motility. Motility disorders are closely related to functional or anatomical changes in the gastrointestinal nervous system. At the same time, some viral infections, such as herpes simplex virus and varicella-zoster virus infections, can cause damage to the gastrointestinal nervous system. Therefore, this paper describes the mechanisms of viral infection in the gastrointestinal nervous system and the associated clinical manifestations. Studies have indicated that the means by which viruses can cause the infection of the enteric nervous system are various, including retrograde transport, hematogenous transmission and centrifugal transmission from the central nervous system. When viruses infect the enteric nervous system, they can cause clinical symptoms, such as abdominal pain, abdominal distension, early satiation, belching, diarrhea, and constipation, by recruiting macrophages, lymphocytes and neutrophils and regulating intestinal microbes. The findings of several case‒control studies suggest that viruses are the cause of some gastrointestinal motility disorders. It is concluded that one of the causes of gastrointestinal motility disorders is viral infection of the enteric nervous system. In such disorders, the relationships between viruses and nerves remain to be studied more deeply. Further studies are necessary to evaluate whether prophylactic antiviral therapy is feasible in gastrointestinal motility disorders.
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Affiliation(s)
- Yaqian Li
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Qiuyu Chen
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, 300110, China
| | - Liwei Wang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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10
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Yip JLK, Xavier S, Balasuriya GK, Hill-Yardin EL, Spencer SJ. Macrophage regulation of the "second brain": CD163 intestinal macrophages interact with inhibitory interneurons to regulate colonic motility - evidence from the Cx3cr1-Dtr rat model. Front Immunol 2023; 14:1269890. [PMID: 37868978 PMCID: PMC10585175 DOI: 10.3389/fimmu.2023.1269890] [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] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/22/2023] [Indexed: 10/24/2023] Open
Abstract
Intestinal macrophages are well-studied for their conventional roles in the immune response against pathogens and protecting the gut from chronic inflammation. However, these macrophages may also have additional functional roles in gastrointestinal motility under typical conditions. This is likely to occur via both direct and indirect influences on gastrointestinal motility through interaction with myenteric neurons that contribute to the gut-brain axis, but this mechanism is yet to be properly characterised. The CX3CR1 chemokine receptor is expressed in the majority of intestinal macrophages, so we used a conditional knockout Cx3cr1-Dtr (diphtheria toxin receptor) rat model to transiently ablate these cells. We then utilized ex vivo video imaging to evaluate colonic motility. Our previous studies in brain suggested that Cx3cr1-expressing cells repopulate by 7 days after depletion in this model, so we performed our experiments at both the 48 hr (macrophage depletion) and 7-day (macrophage repopulation) time points. We also investigated whether inhibitory neuronal input driven by nitric oxide from the enteric nervous system is required for the regulation of colonic motility by intestinal macrophages. Our results demonstrated that CD163-positive resident intestinal macrophages are important in regulating colonic motility in the absence of this major inhibitory neuronal input. In addition, we show that intestinal macrophages are indispensable in maintaining a healthy intestinal structure. Our study provides a novel understanding of the interplay between the enteric nervous system and intestinal macrophages in colonic motility. We highlight intestinal macrophages as a potential therapeutic target for gastrointestinal motility disorders when inhibitory neuronal input is suppressed.
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Affiliation(s)
- Jackson L. K. Yip
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Soniya Xavier
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Gayathri K. Balasuriya
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
- Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
| | - Elisa L. Hill-Yardin
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Sarah J. Spencer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
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11
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Choi EL, Taheri N, Tan E, Matsumoto K, Hayashi Y. The Crucial Role of the Interstitial Cells of Cajal in Neurointestinal Diseases. Biomolecules 2023; 13:1358. [PMID: 37759758 PMCID: PMC10526372 DOI: 10.3390/biom13091358] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/03/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung's disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions.
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Affiliation(s)
- Egan L. Choi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Negar Taheri
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Elijah Tan
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Kenjiro Matsumoto
- Laboratory of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan;
| | - Yujiro Hayashi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
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12
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Wang L, Yuan PQ, Taché Y. Vasculature in the mouse colon and spatial relationships with the enteric nervous system, glia, and immune cells. Front Neuroanat 2023; 17:1130169. [PMID: 37332321 PMCID: PMC10272736 DOI: 10.3389/fnana.2023.1130169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/15/2023] [Indexed: 06/20/2023] Open
Abstract
The distribution, morphology, and innervation of vasculature in different mouse colonic segments and layers, as well as spatial relationships of the vasculature with the enteric plexuses, glia, and macrophages are far from being complete. The vessels in the adult mouse colon were stained by the cardiovascular perfusion of wheat germ agglutinin (WGA)-Alexa Fluor 448 and by CD31 immunoreactivity. Nerve fibers, enteric glia, and macrophages were immunostained in the WGA-perfused colon. The blood vessels entered from the mesentery to the submucosa and branched into the capillary networks in the mucosa and muscularis externa. The capillary net formed anastomosed rings at the orifices of mucosa crypts, and the capillary rings surrounded the crypts individually in the proximal colon and more than two crypts in the distal colon. Microvessels in the muscularis externa with myenteric plexus were less dense than in the mucosa and formed loops. In the circular smooth muscle layer, microvessels were distributed in the proximal, but not the distal colon. Capillaries did not enter the enteric ganglia. There were no significant differences in microvascular volume per tissue volume between the proximal and distal colon either in the mucosa or muscularis externa containing the myenteric plexus. PGP9.5-, tyrosine hydroxylase-, and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers were distributed along the vessels in the submucosa. In the mucosa, PGP9.5-, CGRP-, and vasoactive intestinal peptide (VIP)-immunoreactive nerves terminated close to the capillary rings, while cells and processes labeled by S100B and glial fibrillary acidic protein were distributed mainly in the lamina propria and lower portion of the mucosa. Dense Iba1 immunoreactive macrophages were closely adjacent to the mucosal capillary rings. There were a few macrophages, but no glia in apposition to microvessels in the submucosa and muscularis externa. In conclusion, in the mouse colon, (1) the differences in vasculature between the proximal and distal colon were associated with the morphology, but not the microvascular amount per tissue volume in the mucosa and muscle layers; (2) the colonic mucosa contained significantly more microvessels than the muscularis externa; and (3) there were more CGRP and VIP nerve fibers found close to microvessels in the mucosa and submucosa than in the muscle layers.
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Affiliation(s)
- Lixin Wang
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Pu-Qing Yuan
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Yvette Taché
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
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13
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Ma T, Xue X, Tian H, Zhou X, Wang J, Zhao Z, Wang M, Song J, Feng R, Li L, Jing C, Tian F. Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms. J Transl Med 2023; 21:349. [PMID: 37237321 DOI: 10.1186/s12967-023-04215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.
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Affiliation(s)
- TianRong Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - XiaoLei Xue
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Pharmacy, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, China
| | - Hui Tian
- Department of Gastroenterology, Liaocheng People's Hospital, Shandong First Medical University, Liaocheng, 252000, China
| | - XinXiu Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - JunKe Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - ZhiWen Zhao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - MingFei Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - JiYuan Song
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - RenXiang Feng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
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14
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Souza RF, Caetano MAF, Magalhães HIR, Castelucci P. Study of tumor necrosis factor receptor in the inflammatory bowel disease. World J Gastroenterol 2023; 29:2733-2746. [PMID: 37274062 PMCID: PMC10237104 DOI: 10.3748/wjg.v29.i18.2733] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/14/2023] [Accepted: 04/04/2023] [Indexed: 05/11/2023] Open
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are part of Inflammatory Bowel Diseases (IBD) and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells. In addition, the main inflammatory mediator is related to the tumor necrosis factor-alpha (TNF-α). TNF-α is a me-diator of the intestinal inflammatory processes, thus being one of the main cytokines involved in the pathogenesis of IBD, however, its levels, when measured, are present in the serum of patients with IBD. In addition, TNF-α plays an important role in promoting inflammation, such as the production of interleukins (IL), for instance IL-1β and IL-6. There are two receptors for TNF as following: The tumor necrosis factor 1 receptor (TNFR1); and the tumor necrosis factor 2 receptor (TNFR2). They are involved in the pathogenesis of IBD and their receptors have been detected in IBD and their expression is correlated with disease activity. The soluble TNF form binds to the TNFR1 receptor with, and its activation results in a signaling cascade effects such as apoptosis, cell proliferation and cytokine secretion. In contrast, the transmembrane TNF form can bind both to TNFR1 and TNFR2. Recent studies have suggested that TNF-α is one of the main pro-inflammatory cytokines involved in the pathogenesis of IBD, since TNF levels are present in the serum of both patients with UC and CD. Intravenous and subcutaneous biologics targeting TNF-α have revolutionized the treatment of IBD, thus becoming the best available agents to induce and maintain IBD remission. The application of antibodies aimed at neutralizing TNF-α in patients with IBD that induce a satisfactory clinical response in up to 60% of patients, and also induced long-term maintenance of disease remission in most patients. It has been suggested that anti-TNF-α agents inactivate the pro-inflammatory cytokine TNF-α by direct neutralization, i.e., resulting in suppression of inflammation. However, anti-TNF-α antibodies perform more complex functions than a simple blockade.
