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Tsubota M, Sasaki K, Shin E, Okamura Y, Nishimura A, Yamagata A, Nonaka Y, Sekiguchi F, Tomono Y, Nishibori M, Okada T, Toyooka N, Kawabata A. HMGB1 derived from macrophages and enteric glial cells contributes to the butyrate-induced colonic hypersensitivity in mice. Eur J Pharmacol 2025; 999:177660. [PMID: 40274181 DOI: 10.1016/j.ejphar.2025.177660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 03/30/2025] [Accepted: 04/22/2025] [Indexed: 04/26/2025]
Abstract
High mobility group box1 (HMGB1), a nuclear protein, once acetylated by histone acetyltransferase, is released into the extracellular space, and causes pain signals, thereby contributing to pathological pain. Repeated intracolonic administration of butyrate, known to inhibit histone deacetylase (HDAC), produces colonic hypersensitivity in rodents, being widely used as models for irritable bowel syndrome (IBS). Thus, we asked whether HMGB1 would participate in the butyrate-induced colonic hypersensitivity in mice, and analyzed the underlying mechanisms. Repeated butyrate treatment caused colonic hypersensitivity to distension and intraluminal sulfide, a functional enhancer of Cav3.2 channels, in mice, which was prevented by repeated treatment with an anti-HMGB1-neutralizing antibody, thrombomodulin alfa (TMα) capable of causing thrombin-dependent degradation of HMGB1, antagonists for RAGE, TLR4 and CXCR4, membrane receptors of HMGB1, liposomal clodronate, a macrophage depletor, and ethyl pyruvate capable of inhibiting HMGB1 release from macrophages. Butyrate treatment increased the number of Iba1-positive macrophages, but not S100B-positive enteric glial cells (EGCs), and the rate of cytosolic/whole cell HMGB1 levels in both types of cells in the colonic mucosa. In macrophage-like RAW264.7 cells and EGC-like CRL-2690 cells, butyrate as well as trichostatin A, a well-known HDAC inhibitor, at the same concentrations that increased histone acetylation, evoked cytoplasmic translocation and extracellular release of nuclear HMGB1. Together, butyrate is considered to cause HMGB1 release from macrophages and EGCs most probably by inhibiting HDAC, resulting in colonic hypersensitivity in mice. HMGB1 and its membrane receptors might serve as drug targets for colonic hypersensitivity in IBS patients.
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Affiliation(s)
- Maho Tsubota
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Kana Sasaki
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Eunkyung Shin
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Yuta Okamura
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Ayaka Nishimura
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Ayumu Yamagata
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Yui Nonaka
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Fumiko Sekiguchi
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Yasuko Tomono
- Department of Translational Research and Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Masahiro Nishibori
- Department of Translational Research and Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Takuya Okada
- Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan
| | - Naoki Toyooka
- Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan
| | - Atsufumi Kawabata
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan.
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Meerschaert KA, Chiu IM. The gut-brain axis and pain signalling mechanisms in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2025; 22:206-221. [PMID: 39578592 DOI: 10.1038/s41575-024-01017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 11/24/2024]
Abstract
Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut-brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell-cell communication is integrated into this gut-brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain.