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Affiliation(s)
- Roberta Figueiroa Souza
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | | | | | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
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15
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Sui C, Tao L, Bai C, Shao L, Miao J, Chen K, Wang M, Hu Q, Wang F. Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types. Front Pharmacol 2022; 13:929901. [PMID: 35991871 PMCID: PMC9385171 DOI: 10.3389/fphar.2022.929901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.
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Affiliation(s)
- Chao Sui
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Liang Tao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunhua Bai
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Lihua Shao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ji Miao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Kai Chen
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Meng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Qiongyuan Hu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Feng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
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16
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Singh R, Zogg H, Ghoshal UC, Ro S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front Pharmacol 2022; 13:808195. [PMID: 35145413 PMCID: PMC8822166 DOI: 10.3389/fphar.2022.808195] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) have been re-named as disorders of gut-brain interactions. These conditions are not only common in clinical practice, but also in the community. In reference to the Rome IV criteria, the most common FGIDs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific gastrointestinal motility disorders, such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The treatment options currently available include lifestyle modifications, dietary and gut microbiota manipulation interventions including fecal microbiota transplantation, prokinetics, antispasmodics, laxatives, and centrally and peripherally acting neuromodulators. However, treatment that targets the pathophysiological mechanisms underlying the symptoms are scanty. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying pathologies of these disorders might provide the best avenue for future pharmaceutical development. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and FGIDs. Furthermore, the fundamental challenges in treating these disorders should be defined; for instance, 1. Cause and effect cannot be disentangled between symptoms and pathophysiological mechanisms due to current therapies that entail the off-label use of medications to treat symptoms. 2. Despite the knowledge that the microbiota in our gut plays an essential part in maintaining gut health, their exact functions in gut homeostasis are still unclear. What constitutes a healthy microbiome and further, the precise definition of gut microbial dysbiosis is lacking. More comprehensive, large-scale, and longitudinal studies utilizing multi-omics data are needed to dissect the exact contribution of gut microbial alterations in disease pathogenesis. Accordingly, we review the current treatment options, clinical insight on pathophysiology, therapeutic modalities, current challenges, and therapeutic clues for the clinical care and management of functional dyspepsia, gastroparesis, irritable bowel syndrome, functional constipation, and functional diarrhea.
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Affiliation(s)
- Rajan Singh
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
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17
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Abstract
Gastroparesis is a neuromuscular disorder whose hallmark is delayed gastric emptying. It is a global challenge to the healthcare system because of poor treatment satisfaction for both the patients and clinicians, eventually leading to a reduction in the quality of life, with antecedent anxiety and depression. Although it is multifactorial in origin, diabetic, idiopathic, and drug-induced gastroparesis are the major risk factors. Disrupted interstitial cells of Cajal (ICC) and gastric dysrhythmia are pivotal to the pathogenesis, with most of the investigations targeted toward assessing gastric emptying and accommodation usually affected by distorted ICC and other neural networks. The treatment challenges can be overcome by a multidisciplinary approach involving gastroenterologists, gastrointestinal surgeons, biomedical engineers, nutritionists, psychologists, nurses, radionuclide radiologists, pharmacists, and family physicians. The exploration of the fundamental physiological processes underlying gastroparesis with the use of biomechanical materials should be given more attention by biomedical engineers to integrate innovative engineering with medicine for solving complex medical issues.
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Affiliation(s)
| | - Sarah Abere
- Internal Medicine, Rivers State University Teaching Hospital, Port Harcourt, NGA
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18
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Novel role of zonulin in the pathophysiology of gastro-duodenal transit: a clinical and translational study. Sci Rep 2021; 11:22462. [PMID: 34789790 PMCID: PMC8599512 DOI: 10.1038/s41598-021-01879-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/25/2021] [Indexed: 12/29/2022] Open
Abstract
We examined the relationship between zonulin and gastric motility in critical care patients and a translational mouse model of systemic inflammation. Gastric motility and haptoglobin (HP) 2 isoform quantification, proxy for zonulin, were examined in patients. Inflammation was triggered by lipopolysaccharide (LPS) injection in C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice as controls, and gastro-duodenal transit was examined by fluorescein-isothiocyanate, 6 and 12 h after LPS-injection. Serum cytokines and zonulin protein levels, and zonulin gastric-duodenal mRNA expression were examined. Eight of 20 patients [14 years, IQR (12.25, 18)] developed gastric dysmotility and were HP2 isoform-producing. HP2 correlated with gastric dysmotility (r = − 0.51, CI − 0.81 to 0.003, p = 0.048). LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels in all mice (p < 0.0001). Gastric dysmotility was reduced similarly in Ztm and WT mice in a time-dependent manner. Ztm had 16% faster duodenal motility than WT mice 6H post-LPS, p = 0.01. Zonulin mRNA expression by delta cycle threshold (dCT) was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p = 0.04. Serum zonulin protein levels were higher in LPS-injected mice compared to vehicle-injected animals in a time-dependent manner. Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression and protein levels.
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19
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Singh R, Zogg H, Ro S. Role of microRNAs in Disorders of Gut-Brain Interactions: Clinical Insights and Therapeutic Alternatives. J Pers Med 2021; 11:1021. [PMID: 34683162 PMCID: PMC8541612 DOI: 10.3390/jpm11101021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/08/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Disorders of gut-brain interactions (DGBIs) are heterogeneous in nature and intertwine with diverse pathophysiological mechanisms. Regular functioning of the gut requires complex coordinated interplay between a variety of gastrointestinal (GI) cell types and their functions are regulated by multiple mechanisms at the transcriptional, post-transcriptional, translational, and post-translational levels. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression by binding to specific mRNA targets to repress their translation and/or promote the target mRNA degradation. Dysregulation of miRNAs might impair gut physiological functions leading to DGBIs and gut motility disorders. Studies have shown miRNAs regulate gut functions such as visceral sensation, gut immune response, GI barrier function, enteric neuronal development, and GI motility. These biological processes are highly relevant to the gut where neuroimmune interactions are key contributors in controlling gut homeostasis and functional defects lead to DGBIs. Although extensive research has explored the pathophysiology of DGBIs, further research is warranted to bolster the molecular mechanisms behind these disorders. The therapeutic targeting of miRNAs represents an attractive approach for the treatment of DGBIs because they offer new insights into disease mechanisms and have great potential to be used in the clinic as diagnostic markers and therapeutic targets. Here, we review recent advances regarding the regulation of miRNAs in GI pacemaking cells, immune cells, and enteric neurons modulating pathophysiological mechanisms of DGBIs. This review aims to assess the impacts of miRNAs on the pathophysiological mechanisms of DGBIs, including GI dysmotility, impaired intestinal barrier function, gut immune dysfunction, and visceral hypersensitivity. We also summarize the therapeutic alternatives for gut microbial dysbiosis in DGBIs, highlighting the clinical insights and areas for further exploration. We further discuss the challenges in miRNA therapeutics and promising emerging approaches.
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Affiliation(s)
| | | | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, 1664 North Virginia Street, Reno, NV 89557, USA; (R.S.); (H.Z.)
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20
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Wang YJ, Jia QL, Li L, Wang XX, Ling JH. Progress in understanding of relationship between gut microbiota and gastrointestinal motility. Shijie Huaren Xiaohua Zazhi 2021; 29:1020-1025. [DOI: 10.11569/wcjd.v29.i17.1020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal motility disorders are a group of common clinical disorders in which abnormal gastrointestinal motility is the major pathogenesis, including irritable bowel syndrome, functional dyspepsia, and diabetic gastroparesis. With the rapid development of microbial sequencing technology in the past 10 years, the understanding of the gut microbiota has greatly improved, and it is generally found that patients with gastrointestinal motility diseases have gut microbiota disorders. Some progress has been made on the correlation between gut microbiota and gastrointestinal motility. This review aims to elucidate the relationship between gut microbiota and gastrointestinal motility and the mechanism of their interaction.
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Affiliation(s)
- Yu-Jiao Wang
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Qing-Ling Jia
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Li Li
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Xiang-Xiang Wang
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Jiang-Hong Ling
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
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21
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Ohtsu T, Haruma K, Ide Y, Takagi A. The Effect of Continuous Intake of Lactobacillus gasseri OLL2716 on Mild to Moderate Delayed Gastric Emptying: A Randomized Controlled Study. Nutrients 2021; 13:1852. [PMID: 34071718 PMCID: PMC8230235 DOI: 10.3390/nu13061852] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 11/17/2022] Open
Abstract
Probiotics have been suggested to be effective for functional dyspepsia, but their effect on gastric motility is not clear. We evaluated the effect of Lactobacillus gasseri OLL2716 (LG21 strain) on mild to moderate delayed gastric emptying by a double-blind, parallel-group, placebo-controlled, randomized trial. Participants (n = 28) were randomly assigned to ingest LG21 strain-containing yogurt (LG21 strain group) or LG21 strain-free yogurt (placebo group) for 12 weeks. The 13C gastric emptying breath test was performed to measure the gastric emptying rate over time following ingestion of a liquid meal, and the time to reach the peak (Tmax) was used as an indicator of gastric emptying. We also measured the salivary amylase concentration, an indicator of autonomic dysfunction under stress. The per-protocol population (n = 27, male n = 4, female n = 23) was evaluated for efficacy. When a ≥30% reduction in the difference between participant's Tmax and the Japanese mean Tmax was defined as an improvement, the odds ratio of improvement in delayed gastric emptying compared to placebo after 12 weeks was 4.1 (95% confidence interval, 0.8 to 20.2). Moreover, salivary amylase concentrations were significantly lower than in the placebo group, indicating an improvement in autonomic function. The present data were not enough to support the beneficial effects of the LG21 strain on delayed gastric emptying. However, if we define the odds ratio in further study investigated with a larger number of participants, LG21 strain might be expected to have some impact on delayed gastric emptying.
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Affiliation(s)
- Toshihiro Ohtsu
- Food Microbiology Research Laboratories, Applied Microbiology Research Department, Meiji Co. Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan
| | - Ken Haruma
- General Medical Center, Department of Internal Medicine 2, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan;
| | - Yumiko Ide
- Doctor’s Office, Tokyo Center Clinic, 1-1-8 Yaesu, Chuo-ku, Tokyo 103-0028, Japan;
| | - Atsushi Takagi
- Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa 259-1193, Japan;
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22
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Diaz-Jimenez D, Kolb JP, Cidlowski JA. Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis. Front Immunol 2021; 12:669891. [PMID: 34079551 PMCID: PMC8165320 DOI: 10.3389/fimmu.2021.669891] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/05/2021] [Indexed: 02/06/2023] Open
Abstract
Our immune system has evolved as a complex network of cells and tissues tasked with maintaining host homeostasis. This is evident during the inflammatory responses elicited during a microbial infection or traumatic tissue damage. These responses seek to eliminate foreign material or restore tissue integrity. Even during periods without explicit disturbances, the immune system plays prominent roles in tissue homeostasis. Perhaps one of the most studied cells in this regard is the macrophage. Tissue-resident macrophages are a heterogenous group of sensory cells that respond to a variety of environmental cues and are essential for organ function. Endogenously produced glucocorticoid hormones connect external environmental stress signals with the function of many cell types, producing profound changes in immune cells, including macrophages. Here, we review the current literature which demonstrates specific effects of glucocorticoids in several organ systems. We propose that tissue-resident macrophages, through glucocorticoid signaling, may play an underappreciated role as regulators of organ homeostasis.
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Affiliation(s)
- David Diaz-Jimenez
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
| | - Joseph P Kolb
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
| | - John A Cidlowski
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
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23
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Agnes A, Puccioni C, D'Ugo D, Gasbarrini A, Biondi A, Persiani R. The gut microbiota and colorectal surgery outcomes: facts or hype? A narrative review. BMC Surg 2021; 21:83. [PMID: 33579260 PMCID: PMC7881582 DOI: 10.1186/s12893-021-01087-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/01/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The gut microbiota (GM) has been proposed as one of the main determinants of colorectal surgery complications and theorized as the "missing factor" that could explain still poorly understood complications. Herein, we investigate this theory and report the current evidence on the role of the GM in colorectal surgery. METHODS We first present the findings associating the role of the GM with the physiological response to surgery. Second, the change in GM composition during and after surgery and its association with colorectal surgery complications (ileus, adhesions, surgical-site infections, anastomotic leak, and diversion colitis) are reviewed. Finally, we present the findings linking GM science to the application of the enhanced recovery after surgery (ERAS) protocol, for the use of oral antibiotics with mechanical bowel preparation and for the administration of probiotics/synbiotics. RESULTS According to preclinical and translational evidence, the GM is capable of influencing colorectal surgery outcomes. Clinical evidence supports the application of an ERAS protocol and the preoperative administration of multistrain probiotics/synbiotics. GM manipulation with oral antibiotics with mechanical bowel preparation still has uncertain benefits in right-sided colic resection but is very promising for left-sided colic resection. CONCLUSIONS The GM may be a determinant of colorectal surgery outcomes. There is an emerging need to implement translational research on the topic. Future clinical studies should clarify the composition of preoperative and postoperative GM and the impact of the GM on different colorectal surgery complications and should assess the validity of GM-targeted measures in effectively reducing complications for all colorectal surgery locations.
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Affiliation(s)
- Annamaria Agnes
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy
- Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Caterina Puccioni
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy
| | - Domenico D'Ugo
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy
- Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Antonio Gasbarrini
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy
- Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Alberto Biondi
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy.
- Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli n. 8, 00168, Rome, Italy.
| | - Roberto Persiani
- Università Cattolica del Sacro Cuore, Largo F. Vito n.1, 00168, Rome, Italy
- Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli n. 8, 00168, Rome, Italy
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24
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Elfar W, Gurjar AA, Talukder MAH, Noble M, Di Lorenzo C, Elfar J. Erythropoietin promotes functional recovery in a mouse model of postoperative ileus. Neurogastroenterol Motil 2021; 33:e14049. [PMID: 33368893 DOI: 10.1111/nmo.14049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 07/27/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dysmotility and postoperative ileus (POI) are major clinical problems after surgical trauma and it is associated with increased intestinal inflammation and oxidative stress. Despite the high occurrence of POI following intra-abdominal surgeries, no effective treatment is currently available. Erythropoietin (EPO) is a multifunctional tissue-protective cytokine with potent anti-inflammatory and anti-oxidative properties, and it is an FDA approved medicine for clinical use. While both EPO and EPO receptors (EPOR) are widely expressed in the gut, the role of EPO in POI is largely unknown. This study was designed to explore the possible beneficial effect of EPO in a mouse model of POI. METHODS Mice were subjected to intestinal manipulation to induce standard POI and intestinal transit time was determined at 24-h post-injury with or without EPO treatment (5000 units/kg, once, IP, immediately after intestinal trauma). Intestinal samples were harvested for histological and immunohistochemical analysis. RESULTS Systemic EPO significantly improved intestinal transit time compared with control group and it was associated with significantly increased levels of tissue macrophages and reduced levels of oxidative stress. CONCLUSIONS AND INFERENCES This is the first pre-clinical study to document novel beneficial effects of EPO in gut dysmotility and our findings suggest that the beneficial effects of EPO in POI is predominantly mediated by its anti-oxidative and immunomodulatory properties.
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Affiliation(s)
- Walaa Elfar
- Division of Gastroenterology and Nutrition, Department of Pediatrics, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Anagha A Gurjar
- Department of Orthopedics and Rehabilitation, Center for Orthopedics and Translational Sciences (CORTS), The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - M A Hassan Talukder
- Department of Orthopedics and Rehabilitation, Center for Orthopedics and Translational Sciences (CORTS), The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Mark Noble
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
| | - Carlo Di Lorenzo
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - John Elfar
- Department of Orthopedics and Rehabilitation, Center for Orthopedics and Translational Sciences (CORTS), The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
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25
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Gamez-Belmonte R, Erkert L, Wirtz S, Becker C. The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses. Int J Mol Sci 2020; 21:ijms21249772. [PMID: 33371444 PMCID: PMC7767427 DOI: 10.3390/ijms21249772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.
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26
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Martinez EE, Zurakowski D, Pereira L, Freire R, Emans JB, Nurko S, Duggan CP, Fasano A, Mehta NM. Interleukin-10 and Zonulin Are Associated With Postoperative Delayed Gastric Emptying in Critically Ill Surgical Pediatric Patients: A Prospective Pilot Study. JPEN J Parenter Enteral Nutr 2020; 44:1407-1416. [PMID: 32386238 PMCID: PMC7754495 DOI: 10.1002/jpen.1874] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 04/27/2020] [Accepted: 05/04/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Impaired gastric emptying (GE) is associated with morbidity in surgical critically ill children. The relationship between inflammation, gut barrier integrity (lipopolysaccharide binding protein [LBP]; zonulin), and GE has not been described in this cohort. METHODS Children ≥2 years of age and requiring critical care after surgery were enrolled. Preoperative and postoperative levels of serum cytokines, LBP, and zonulin, and GE by the acetaminophen absorption test, were measured, allowing patients to serve as their own controls. Postoperative delayed GE was defined as a decrease in GE by ≥20% compared with preoperative GE. The following were examined : comparison between postoperative andpreoperative values, correlations between fold change (postoperative/preoperative) in study variables, and fold change in study variables between patients with and without postoperative delayed GE. RESULTS Twenty patients, median age 14 years (12.25, 18), 12 female, were included. Eight of 20 patients had postoperative delayed GE. Postoperative interleukin-6 (IL-6), IL-8, IL-10, and LBP were increased, and zonulin was decreased (P-values < .05). Fold change in IL-10 and zonulin were inversely correlated (ρ -0.618, P = .004). Patients with postoperative delayed GE had greater fold increase in IL-10 (P = .0159) and fold decrease in zonulin (P = .0160). Five of 7 (71%) patients with both fold increase in IL-10 and decrease in zonulin had delayed GE. CONCLUSION Postoperative changes in IL-10 and zonulin were associated with delayed GE in surgical critically ill children, which might suggest a mechanism to for delayed GE in postoperative inflammation and gut barrier dysregulation after surgery.