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Affiliation(s)
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
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Feng A, Su S, Li Q, Li C, Liu Y, Qiu J. 1,25-dihydroxyvitamin D3 regulates enteroglial bioactivity through butyric acid pathway in a high-fat diet mouse model. J Steroid Biochem Mol Biol 2025; 247:106655. [PMID: 39647536 DOI: 10.1016/j.jsbmb.2024.106655] [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: 11/07/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 12/10/2024]
Abstract
1,25-dihydroxyvitamin D3 (1,25(OH)2D3), affects enteric glial cells (EGCs) activity, but the mechanism is still unknown. The current study aimed to explore whether 1,25(OH)2D3 could regulate EGCs activity via butyrate pathway in a high-fat diet model. Male C57BL/6 J mice were fed with standard diet (SDD), or vitamin-D-deficient diet (VDD), or high-fat diet (HFD), or HFD plus sodium butyrate (SBR), or HFD plus 1,25(OH)2D3, or HFD plus S100B inhibitor ONO-2506 in vivo. CRL-2690 and Caco-2 cells were treated with palmitic acid (PA) and oleic acid (OA) complex, or S100B, or S100B plus butyric acid (BA) in vitro. 25(OH)D3, 1,25(OH)2D3, TNF-α and S100B concentrations were assayed by enzyme-linked immuno- sorbent assay (ELISA). Colonic mucosal permeability was measured by using FITC-dextran 4 kDa. Colonic butyrate was detected using high-performance liquid chromatography (HPLC). The results showed HFD decreased serum 25(OH)D3 and 1,25(OH)2D3 concentrations and colonic butyrate generation. 1,25(OH)2D3 supplementation raised butyrate production in the colon. 1,25(OH)2D3 and sodium butyrate supplementation inhibited EGCs to produce S100B and reduced colonic permeability to FITC-dextran. Inhibition of S100B pathway by ONO- 2506 decreased colonic hyperpermeability. In vitro experiments showed butyrate treatment not only reduced S100B and TNF-α secretion from PA/OA-treated CRL-2690 cells, but also decreased the permeability of S100B-treated Caco-2 cells. Collectively, 1,25(OH)2D3 elicited butyrate to suppress EGCs activation, which helped to prevent intestinal barrier injury.
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Affiliation(s)
- Aiwen Feng
- The First Clinical Medical College, Guangdong Medical University, China; Department I of Gastrointestinal Surgery, Affiliated Maoming Hospital, Southern Medical University, China; Department I of Gastrointestinal Surgery, Maoming People's Hospital, Maoming City, China.
| | - Shaosheng Su
- The First Clinical Medical College, Guangdong Medical University, China
| | - Qian Li
- The First Clinical Medical College, Guangdong Medical University, China; Department I of Gastrointestinal Surgery, Affiliated Maoming Hospital, Southern Medical University, China; Department I of Gastrointestinal Surgery, Maoming People's Hospital, Maoming City, China
| | - Cheng Li
- Department I of Gastrointestinal Surgery, Affiliated Maoming Hospital, Southern Medical University, China
| | - Yingyan Liu
- The First Clinical Medical College, Guangdong Medical University, China
| | - Jiasheng Qiu
- The First Clinical Medical College, Guangdong Medical University, China; Department I of Gastrointestinal Surgery, Affiliated Maoming Hospital, Southern Medical University, China; Department I of Gastrointestinal Surgery, Maoming People's Hospital, Maoming City, China
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Deng N, Xie S, Liu Q, Peng H, Fang L, Shen J, Lin X. The intestinal microbiota modulates the visceral sensitivity involved in IBS induced by restraint combined with tail clustering. Front Cell Infect Microbiol 2025; 15:1549617. [PMID: 40051709 PMCID: PMC11882872 DOI: 10.3389/fcimb.2025.1549617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 01/28/2025] [Indexed: 03/09/2025] Open
Abstract
Objective To compare three common stimuli that induce emotional stress to identify the optimal method for establishing an animal model that aligns with the clinical pathogenesis of irritable bowel syndrome (IBS) and to explore the gut microbiota mechanisms underlying IBS development. Methods Thirty-six SPF-grade female Kunming mice were randomly divided into four groups: the normal control (NC) group, the restraint stress (BM) group, the tail clamp stress (CTM) group, and the restraint combined with tail clamp stress (BCTM) group, with 9 mice in each group. The NC group was fed normally without any stimulation. The BM group was subjected to restraint stress. The CTM group received intermittent tail clamp stress. The BCTM group underwent both restraint stress and intermittent tail clamp stress. The stimulation time for each group was 1 hour, and the modeling duration was 7 days. General behavioral changes in the mice were observed. The fecal water content was measured and calculated. The pain threshold, gastric residue rate, small intestine propulsion rate, and serum levels of short-chain fatty acids (SCFAs), serotonin (5-HT), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α) were assessed. Histopathological analysis of the small intestine and colon tissues was performed. 