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Affiliation(s)
- Enid E. Martinez
- Department of Anesthesiology, Critical Care and Pain MedicineBoston Children's HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
| | - David Zurakowski
- Department of Anesthesiology, Critical Care and Pain MedicineBoston Children's HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
| | - Luis Pereira
- Department of Anesthesiology, Critical Care and Pain MedicineBoston Children's HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
| | - Rachel Freire
- Division of Pediatric Gastroenterology and NutritionDepartment of PediatricsMassachusetts General Hospital for ChildrenBostonMassachusettsUSA
| | - John B. Emans
- Harvard Medical SchoolBostonMassachusettsUSA
- Orthopedic CenterBoston Children's HospitalBostonMassachusettsUSA
| | - Samuel Nurko
- Harvard Medical SchoolBostonMassachusettsUSA
- Division of Gastroenterology, Hepatology and NutritionBoston Children's HospitalBostonMassachusettsUSA
| | - Christopher P. Duggan
- Harvard Medical SchoolBostonMassachusettsUSA
- Division of Gastroenterology, Hepatology and NutritionBoston Children's HospitalBostonMassachusettsUSA
- Center for NutritionBoston Children's HospitalBostonMassachusettsUSA
| | - Alessio Fasano
- Harvard Medical SchoolBostonMassachusettsUSA
- Division of Pediatric Gastroenterology and NutritionDepartment of PediatricsMassachusetts General Hospital for ChildrenBostonMassachusettsUSA
| | - Nilesh M. Mehta
- Department of Anesthesiology, Critical Care and Pain MedicineBoston Children's HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
- Center for NutritionBoston Children's HospitalBostonMassachusettsUSA
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27
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Grubišić V, McClain JL, Fried DE, Grants I, Rajasekhar P, Csizmadia E, Ajijola OA, Watson RE, Poole DP, Robson SC, Christofi FL, Gulbransen BD. Enteric Glia Modulate Macrophage Phenotype and Visceral Sensitivity following Inflammation. Cell Rep 2020; 32:108100. [PMID: 32905782 PMCID: PMC7518300 DOI: 10.1016/j.celrep.2020.108100] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 07/02/2020] [Accepted: 08/11/2020] [Indexed: 12/20/2022] Open
Abstract
Mechanisms resulting in abdominal pain include altered neuro-immune interactions in the gastrointestinal tract, but the signaling processes that link immune activation with visceral hypersensitivity are unresolved. We hypothesized that enteric glia link the neural and immune systems of the gut and that communication between enteric glia and immune cells modulates the development of visceral hypersensitivity. To this end, we manipulated a major mechanism of glial intercellular communication that requires connexin-43 and assessed the effects on acute and chronic inflammation, visceral hypersensitivity, and immune responses. Deleting connexin-43 in glia protected against the development of visceral hypersensitivity following chronic colitis. Mechanistically, the protective effects of glial manipulation were mediated by disrupting the glial-mediated activation of macrophages through the macrophage colony-stimulating factor. Collectively, our data identified enteric glia as a critical link between gastrointestinal neural and immune systems that could be harnessed by therapies to ameliorate abdominal pain.
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Affiliation(s)
- Vladimir Grubišić
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - Jonathon L McClain
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - David E Fried
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - Iveta Grants
- Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, 420 West 12th Avenue, Room 216, Columbus, OH 43210, USA
| | - Pradeep Rajasekhar
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Melbourne, VIC, Australia
| | - Eva Csizmadia
- Division of Gastroenterology, Department of Medicine and of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Olujimi A Ajijola
- Cardiac Arrhythmia Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
| | - Ralph E Watson
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Melbourne, VIC, Australia
| | - Simon C Robson
- Division of Gastroenterology, Department of Medicine and of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Fievos L Christofi
- Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, 420 West 12th Avenue, Room 216, Columbus, OH 43210, USA
| | - Brian D Gulbransen
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA.
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28
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Serna-Duque JA, Esteban MÁ. Effects of inflammation and/or infection on the neuroendocrine control of fish intestinal motility: A review. FISH & SHELLFISH IMMUNOLOGY 2020; 103:342-356. [PMID: 32454211 DOI: 10.1016/j.fsi.2020.05.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/06/2020] [Indexed: 06/11/2023]
Abstract
Food is the largest expense in fish farms. On the other hand, the fish health and wellbeing are determining factors in aquaculture production where nutrition is a vital process for growing animals. In fact, it is important to remember that digestion and nutrition are crucial for animals' physiology. However, digestion is a very complex process in which food is processed to obtain necessary nutrients and central mechanisms of this process require both endocrine and neuronal regulation. In this context, intestinal motility is essential for the absorption of the nutrients (digestive process determining nutrition). An imbalance in the intestinal motility due to an inadequate diet or an infectious process could result in a lower use of the food and inefficiency in obtaining nutrients from food. Very frequently, farmed fish are infected with different pathogenic microorganism and this situation could alter gastrointestinal physiology and, indirectly reduce fish growth. For these reasons, the present review focuses on analysing how different inflammatory molecules or infections can alter conventional modulators of fish intestinal motility.
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Affiliation(s)
- Jhon A Serna-Duque
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus of International Excellence, Campus Mare Nostrum, University of Murcia, Murcia, Spain
| | - M Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus of International Excellence, Campus Mare Nostrum, University of Murcia, Murcia, Spain.
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29
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Abstract
Bowel dysfunction, especially ileus, has been increasingly recognized in critically ill patients. Ileus is commonly associated to constipation, however abnormal motility can also concern the upper digestive tract, therefore impaired gastrointestinal transit (IGT) seems to be a more appropriate term. IGT, especially constipation, is common among patients under mechanical ventilation, occurring in up to 80% of the patients during the first week, and has been associated with worse outcome in intensive care unit (ICU). It is acknowledged that the most relevant definition for constipation in ICU is the absence of stool for the first six days after admission. Concerning the upper digestive intolerance (UDI), the diagnosis should rely only on vomiting and the systematic gastric residual volume (GRV) monitoring should be avoided. IGT results from a complex pathophysiology in which both the critical illness and its specific treatments may have a deleterious role. Both observational and experimental studies have shown the deleterious effect of sepsis, multiorgan failure, sedation (especially opioids) and mechanical ventilation on gut function. To date few studies have reported effect of treatment on IGT and the level of evidence is low. However, cholinesterase inhibitors seem safe and could probably be used in case of constipation but remains poorly prescribed. Prevention with bowel management protocol using osmotic laxatives appears to be safe but did not demonstrate its effectiveness. For patients treated with high posology of opioids during sedation, enteral opioid antagonists may be a promising strategy.
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Affiliation(s)
- Philippe Ariès
- Clermont-Tonnerre Military Teaching Hospital, Brest, France.,Val-de-Grâce French Military Health Service Academy, Paris, France.,Department of Anesthesia and Surgical Intensive Care, Brest Teaching Hospital, Brest, France
| | - Olivier Huet
- Department of Anesthesia and Surgical Intensive Care, Brest Teaching Hospital, Brest, France - .,UFR of Medicine, University of Western Brittany, Brest, France
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30
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Caër C, Wick MJ. Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease. Front Immunol 2020; 11:410. [PMID: 32256490 PMCID: PMC7093381 DOI: 10.3389/fimmu.2020.00410] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/21/2020] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Intestinal mononuclear phagocytes (MNPs) have a crucial role in maintaining epithelial barrier integrity while controlling pathogen invasion by activating an appropriate immune response. However, in genetically predisposed individuals, uncontrolled immune activation to intestinal flora is thought to underlie the chronic mucosal inflammation that can ultimately result in IBD. Thus, MNPs are involved in fine-tuning mucosal immune system responsiveness and have a critical role in maintaining homeostasis or, potentially, the emergence of IBD. MNPs include monocytes, macrophages and dendritic cells, which are functionally diverse but highly complementary. Despite their crucial role in maintaining intestinal homeostasis, specific functions of human MNP subsets are poorly understood, especially during diseases such as IBD. Here we review the current understanding of MNP ontogeny, as well as the recently identified human intestinal MNP subsets, and discuss their role in health and IBD.
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Affiliation(s)
- Charles Caër
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Mary Jo Wick
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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31
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Anti- and pro-oxidant effects of quercetin stabilized by microencapsulation on interstitial cells of Cajal, nitrergic neurons and M2-like macrophages in the jejunum of diabetic rats. Neurotoxicology 2020; 77:193-204. [PMID: 32007490 DOI: 10.1016/j.neuro.2020.01.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/24/2020] [Accepted: 01/27/2020] [Indexed: 12/13/2022]
Abstract
Given the well-known antioxidant and neuroprotective properties of quercetin, the aim of this work was to evaluate the effects of quercetin stabilized by microencapsulation at two doses (10 mg kg-1 and 100 mg kg-1) on the oxidative/antioxidant status, number and morphological features of ICC, nitrergic neurons and M2-like macrophages in jejunum of diabetic rats. The rats were randomly distributed into six groups: normoglycemic control (N), diabetic control (D) and either normoglycemic or diabetic groups treated with quercetin-loaded microcapsules at a dose of 10 mg kg-1 (NQ10 and DQ10, respectively) or 100 mg kg-1 (NQ100 and DQ100, respectively). After 60 days, the jejunum was collected. Whole mounts were immunostained for Ano1, nNOS and CD206, and oxidative stress levels and total antioxidant capacity of the jejunum were measured. Diabetes led to a loss of ICC and nitrergic neurons, but increased numbers of M2-like macrophages and elevated levels of oxidative stress were seen in diabetic animals. High-dose administration of quercetin (100 mg kg-1) further aggravated the diabetic condition (DQ100) but this treatment resulted in harmful effects on healthy rats (NQ100), pointing to a pro-oxidant activity. However, low-dose administration of quercetin (10 mg kg-1) gave rise to antioxidant and protective effects on ICC, nNOS, macrophages and oxidative/antioxidant status in DQ100, but NQ100 displayed infrequent negative outcomes in normoglycemic animals. Microencapsulation of the quercetin may become promising alternatives to reduce diabetes-induced oxidative stress but antioxidant therapies should be careful used under healthy status to avoid toxic effects.
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32
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Tsuruta S, Uchida H, Akutsu H. Intestinal Organoids Generated from Human Pluripotent Stem Cells. JMA J 2020; 3:9-19. [PMID: 33324771 PMCID: PMC7733741 DOI: 10.31662/jmaj.2019-0027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 10/23/2019] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal system is one of the most complex organ systems in the human body, and consists of numerous cell types originating from three germ layers. To understand intestinal development and homeostasis and elucidate the pathogenesis of intestinal disorders, including unidentified diseases, several in vitro models have been developed. Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have remarkable developmental plasticity and possess the potential for a wide variety of applications. Three-dimensional organs, termed organoids and produced in vitro by PSCs, contain not only epithelium but also mesenchymal tissue and partially recapitulate intestinal functions. Such intestinal organoids have begun to be applied in disease models and drug development and have contributed to a detailed analysis of molecular interactions and findings in the synergistic development of biomedicine for human digestive organs. In this review, we describe gastrointestinal organoid technology derived from PSCs and consider its potential applications.
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Affiliation(s)
- Satoru Tsuruta
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Centre for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Transplantation Centre, National Centre for Child Health and Development, Tokyo, Japan
| | - Hidenori Akutsu
- Centre for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
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33
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Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut 2019; 68:2238-2250. [PMID: 31563877 PMCID: PMC6874806 DOI: 10.1136/gutjnl-2019-318712] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/29/2019] [Accepted: 08/22/2019] [Indexed: 12/21/2022]
Abstract
Gastroparesis is defined by delayed gastric emptying (GE) and symptoms of nausea, vomiting, bloating, postprandial fullness, early satiety and abdominal pain. Most common aetiologies include diabetes, postsurgical and postinfectious, but in many cases it is idiopathic. Clinical presentation and natural history vary by the aetiology. There is significant morbidity and healthcare utilisation associated with gastroparesis. Mechanistic studies from diabetic animal models of delayed GE as well as human full-thickness biopsies have significantly advanced our understanding of this disorder. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system through paracrine and oxidative stress mediators is likely central to the pathogenesis of gastroparesis. Scintigraphy and 13C breath testing provide the most validated assessment of GE. The stagnant gastroparesis therapeutic landscape is likely to soon see significant changes. Relatively newer treatment strategies include antiemetics (aprepitant), prokinetics (prucalopride, relamorelin) and fundic relaxants (acotiamide, buspirone). Endoscopic pyloromyotomy appears promising over the short term, especially for symptoms of nausea and vomiting. Further controlled trials and identification of the appropriate subgroup with pyloric dysfunction and assessment of long-term outcomes are essential. This review highlights the clinical presentation, diagnosis, mechanisms and treatment advancements for gastroparesis.
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Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vincenzo Stanghellini
- Department of Digestive Diseases and Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Ariyaratne A, Finney CAM. Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space. Infect Immun 2019; 87:e00127-19. [PMID: 31285249 PMCID: PMC6759305 DOI: 10.1128/iai.00127-19] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Granuloma formation is a key host immune response generated to confine invading pathogens and limit extensive host damage. It consists of an accumulation of host immune cells around a pathogen. This host response has been extensively studied in the context of inflammatory diseases. However, there is much less known about Th2-type granulomas generated in response to parasitic worms. Based on in vitro data, innate immune cells within the granuloma are thought to immobilize and kill parasites but also act to repair damaged tissue. Understanding this dual function is key. The two billion people and many livestock/wild animals infected with helminths demonstrate that granulomas are not effective at clearing infection. However, the lack of high mortality highlights their importance in ensuring that parasite migration/tissue damage is restricted and wound healing is effective. In this review, we define two key cellular players (macrophages and eosinophils) and their associated molecular players involved in Th2 granuloma function. To date, the underlying mechanisms remain poorly understood, which is in part due to a lack of conclusive studies. Most have been performed in vitro rather than in vivo, using cells that have not been obtained from granulomas. Experiments using genetically modified mouse strains and/or antibody/chemical-mediated cell depletion have also generated conflicting results depending on the model. We discuss the caveats of previous studies and the new tools available that will help fill the gaps in our knowledge and allow a better understanding of the balance between immune killing and healing.
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Affiliation(s)
- Anupama Ariyaratne
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada
| | - Constance A M Finney
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada
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Systemically Administered Plant Recombinant Holo-Intrinsic Factor Targets the Liver and is not Affected by Endogenous B12 levels. Sci Rep 2019; 9:12269. [PMID: 31439908 PMCID: PMC6706418 DOI: 10.1038/s41598-019-48555-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 08/06/2019] [Indexed: 01/09/2023] Open
Abstract
Precision targeting imaging agents and/or treatment agents to select cells or organs in the body remains a significant need and is an area of intense research. It has been hypothesized that the vitamin B12 (B12) dietary pathway, or components thereof, may be exploitable in this area. The question of whether gastric Intrinsic factor (IF), critical for B12 absorption in the GI tract via the cubilin receptor, could be used as a targeting moiety for the cubilin receptor systemically, has not been investigated. Cubilin is the only known receptor for holo-IF and is found primarily in the kidney and ear (outside of the ileum of the GI) offering significant scope for specific targeting. We utilized plant derived human gastric IF in fluorescent cell and PET based in vivo imaging and biodistribution studies and demonstrated that plant derived IF primarily targets the liver, likely a consequence of the unique glycosylation profile of the IF, and is not affected by endogenous B12 levels.
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Cogliandro RF, Rizzoli G, Bellacosa L, De Giorgio R, Cremon C, Barbara G, Stanghellini V. Is gastroparesis a gastric disease? Neurogastroenterol Motil 2019; 31:e13562. [PMID: 30773743 DOI: 10.1111/nmo.13562] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 01/03/2019] [Accepted: 01/07/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastroparesis is a digestive syndrome characterized by delayed gastric emptying (GE) and by symptoms that are suggestive of gastroduodenal motor disorders. There are three grades of gastroparesis of increasing severity: (a) mild gastroparesis; (b) compensated gastroparesis; and (c) gastric failure. GE abnormalities are partially related to symptom type and severity, and other mechanisms may be involved. AIM To investigate enteric dysmotility (ED) in patients with suspected gastroparesis. METHODS Patients with symptoms suggestive of gastroparesis were consecutively included in the study and underwent a 13 C-octanoic acid GE breath test and small bowel manometry (SBM). Clinical features were recorded using predefined, validated questionnaires at entry. KEY RESULTS The study enrolled 88 patients (71 women; mean age: 37.8 ± 14.3 years). Gastric emptying was delayed in 25 patients (28.4%), and 70 patients (79.5%) presented small bowel motor abnormalities including bursts, abnormal activity fronts, inability to respond to meal ingestion, and hypocontractility. Gastric emptying was delayed in 24 of the 70 patients with ED (34.3% vs 5.5% of patients with normal SBM). Enteric dysmotility was detected in 24 of 25 patients (96%) with delayed GE. Patients with and without delayed GE showed similar moderate/severe gastroparesis manifestations, but patients with ED significantly more often had moderate/severe gastroparesis manifestations than patients with normal SBM (grade 1:14% vs 39%, grade 2:62% vs 56%, grade 3:24% vs 5%, respectively). CONCLUSIONS AND INFERENCES Enteric dysmotility was more frequent than delayed GE in patients with symptoms suggestive of gastroparesis. Gastroparesis severity was associated with small bowel motor abnormalities but not with delayed GE.