16S rRNA high-throughput sequencing was subsequently conducted. The effects of different stimuli on mouse symptoms, gastrointestinal motility, visceral hypersensitivity, inflammation levels, and the gut microbiota were analyzed, and correlation analysis was performed. Results Compared with the NC group, the BM, CTM, and BCTM groups of mice presented varying degrees of emotional hyperreactivity, accompanied by significantly reduced food intake and fecal water content and markedly elevated levels of inflammation, all of which are indicative of IBS symptoms. Among them, the BCTM group presented the most pronounced emotional hyperreactivity and irritability. The mice in the BCTM group had significantly higher gastric residue rates and 5-HT levels, with a marked reduction in pain tolerance. The gut microbiota of the mice in the BM, CTM, and BCTM groups all exhibited dysbiosis, with changes in the diversity, structural composition, and function of the microbial community. Specific bacterial taxa were enriched in each stress group, and their corresponding KEGG pathways were also significantly altered. Correlation analysis revealed that SCFAs were significantly positively correlated with the small intestine propulsion rate, whereas 5-HT was positively correlated with the gastric residue rate and negatively correlated with the pain threshold. SCFAs were positively correlated with IL-10 and TNF-α, and 5-HT was significantly positively correlated with IL-10 and TNF-α. In the BCTM group, the characteristic bacteria Acinetobacter and Akkermansia were significantly correlated with SCFAs and 5-HT. Conclusion 1. The restraint combined with the tail clamp stress method is superior among the three stress protocols and successfully induces the IBS mouse model. 2. Acinetobacter and Akkermansia may contribute to the development of IBS induced by restraint combined with tail clamp stress through the regulation of SCFAs and 5-HT.
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Affiliation(s)
- Na Deng
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Siqin Xie
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Qin Liu
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Huiyi Peng
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Leyao Fang
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Junxi Shen
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xiaoyuan Lin
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Fan M, Chen T, Tian J, Zhang C, Zhao Z, Liu X, Zhang S, Chen Y. Electroacupuncture at ST36 Relieves Visceral Hypersensitivity Based on the Vagus-Adrenal Axis in the Remission Stage of Ulcerative Colitis. Neuromodulation 2025:S1094-7159(25)00004-2. [PMID: 39955664 DOI: 10.1016/j.neurom.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/28/2024] [Accepted: 12/31/2024] [Indexed: 02/17/2025]
Abstract
BACKGROUND AND AIMS Although electroacupuncture (EA) at ST36 has been shown to alleviate visceral hypersensitivity in rats with ulcerative colitis (UC), the exact mechanism remains unknown. This study aims to investigate whether EA can effectively inhibit the activity of enteric glial cells (EGCs) through the adrenergic antiinflammatory pathway and thereby attenuate visceral hypersensitivity in rats with UC in remission. MATERIALS AND METHODS Sprague-Dawley rats were continuously fed 5% dextran sulfate sodium (DSS) for seven days to establish intestinal inflammation. After seven days of remission, rats underwent EA (n = 6, 100 Hz, 1 mA, one hour) or sham EA (n = 6) for 14 days. A normal control group (n = 6) received no treatment. Inflammation was assessed using disease activity index (DAI) inflammatory cytokines. Visceral sensitivity was examined weekly by abdominal withdrawal reflexes (AWR) score. We used the enzyme-linked immunosorbent assay method to measure levels of norepinephrine (NE) in serum after EA. The expression of EGCs, levels of inflammatory cytokine S100 calcium-binding protein β (S100β), and associated pathway proteins receptor for advanced glycosylation end-products (RAGE), myeloid differentiation factor 88 (MyD88), and nuclear factor-κ B (NF-κB) in the colon were assessed using immunofluorescence staining and Western blotting. RESULTS The Model group exhibited elevated DAI scores, shortened colon, and increased inflammatory cytokines; the EA group showed significant relief of symptoms. The Model group exhibited elevated visceral hypersensitivity, which resolved after 14 days of EA treatment. The EA group exhibited higher NE levels than did the Model group. Compared with the Model group, the expression of EGCs in the colonic submucosa was reduced in the EA group, and the expression of S100β, RAGE, MyD88, and NF-κB proteins were downregulated. CONCLUSION This study suggests that EA potentially reduces visceral hypersensitivity in UC by decreasing the activity of EGCs and the release of S100β through noradrenergic pathway.
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Affiliation(s)
- Mingwei Fan
- Binzhou Medical University, Binzhou, Shandong, China
| | - Tan Chen
- Binzhou Medical University, Binzhou, Shandong, China
| | - Jinlan Tian
- Binzhou Medical University, Binzhou, Shandong, China
| | - Can Zhang
- Binzhou Medical University, Binzhou, Shandong, China
| | - Zijian Zhao
- Binzhou Medical University, Binzhou, Shandong, China
| | - Xinru Liu
- Binzhou Medical University, Binzhou, Shandong, China
| | - Shuhui Zhang
- Binzhou Medical University, Binzhou, Shandong, China; Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yan Chen
- Binzhou Medical University, Binzhou, Shandong, China; Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China.
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Li YJ, Li J, Dai C. Butyrate promotes visceral hypersensitivity in IBS model via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway. mBio 2024; 15:e0153324. [PMID: 38953358 PMCID: PMC11323730 DOI: 10.1128/mbio.01533-24] [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: 05/24/2024] [Accepted: 06/02/2024] [Indexed: 07/04/2024] Open
Abstract
Emerging evidence indicates that gut dysbiosis is involved in the pathogenesis of visceral hypersensitivity (VH). However, how gut microbiota contributes to the development of VH is unknown. Here, we sought to examine the signal transduction pathways from gut to dorsal root ganglion (DRG) responsible for this. Therefore, abdominal withdrawal reflex (AWR) scores, fecal output, fecal water content, and total gastrointestinal transit time (TGITT) were assessed in Con rats, VH rats, rats treated with NaB, and VH rats treated with VSL#3. Fecal microbiota and its metabolite (short-chain fatty acids, SCFAs), mast cell degranulation in colon, lincRNA-01028, miR-143, and protease kinase C (PKC) and TRPV1 expression in DRGs were further detected. VH rats showed an increased fecal water content, a shortened TGITT, an increased abundance of Clostridium sensu stricto 1 and increased butyrate in fecal samples, an increased mast cell degranulation, an increased expression of lincRNA-01028, PKC, and TRPV1, and a decreased expression of miR-143 in DRGs compared with control rats, which could be restored by the application of probiotic VSL#3. The above-mentioned detection in rats treated with butyrate was similar to that of VH rats. We further confirm whether butyrate sensitized DRG neurons by a lincRNA-01028, miR-143, and PKC-dependent mechanism via mast cell in vitro. In co-cultures, MCs treated with butyrate elicited a higher TRPV1 current, a higher expression of lincRNA-01028, PKC, and a lower expression of miR-143 in DRG neurons, which could be inhibited by a lincRNA-01028 inhibitor. These findings indicate that butyrate promotes visceral hypersensitivity via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.IMPORTANCEIrritable bowel syndrome (IBS), characterized by visceral hypersensitivity, is a common gastrointestinal dysfunction syndrome. Although the gut microbiota plays a role in the pathogenesis and treatment of irritable bowel syndrome (IBS), the possible underlying mechanisms are unclear. Therefore, it is of critical importance to determine the signal transduction pathways from gut to DRG responsible for this in vitro and in vivo assay. This study demonstrated that butyrate sensitized TRPV1 in DRG neurons via mast cells in vivo and in vitro by a lincRNA-01028, miR-143, and PKC-dependent mechanism. VH rats similarly showed an increased abundance of Clostridium sensu stricto 1, an increased fecal butyrate, an increased mast cell degranulation, and increased expression of TRPV1 compared with control rats, which could be restored by the application of VSL#3. In conclusion, butyrate produced by the altered intestinal microbiota is associated with increased VH.