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Affiliation(s)
| | - Giada Rizzoli
- Department of Digestive Diseases, S. Orsola University Hospital, Bologna, Italy
| | - Lara Bellacosa
- Department of Digestive Diseases, S. Orsola University Hospital, Bologna, Italy
| | | | - Cesare Cremon
- Department of Digestive Diseases, S. Orsola University Hospital, Bologna, Italy
| | - Giovanni Barbara
- Department of Digestive Diseases, S. Orsola University Hospital, Bologna, Italy
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Schneider S, Wright CM, Heuckeroth RO. Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function. Annu Rev Physiol 2019; 81:235-259. [DOI: 10.1146/annurev-physiol-021317-121515] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
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Affiliation(s)
- Sabine Schneider
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Christina M. Wright
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Robert O. Heuckeroth
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA
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Inoue Y, Fukui H, Xu X, Ran Y, Tomita T, Oshima T, Watari J, Miwa H. Colonic M1 macrophage is associated with the prolongation of gastrointestinal motility and obesity in mice treated with vancomycin. Mol Med Rep 2019; 19:2591-2598. [PMID: 30720127 PMCID: PMC6423659 DOI: 10.3892/mmr.2019.9920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 01/28/2019] [Indexed: 11/07/2022] Open
Abstract
Gut microbiota plays a pivotal role in not only the gastrointestinal (GI) immune system but also GI motility and metabolism. Antibiotic treatments are likely to affect the gut flora and GI immune system, subsequently disturbing GI motility and body metabolism. In the present study, we investigated antibiotic-induced alterations of body metabolism and GI motility in association with the macrophage profile in the colon. Specific pathogen-free (SPF) mice (ICR; 6 weeks old; female) were orally administered vancomycin (0.2 mg/ml) in drinking water for 5 weeks, and subsequent changes in pathophysiology were observed. The expression of CD80 and CD163 was examined by immunohistochemistry and the expression of cytokines in colonic tissues was evaluated by reverse transcription-quantitative polymerase chain reaction. The gastrointestinal transit time (GITT) was measured by administration of carmine red (6% w/v) solution. In the vancomycin-treated SPF mice, significant increases in body weight, cecum weight and GITT were observed compared with the controls. The number of CD80-positive M1 macrophages and the expression of interferon-γ and interleukin-12 were significantly increased, whereas, the numbers of CD163-positive M2 macrophages in the mucosal and muscular layers were decreased in the colon of vancomycin-treated mice. GITT was positively correlated with the number of CD80-positive M1 macrophages in the colonic mucosa; however, was negatively correlated with the number of CD163-positive M2 macrophages in the mucosal and muscular layers. Therefore, it was suggested that antibiotic treatment affects body metabolism and GI motility, accompanied by alterations in macrophage polarization and cytokine profiles in the colon.
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Affiliation(s)
- Yoshihito Inoue
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Xin Xu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Ying Ran
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
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1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid impairs intestinal motility and olfaction in the early stages of Parkinson's disease in mice. J Neurol Sci 2018; 392:77-82. [DOI: 10.1016/j.jns.2018.07.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 06/28/2018] [Accepted: 07/12/2018] [Indexed: 12/18/2022]
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Grover M, Gibbons SJ, Nair AA, Bernard CE, Zubair AS, Eisenman ST, Wilson LA, Miriel L, Pasricha PJ, Parkman HP, Sarosiek I, McCallum RW, Koch KL, Abell TL, Snape WJ, Kuo B, Shulman RJ, McKenzie TJ, Kellogg TA, Kendrick ML, Tonascia J, Hamilton FA, Farrugia G. Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis. BMC Med Genomics 2018; 11:62. [PMID: 30086735 PMCID: PMC6081936 DOI: 10.1186/s12920-018-0379-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 07/23/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear. METHODS Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR. RESULTS 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log2fold difference of | ≥ 2| and false detection rate (FDR) < 5%. Top canonical pathways in diabetic gastroparesis included genes involved with macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, osteoarthritis pathway and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F. Top canonical pathways in idiopathic gastroparesis included genes involved in granulocyte adhesion and diapedesis, agranulocyte adhesion and diapedesis, and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Sixty-five differentially expressed genes (log2fold difference | ≥ 2|, FDR < 5%) were common in both diabetic and idiopathic gastroparesis with genes in the top 5 canonical pathways associated with immune signaling. 4/5 highly differentially expressed genes (SGK1, APOLD1, CXCR4, CXCL2, and FOS) in diabetic gastroparesis were validated in a separate cohort of patients using RT-PCR. Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05). CONCLUSIONS Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.
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Affiliation(s)
- Madhusudan Grover
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
| | - Simon J. Gibbons
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
| | - Asha A. Nair
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN USA
| | - Cheryl E. Bernard
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
| | - Adeel S. Zubair
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
| | - Seth T. Eisenman
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
| | - Laura A. Wilson
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA
| | - Laura Miriel
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA
| | | | | | | | | | | | | | | | - Braden Kuo
- Massachusetts General Hospital, Boston, MA USA
| | | | | | | | | | - James Tonascia
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA
| | - Frank A. Hamilton
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD USA
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 USA
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Fukui H, Xu X, Miwa H. Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders. J Neurogastroenterol Motil 2018; 24:367-386. [PMID: 29969855 PMCID: PMC6034676 DOI: 10.5056/jnm18071] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/21/2018] [Indexed: 12/13/2022] Open
Abstract
Gut microbiota exert a pivotal influence on various functions including gastrointestinal (GI) motility, metabolism, nutrition, immunity, and the neuroendocrine system in the host. These effects are mediated by not only short-chain fatty acids produced by microbiota but also gut hormones and inflammatory signaling by enteroendocrine and immune cells under the influence of the microbiota. GI motility is orchestrated by the enteric nervous system and hormonal networks, and disturbance of GI motility plays an important role in the pathophysiology of functional gastrointestinal disorders (FGIDs). In this context, microbiota-associated mediators are considered to act on specific receptors, thus affecting the enteric nervous system and, subsequently, GI motility. Thus, the pathophysiology of FGIDs is based on alterations of the gut microbiota/gut hormone axis, which have crucial effects on GI motility.
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Affiliation(s)
- Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
| | - Xin Xu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
- Department of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin,
China
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
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Matsumoto K, Kawanaka H, Hori M, Kusamori K, Utsumi D, Tsukahara T, Amagase K, Horie S, Yamamoto A, Ozaki H, Mori Y, Kato S. Role of transient receptor potential melastatin 2 in surgical inflammation and dysmotility in a mouse model of postoperative ileus. Am J Physiol Gastrointest Liver Physiol 2018; 315:G104-G116. [PMID: 29565641 DOI: 10.1152/ajpgi.00305.2017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this study, we investigated the role of transient receptor potential melastatin 2 (TRPM2), a nonselective cation channel abundantly expressed in inflammatory cells such as macrophages, in the development of postoperative ileus, a complication of abdominal surgery characterized by gastrointestinal dysmotility. In wild-type mice, we found that intestinal manipulation, a maneuver that elicits symptoms typical of postoperative ileus, delays the transit of fluorescein-labeled dextran, promotes the infiltration of CD68+ macrophages, Ly6B.2+ neutrophils, and MPO+ cells into intestinal muscles, boosts expression of IL-1β, IL-6, TNF-α, iNOS, and CXCL2 in intestinal muscles and peritoneal macrophages, enhances phosphorylation of ERK and p38 MAPK in intestinal muscles, and amplifies IL-1β, IL-6, TNF-α, iNOS, and CXCL2 expression in resident and thioglycolate-elicited peritoneal macrophages following exposure to lipopolysaccharide. Remarkably, TRPM2 deficiency completely blocks or diminishes these effects. Indeed, intestinal manipulation appears to activate TRPM2 in resident muscularis macrophages and elicits release of inflammatory cytokines and chemokines, which, in turn, promote infiltration of macrophages and neutrophils into the muscle, ultimately resulting in dysmotility. NEW & NOTEWORTHY Activation of transient receptor potential melastatin 2 (TRPM2) releases inflammatory cytokines and chemokines, which, in turn, promote the infiltration of inflammatory cells and macrophages into intestinal muscles, ultimately resulting in dysmotility. Thus TRPM2 is a promising target in treating dysmotility due to postoperative ileus, a complication of abdominal surgery.