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Affiliation(s)
- Ying-Jie Li
- Department of Gastroenterology, First Affiliated Hospital, Jinzhou Medical University, Jinzhou City, Liaoning Province, China
| | - Jing Li
- Department of Gastroenterology, First Affiliated Hospital, Jinzhou Medical University, Jinzhou City, Liaoning Province, China
| | - Cong Dai
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China
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Tang Y, Du J, Wu H, Wang M, Liu S, Tao F. Potential Therapeutic Effects of Short-Chain Fatty Acids on Chronic Pain. Curr Neuropharmacol 2024; 22:191-203. [PMID: 36173071 PMCID: PMC10788890 DOI: 10.2174/1570159x20666220927092016] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/03/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022] Open
Abstract
The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.
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Affiliation(s)
- Yuanyuan Tang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Key Laboratory for Molecular Neurology of Xinxiang, Xinxiang, Henan, China
| | - Juan Du
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hongfeng Wu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Mengyao Wang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Sufang Liu
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
| | - Feng Tao
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
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Verma N, Kumar J, Kanojia N, Thapa K, Dua K. Nutraceuticals and phytoceuticals in the treatment of colon disorders. ADVANCED DRUG DELIVERY SYSTEMS FOR COLONIC DISORDERS 2024:223-241. [DOI: 10.1016/b978-0-443-14044-0.00011-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Fujikawa Y, Tominaga K. Enhanced neuron-glia network in the submucosa and increased neuron outgrowth into the mucosa are associated with distinctive expressions of neuronal factors in the colon of rat IBS model. Neurogastroenterol Motil 2023; 35:e14595. [PMID: 37170695 DOI: 10.1111/nmo.14595] [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: 08/01/2022] [Revised: 01/16/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023]
Abstract
BACKGROUND Neuronal attraction and repulsion factors regulate neuron network formation. In the colon of irritable bowel syndrome (IBS), neuron network and enteric glial cells (EGCs) in the submucosa, neuronal outgrowth in the mucosa, and expressions of neuronal factors remain unknown. METHODS IBS models were prepared by intracolonic injections of acetic acid to Wistar Kyoto (WKY) rats. Using whole-mount submucosal plexus tissue stripped from the distal colon, we examined neuron network, EGC morphology, and localization of both attraction factor (nerve growth factor: NGF) and repulsion factor (semaphorin3A: Sema3A). We evaluated mRNA expressions of NGF and Sema3A in the mucosa and submucosa and neuron outgrowth into the mucosa. KEY RESULTS In IBS models, nerve fibers were thickened and densely increased in the submucosa remarkably from the outer toward the inner plexus. Submucosal EGCs exhibited process hyperplasia and bulbous swelling of terminals. NGF was predominantly expressed in EGCs than neurons in the submucosa. NGF mRNA expressions were increased in the submucosa in WKY, and their expressions were increased in the mucosa after the injection. Sema3A mRNA expressions were increased in both layers of WKY but tended to be decreased in the mucosa alone after the injection. Neuron outgrowth was increased into the mucosa. NGF was localized at EGCs in the lamina propria mucosae but not mucosal mast cells. CONCLUSIONS & INFERENCES Neuron network enhancement in the submucosa and neuron outgrowth into the mucosa may be associated with axon guidance factors expressed in hyperplastic EGCs in the colonic submucosa of IBS models.
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Dothel G, Barbaro MR, Di Vito A, Ravegnini G, Gorini F, Monesmith S, Coschina E, Benuzzi E, Fuschi D, Palombo M, Bonomini F, Morroni F, Hrelia P, Barbara G, Angelini S. New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics. J Gastroenterol 2023; 58:605-621. [PMID: 37160449 PMCID: PMC10307698 DOI: 10.1007/s00535-023-01997-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/19/2023] [Indexed: 05/11/2023]
Abstract
Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology.