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Affiliation(s)
- Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Hiroki Kawanaka
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo , Tokyo , Japan
| | - Kosuke Kusamori
- Division of Clinical Pharmaceutical Sciences, Department of Biopharmaceutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Daichi Utsumi
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Takuya Tsukahara
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Kikuko Amagase
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Syunji Horie
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University , Chiba , Japan
| | - Akira Yamamoto
- Division of Clinical Pharmaceutical Sciences, Department of Biopharmaceutics, Kyoto Pharmaceutical University , Kyoto , Japan
| | - Hiroshi Ozaki
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo , Tokyo , Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University , Kyoto , Japan
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University , Kyoto , Japan
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Cipriani G, Gibbons SJ, Miller KE, Yang DS, Terhaar ML, Eisenman ST, Ördög T, Linden DR, Gajdos GB, Szurszewski JH, Farrugia G. Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice. Gastroenterology 2018; 154:2122-2136.e12. [PMID: 29501441 PMCID: PMC5985210 DOI: 10.1053/j.gastro.2018.02.027] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/15/2018] [Accepted: 02/16/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Muscularis propria macrophages lie close to cells that regulate gastrointestinal motor function, including interstitial cells of Cajal (ICC) and myenteric neurons. In animal models of diabetic gastroparesis, development of delayed gastric emptying has been associated with loss of macrophages that express cytoprotective markers and reduced networks of ICC. Mice with long-term diabetes and normal gastric emptying have macrophages that express anti-inflammatory markers and have normal gastric ICC. Mice homozygous for the osteopetrosis spontaneous mutation in the colony-stimulating factor 1 gene (Csf1op/op) do not have macrophages; when they are given streptozotocin to induce diabetes, they do not develop delayed gastric emptying. We investigated whether population of the gastric muscularis propria of diabetic Csf1op/op mice with macrophages is necessary to change gastric emptying, ICC, and myenteric neurons and investigated the macrophage-derived factors that determine whether diabetic mice do or do not develop delayed gastric emptying. METHODS Wild-type and Csf1op/op mice were given streptozotocin to induce diabetes. Some Csf1op/op mice were given daily intraperitoneal injections of CSF1 for 7 weeks; gastric tissues were collected and cellular distributions were analyzed by immunohistochemistry. CD45+, CD11b+, F4/80+ macrophages were dissociated from gastric muscularis propria, isolated by flow cytometry and analyzed by quantitative real-time polymerase chain reaction. Cultured gastric muscularis propria from Csf1op/op mice was exposed to medium that was conditioned by culture with bone marrow-derived macrophages from wild-type mice. RESULTS Gastric muscularis propria from Csf1op/op mice given CSF1 contained macrophages; 11 of 15 diabetic mice given CSF1 developed delayed gastric emptying and had damaged ICC. In non-diabetic Csf1op/op mice, administration of CSF1 reduced numbers of gastric myenteric neurons but did not affect the proportion of nitrergic neurons or ICC. In diabetic Csf1op/op mice given CSF1 that developed delayed gastric emptying, the proportion of nitrergic neurons was the same as in non-diabetic wild-type controls. Medium conditioned by macrophages previously exposed to oxidative injury caused damage to ICC in cultured gastric muscularis propria from Csf1op/op mice; neutralizing antibodies against IL6R or TNF prevented this damage to ICC. CD45+, CD11b+, and F4/80+ macrophages isolated from diabetic wild-type mice with delayed gastric emptying expressed higher levels of messenger RNAs encoding inflammatory markers (IL6 and inducible nitric oxide synthase) and lower levels of messenger RNAs encoding markers of anti-inflammatory cells (heme oxygenase 1, arginase 1, and FIZZ1) than macrophages isolated from diabetic mice with normal gastric emptying. CONCLUSIONS In studies of Csf1op/op and wild-type mice with diabetes, we found delayed gastric emptying to be associated with increased production of inflammatory factors, and reduced production of anti-inflammatory factors, by macrophages, leading to loss of ICC.
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Kodani M, Fukui H, Tomita T, Oshima T, Watari J, Miwa H. Association between gastrointestinal motility and macrophage/mast cell distribution in mice during the healing stage after DSS‑induced colitis. Mol Med Rep 2018; 17:8167-8172. [PMID: 29693127 PMCID: PMC5983995 DOI: 10.3892/mmr.2018.8926] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 04/11/2018] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) frequently occurs after infectious colitis or inflammatory bowel disease in patients with complete remission. This suggests that post‑inflammation‑associated factors may serve a role in the pathophysiology of IBS; however, the mechanism responsible remains unclear. In the present study, the involvement of macrophages and mast cells in alteration of gastrointestinal (GI) motility was investigated in mice in the remission stage after acute colitis. C57BL/6 mice were administered 2% dextran sulfate sodium in drinking water for 5 days and their intestinal tissues were investigated at intervals for up to 24 weeks. Expression of the mannose receptor (MR) and tryptase was examined by immunohistochemistry, and the GI transit time (GITT) was measured by administration of carmine red solution. A minimal degree of inflammatory cell infiltration persisted in the colon and also the small intestine of mice in remission after colitis and the GITT was significantly shorter. The number of muscularis MR‑positive macrophages was significantly increased in the small intestine of mice in remission after colitis and negatively correlated with GITT. Furthermore, results indicated that the number of muscularis tryptase‑positive mast cells was significantly increased throughout the intestine of mice during the healing process after colitis and was positively correlated with GITT. The present findings suggested an increased number of macrophages and/or mast cells in the intestinal muscular layer may be associated with the pathophysiology of GI dysmotility after colitis.
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Affiliation(s)
- Mio Kodani
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
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Abstract
Impaired Paneth cell expression of antimicrobial protein (AMP) lysozyme is found in patients with Crohn's disease with the autophagy gene ATG16L1 risk allele, in mice with mutations in autophagy genes Atg16L1, Atg5 and Atg7, and in Irgm1 knockout mice. Defective autophagy is also associated with expansion of resident Gram-negative bacteria in the intestinal lumen. These findings suggest that autophagy may control extracellular resident microbes by governing expression of lysozyme. To test the hypothesis that autophagy may have a defensive role in host response to resident extracellular microbes, we investigated the relationship between gut microbes, autophagy, and lysozyme. RAW 264.7 macrophages were treated with fecal slurry (FS), representing the resident microbial community; lipopolysaccharide (LPS); or butyrate, representing microbial products; or a representative resident Gram-negative bacterium Desulfovibrio vulgaris (DSV). FS, LPS, and DSV inhibited lysozyme expression, whereas butyrate had no effect. Induction of autophagy by rapamycin countered this inhibition, whereas silencing of the autophagy gene Irgm1 exacerbated the inhibitory effects of LPS on lysozyme expression. LPS also inhibited lysozyme activity against DSV and autophagy reversed this effect. Our results provide a novel insight into an interaction between gut bacteria, autophagy and AMP whereby autophagy may defend the host by countering the suppression of antimicrobial protein by Gram-negative bacteria.
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Affiliation(s)
- Sudha B Singh
- 1 Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, USA.,2 Division of Gastroenterology and Hepatology, Department of Medicine, the University of New Mexico, Albuquerque, NM, USA
| | - Henry C Lin
- 1 Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, USA.,2 Division of Gastroenterology and Hepatology, Department of Medicine, the University of New Mexico, Albuquerque, NM, USA
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Liu YH, Ding Y, Gao CC, Li LS, Wang YX, Xu JD. Functional macrophages and gastrointestinal disorders. World J Gastroenterol 2018; 24:1181-1195. [PMID: 29568199 PMCID: PMC5859221 DOI: 10.3748/wjg.v24.i11.1181] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 02/12/2018] [Accepted: 02/25/2018] [Indexed: 02/06/2023] Open
Abstract
Macrophages (MΦ) differentiate from blood monocytes and participate in innate and adaptive immunity. Because of their abilities to recognize pathogens and activate bactericidal activities, MΦ are always discovered at the site of immune defense. MΦ in the intestine are unique, such that in the healthy intestine, they possess complex mechanisms to protect the gut from inflammation. In these complex mechanisms, they produce anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor-β, and inhibit the inflammatory pathways mediated by Toll-like receptors. It has been demonstrated that resident MΦ play a crucial role in maintaining intestinal homeostasis, and they can be recognized by their unique markers. Nonetheless, in the inflamed intestine, the function of MΦ will change because of environmental variation, which may be one of the mechanisms of inflammatory bowel disease (IBD). We provide further explanation about these mechanisms in our review. In addition, we review recent discoveries that MΦ may be involved in the development of gastrointestinal tumors. We will highlight the possible therapeutic targets for the management of IBD and gastrointestinal tumors, and we also discuss why more details are needed to fully understand all other effects of intestinal MΦ.