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Affiliation(s)
- Giovanni Dothel
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Connect By Circular Lab SRL, Madrid, Spain
| | | | - Aldo Di Vito
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Francesca Gorini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Sarah Monesmith
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Emma Coschina
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Eva Benuzzi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Daniele Fuschi
- IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Marta Palombo
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesca Bonomini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabiana Morroni
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Inter-Departmental Center for Health Sciences & Technologies, CIRI-SDV, University of Bologna, Bologna, Italy
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Fusco W, Lorenzo MB, Cintoni M, Porcari S, Rinninella E, Kaitsas F, Lener E, Mele MC, Gasbarrini A, Collado MC, Cammarota G, Ianiro G. Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients 2023; 15:2211. [PMID: 37432351 DOI: 10.3390/nu15092211] [Citation(s) in RCA: 340] [Impact Index Per Article: 170.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 04/30/2023] [Accepted: 05/02/2023] [Indexed: 07/12/2023] Open
Abstract
Short-chain fatty acids (SCFAs) play a key role in health and disease, as they regulate gut homeostasis and their deficiency is involved in the pathogenesis of several disorders, including inflammatory bowel diseases, colorectal cancer, and cardiometabolic disorders. SCFAs are metabolites of specific bacterial taxa of the human gut microbiota, and their production is influenced by specific foods or food supplements, mainly prebiotics, by the direct fostering of these taxa. This Review provides an overview of SCFAs' roles and functions, and of SCFA-producing bacteria, from their microbiological characteristics and taxonomy to the biochemical process that lead to the release of SCFAs. Moreover, we will describe the potential therapeutic approaches to boost the levels of SCFAs in the human gut and treat different related diseases.
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Affiliation(s)
- William Fusco
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Manuel Bernabeu Lorenzo
- Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), 46022 Valencia, Spain
| | - Marco Cintoni
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
| | - Serena Porcari
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Emanuele Rinninella
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
| | - Francesco Kaitsas
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Elena Lener
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Maria Cristina Mele
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Maria Carmen Collado
- Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), 46022 Valencia, Spain
| | - Giovanni Cammarota
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Gianluca Ianiro
- Department of Medical and Surgical Sciences, Digestive Disease Center, Universitary Policlinic Agostino Gemelli Foundation IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
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Shin A, Kashyap PC. Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead. Gut Microbes 2023; 15:2195792. [PMID: 37009874 PMCID: PMC10072066 DOI: 10.1080/19490976.2023.2195792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/23/2023] [Indexed: 04/04/2023] Open
Abstract
Reliable biomarkers for common disorders of gut-brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.
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Affiliation(s)
- Andrea Shin
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Purna C. Kashyap
- Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Enteric Neuromics: How High-Throughput "Omics" Deepens Our Understanding of Enteric Nervous System Genetic Architecture. Cell Mol Gastroenterol Hepatol 2022; 15:487-504. [PMID: 36368612 PMCID: PMC9792566 DOI: 10.1016/j.jcmgh.2022.10.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/09/2022]
Abstract
Recent accessibility to specialized high-throughput "omics" technologies including single cell RNA sequencing allows researchers to capture cell type- and subtype-specific expression signatures. These omics methods are used in the enteric nervous system (ENS) to identify potential subtypes of enteric neurons and glia. ENS omics data support the known gene and/or protein expression of functional neuronal and glial cell subtypes and suggest expression patterns of novel subtypes. Gene and protein expression patterns can be further used to infer cellular function and implications in human disease. In this review we discuss how high-throughput "omics" data add additional depth to the understanding of established functional subtypes of ENS cells and raise new questions by suggesting novel ENS cell subtypes with unique gene and protein expression patterns. Then we investigate the changes in these expression patterns during pathology observed by omics research. Although current ENS omics studies provide a plethora of novel data and therefore answers, they equally create new questions and routes for future study.
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Aguilera-Lizarraga J. Gut reactions: emerging mechanisms of abdominal pain from food intake. Am J Physiol Gastrointest Liver Physiol 2022; 323:G401-G409. [PMID: 36126222 DOI: 10.1152/ajpgi.00173.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Abdominal pain, which is a form of visceral pain, is a highly prevalent symptom worldwide frequently occurring following food ingestion. Its pathophysiology is complex, and many factors, including intestinal environmental cues, the immune system, or the molecular composition of foods, can influence the development of postprandial abdominal pain. Because of the poor efficacy of drug treatments, current strategies are often limited to the exclusion of culprit food(s) from the diet. However, there are two important limitations to this approach. First, patients suffering from food-induced abdominal pain usually recognize several food items as the cause of their gastrointestinal symptoms. Second, not all offending foods can always be identified by these patients. Newly identified mechanisms involving neuroimmune interactions and their communication with the intestinal microbiota shed light on the development of new therapeutic strategies. In this Mini-Review, these novel mechanisms and relevance of such findings are highlighted.
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Affiliation(s)
- Javier Aguilera-Lizarraga
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
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15
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Kolesnikova IM, Gaponov AM, Roumiantsev SA, Karbyshev MS, Grigoryeva TV, Makarov VV, Yudin SM, Borisenko OV, Shestopalov AV. Relationship between Blood Microbiome and Neurotrophin Levels in Different Metabolic Types of Obesity. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022060229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196773. [PMID: 36235308 PMCID: PMC9570628 DOI: 10.3390/molecules27196773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
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El-Salhy M, Mazzawi T, Hausken T, Hatlebakk JG. The fecal microbiota transplantation response differs between patients with severe and moderate irritable bowel symptoms. Scand J Gastroenterol 2022; 57:1036-1045. [PMID: 35486073 DOI: 10.1080/00365521.2022.2064725] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Fecal microbiota transplantation (FMT) is a promising intervention for patients with irritable bowel syndrome (IBS). The present study aimed to identify any differences in FMT response between patients with severe and moderate IBS symptoms. MATERIALS AND METHOD The study included the 164 patients who participated in our previous study, of which 96 (58.5%) and 68 (41.5%) had severe (S-IBS-S) and moderate (Mo-IBS-S) IBS, respectively. The patients were randomly divided into a placebo group (own feces) and 30-g and 60-g (donor feces) FMT groups. Patients completed three questionnaires that assessed their symptoms and quality of life at baseline and at 2 weeks, 1 month, and 3 months after FMT, and provided fecal samples before and 1 month after FMT. The fecal bacteria were analyzed using the 16S rRNA gene in PCR DNA amplification covering the V3-V9 variable genes. RESULTS Response rates of the placebo group did not differ between S-IBS-S and Mo-IBS-S patients at 2 weeks, 1 month and 3 months after FMT. The response rates in the active treatment group were higher in S-IBS-S patients than in Mo-IBS-S patients at each observation time. FMT reduced abdominal symptoms and fatigue and improved the quality of life in patients with both severe and moderate IBS. Patients with S-IBS-S had higher levels of Eubacterium siraeum, and lower levels of Eubacterium rectale than Mo-IBS-S, after FMT. CONCLUSION Patients with S-IBS-S have a higher response rate to FMT and a marked improvement in fatigue and in quality of life compared with those with Mo-IBS-S. The clinical trial registration number is NCT03822299 and is available at www.clinicaltrials.gov.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Stord Hospital, Stord, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Tarek Mazzawi
- Faculty of Medicine, Department of Medicine, Al-Balqa Applied University, Salt, Jordan
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Li N, Xu J, Gao H, Zhang Y, Li Y, Chang H, Tan S, Li S, Wang Q. Effect of Reactive EGCs on Intestinal Motility and Enteric Neurons During Endotoxemia. J Mol Neurosci 2022; 72:1831-1845. [PMID: 35773377 DOI: 10.1007/s12031-022-02044-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/14/2022] [Indexed: 10/17/2022]