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Affiliation(s)
- Yue-Hong Liu
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Yue Ding
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Chen-Chen Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Function Platform Center, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Yue-Xiu Wang
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
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Brun P, Qesari M, Marconi PC, Kotsafti A, Porzionato A, Macchi V, Schwendener RA, Scarpa M, Giron MC, Palù G, Calistri A, Castagliuolo I. Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment. Front Cell Infect Microbiol 2018; 8:74. [PMID: 29600197 PMCID: PMC5862801 DOI: 10.3389/fcimb.2018.00074] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/27/2018] [Indexed: 12/27/2022] Open
Abstract
Herpes Simplex Virus type 1 (HSV-1), a neurotropic pathogen widespread in human population, infects the enteric nervous system (ENS) in humans and rodents and causes intestinal neuromuscular dysfunction in rats. Although infiltration of inflammatory cells in the myenteric plexus and neurodegeneration of enteric nerves are common features of patients suffering from functional intestinal disorders, the proof of a pathogenic link with HSV-1 is still unsettled mainly because the underlying mechanisms are largely unknown. In this study we demonstrated that following intragastrical administration HSV-1 infects neurons within the myenteric plexus resulting in functional and structural alterations of the ENS. By infecting mice with HSV-1 replication-defective strain we revealed that gastrointestinal neuromuscular anomalies were however independent of viral replication. Indeed, enteric neurons exposed to UV-inactivated HSV-1 produced monocyte chemoattractant protein-1 (MCP-1/CCL2) to recruit activated macrophages in the longitudinal muscle myenteric plexus. Infiltrating macrophages produced reactive oxygen and nitrogen species and directly harmed enteric neurons resulting in gastrointestinal dysmotility. In HSV-1 infected mice intestinal neuromuscular dysfunctions were ameliorated by in vivo administration of (i) liposomes containing dichloromethylene bisphosphonic acid (clodronate) to deplete tissue macrophages, (ii) CCR2 chemokine receptor antagonist RS504393 to block the CCL2/CCR2 pathway, (iii) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and AR-C 102222 to quench production of nitrogen reactive species produced via iNOS. Overall these data demonstrate that HSV-1 infection makes enteric neurons recruit macrophages via production of a specific chemoattractant factor. The resulting inflammatory reaction is mandatory for intestinal dysmotility. These findings provide insights into the neuro-immune communication that occurs in the ENS following HSV-1 infection and allow recognition of an original pathophysiologic mechanism underlying gastrointestinal diseases as well as identification of novel therapeutic targets.
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Affiliation(s)
- Paola Brun
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Marsela Qesari
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Peggy C Marconi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Andromachi Kotsafti
- Esophageal and Digestive Tract Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | | | - Veronica Macchi
- Department of Neurosciences, University of Padova, Padova, Italy
| | - Reto A Schwendener
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Marco Scarpa
- Esophageal and Digestive Tract Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Maria C Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Giorgio Palù
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Arianna Calistri
- Department of Molecular Medicine, University of Padova, Padova, Italy
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Yuan PQ, Taché Y. Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats. Am J Physiol Gastrointest Liver Physiol 2017; 313:G320-G329. [PMID: 28684460 PMCID: PMC6134391 DOI: 10.1152/ajpgi.00121.2017] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 06/20/2017] [Accepted: 06/27/2017] [Indexed: 01/31/2023]
Abstract
Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric corpus were determined. AS inhibited GE by 72% vs. control and doubled the number of M1-like macrophage immunoreactive for major histocompatibility complex class II (MHCII; M1 marker) but not for cluster of differentiation 206 (CD206; M2 marker) (MHCII+/CD206-) while there was no change in M2-like macrophages (MHCII-/CD206+). AS increased mRNA levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) by 1.7- and 1.5-fold, respectively, in the gastric submucosa plus muscle layers and the infiltration of neutrophils labeled by myeloperoxidase by 9.5-fold in the muscularis externa. RX-77368 inhibited AS-related gastric changes while not altering these parameters in the sham group. There was a significant negative correlation between GE and IL-1β (r = -0.46), TNF-α (r = -0.44), M1 macrophage (r = -0.82), and neutrophils (r = -0.91). The M2-like macrophages and IL-10 expression were unchanged by AS with intracisternal saline or RX-77368. These data indicate that AS activates gastric M1 macrophages and increases proinflammatory cytokines expression, which are prevented by central vagal activation and may contribute to the correlated dampening of postoperative gastric ileus.NEW & NOTEWORTHY MHCII+/CD206- (M1) and MHCII-/CD206+ (M2) constitute two distinct populations of macrophages that are in close apposition to the cholinergic neurons in the rat gastric myenteric plexus (MP). Abdominal surgery (6 h) activates M1 macrophage leading to inflammation in the gastric MP correlated with the delayed gastric emptying, which was abolished by central vagal stimulation via intracisternal injection of RX-77368. Vagal stimulation linked with the cephalic phase may have potential beneficial effects to curtail postoperative gastric ileus.
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Affiliation(s)
- Pu-Qing Yuan
- CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California; and
| | - Yvette Taché
- 1CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California; and ,2Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, California
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Feldbrügge L, Moss AC, Yee EU, Csizmadia E, Mitsuhashi S, Longhi MS, Sandhu B, Stephan H, Wu Y, Cheifetz AS, Müller CE, Sévigny J, Robson SC, Jiang ZG. Expression of Ecto-nucleoside Triphosphate Diphosphohydrolases-2 and -3 in the Enteric Nervous System Affects Inflammation in Experimental Colitis and Crohn's Disease. J Crohns Colitis 2017; 11:1113-1123. [PMID: 28472257 PMCID: PMC5881706 DOI: 10.1093/ecco-jcc/jjx058] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 04/03/2017] [Accepted: 04/24/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Recent studies have suggested that the enteric nervous system can modulate gut immunity. Ecto-nucleoside triphosphate diphosphohydrolases [E-NTPDases] regulate purinergic signalling by sequential phosphohydrolysis of pro-inflammatory extracellular adenosine 5'-triphosphate [ATP]. Herein, we test the hypothesis that E-NTPDases modulate gut inflammation via neuro-immune crosstalk. DESIGN We determined expression patterns of NTPDase2 and NTPDase3 in murine and human colon. Experimental colitis was induced by dextran sodium sulphate [DSS] in genetically engineered mice deficient in NTPDase2 or NTPDase3. We compared plasma adenosine diphosphatase [ADPase] activity from Crohn's patients and healthy controls, and linked the enzyme activity to Crohn's disease activity. RESULTS NTPDase2 and -3 were chiefly expressed in cells of the enteric nervous system in both murine and human colon. When compared with wild type, DSS-induced colitis was exacerbated in Entpd2, and to a lesser extent, Entpd3 null mice as measured by disease activity score and histology, and marked anaemia was seen in both. Colonic macrophages isolated from Entpd2 null mice displayed a pro-inflammatory phenotype compared with wild type. In human plasma, Crohn's patients had decreases in ADPase activity when compared with healthy controls. The drop in ADPase activity was likely associated with changes in NTPDase2 and -3, as suggested by inhibitor studies, and were correlated with Crohn's disease activity. CONCLUSIONS NTPDase2 and -3 are ecto-enzymes expressed in the enteric nervous system. Both enzymes confer protection against gut inflammation in experimental colitis and exhibit alterations in Crohn's disease. These observations suggest that purinergic signalling modulated by E-NTPDases governs neuro-immune interactions that are relevant in Crohn's disease.
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Affiliation(s)
- Linda Feldbrügge
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Surgery, Charité Universitätsmedizin, Berlin, Germany
| | - Alan C Moss
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Eric U Yee
- Department of Pathology, OU Medical Center, Oklahoma City, USA
| | - Eva Csizmadia
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Shuji Mitsuhashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Maria Serena Longhi
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Bynvant Sandhu
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Holger Stephan
- Helmholtz-Zentrum Dresden–Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Yan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Adam S Cheifetz
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | - Jean Sévigny
- Département de Microbiologie-infectiologie et d’Immunologie, Université Laval, Québec, QC, Canada
- Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada
| | - Simon C Robson
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Z Gordon Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Intestinal macrophages in Peyer's patches, sacculus rotundus and appendix of Angora rabbit. Cell Tissue Res 2017; 370:285-295. [PMID: 28766043 DOI: 10.1007/s00441-017-2659-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 05/30/2017] [Indexed: 12/14/2022]
Abstract
The largest pool of macrophages in the body is harboured by the intestinal mucosa. As the principal phagocytic component of the immune system, macrophages are essential for maintaining mucosal homeostasis as they prevent commensal bacteria from adhering to mucosal epithelial cells. This study provides a RAM11 immunohistochemical and electron microscopic investigation of the existence, localization and distribution of intestinal macrophages in organized gut-associated lymphoid tissue (GALT), including Peyer's patches (PPs), the sacculus rotundus (SR) and the appendix, in the Angora rabbit. Although rabbit intestinal macrophages did not express the tissue macrophage marker macrosialin (CD68), they expressed RAM11. RAM11-positive intestinal macrophages were mostly localized to the subepithelial dome region, interfollicular area and germinal centres (GCs) of the GALT and the lamina propria or submucosa of the ileum and jejunum devoid of PPs and were also observed in the follicle-associated epithelium of PPs, but not in that of the SR and appendix. RAM11-positive macrophages containing engulfed apoptotic bodies were present in the GCs of the lymphoid follicles in the GALT. Electron microscopy further revealed multiple macrophages containing apoptotic bodies within the GCs of the follicles in the GALT. Some macrophage aggregations were observed in the GC and between the GC and the corona region of the follicles in the SR and appendix. Rabbit intestinal macrophages thus undertake both potent phagocytic activity and the efficient scavenging of apoptotic cells. Immunohistochemical data suggest that RAM11 can be reliably used for the determination of intestinal macrophages in the GALT of rabbits.
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