Abstract
Paralytic ileus is common in patients with septic shock, causing high morbidity and mortality. Enteric neurons and enteric glial cells (EGCs) regulate intestinal motility. However, little is known about their interaction in endotoxemia. This study aimed to investigate whether reactive EGCs had harmful effects on enteric neurons and participated in intestinal motility disorder in mice during endotoxemia. Endotoxemia was induced by the intraperitoneal injection of lipopolysaccharide (LPS) in mice. Fluorocitrate (FC) was administered before LPS injection to inhibit the reactive EGCs. The effects of reactive EGCs on intestinal motility were analyzed by motility assays in vivo and colonic migrating motor complexes ex vivo. The number of enteric neurons was evaluated by immunofluorescent staining of HuCD, nNOS, and ChAT in vivo. In addition, we stimulated EGCs with IL-1β and TNF-α in vitro and cultured the primary enteric neurons in the conditioned medium, detecting the apoptosis and morphology of neurons through staining TUNEL, cleaved caspase-3 protein, and anti-β-III tubulin. Intestinal motility and peristaltic reflex were improved by inhibiting reactive EGCs in vivo. The density of the neuronal population in the colonic myenteric plexus increased significantly, while the reactive EGCs were inhibited, especially the nitrergic neurons. In vitro, the enteric neurons cultured in the conditioned medium of reactive EGCs had a considerably higher apoptotic rate, less dendritic complexity, and fewer primary neurites. Reactive enteric glial cells probably participated in paralytic ileus by damaging enteric neurons during endotoxemia. They might provide a novel therapeutic strategy for intestinal motility disorders during endotoxemia or sepsis.
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Affiliation(s)
- Na Li
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jing Xu
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hui Gao
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yuxin Zhang
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yansong Li
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Haiqing Chang
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Shuwen Tan
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Shuang Li
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Qiang Wang
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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Electroacupuncture Alleviates Visceral Hypersensitivity in IBS-D Rats by Inhibiting EGCs Activity through Regulating BDNF/TrkB Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2497430. [PMID: 35198032 PMCID: PMC8860523 DOI: 10.1155/2022/2497430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 01/17/2022] [Indexed: 02/05/2023]
Abstract
Objective To determine whether electroacupuncture (EA) could alleviate visceral hypersensitivity in diarrhea-predominant irritable bowel syndrome (IBS-D) rats by inhibiting EGCs activity via the BDNF/TrkB signaling pathway. Methods Sprague Dawley rats were randomly divided to a control group (n = 8) and a model preparation group (n = 32), which received Senna solution by gavage and CUMS (chronic unpredictable mild stress) for 14 consecutive days and was further divided to a Model group, an EA group (only electroacupuncture), an EA + TrkB agonist group (electroacupuncture and TrkB), and an EA + DMSO group (electroacupuncture and DMSO, n = 8 for each). Rats in the three EA groups were acupunctured at ST25, ST36, and LR3 for 20 min every day for 14 days. Abdominal withdrawal reflex (AWR) was used to quantify visceral sensitivity; reverse transcription polymerase chain reaction (RT-PCR) and double immunofluorescent staining were used to detect the colocalized expression of GFAP/BDNF and GFAP/TrkB. Western Blot (WB) was used to detect the expression of PLC and SP in the colon. Flow cytometry was used to detect the expression of Ca2+. Results EA effectively alleviated visceral hypersensitivity in IBS-D rats (P < 0.05). Compared to the control group, the expression of BDNF, TrkB, PLC, SP, and Ca2+ and the colocalized expression of GFAP/BDNF and GFAP/TrkB increased in the Model group (P < 0.05), while all these parameters decreased in the EA group following EA intervention (P < 0.05). In addition, no significant difference was found between the EA + TrkB agonist group and the control group (P > 0.05). Conclusions EA alleviates visceral hypersensitivity of IBS-D rats possibly by inhibiting the activity of EGCs through the BDNF/TrkB-PLC-Ca2+ signaling pathway in the colon.
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El-Salhy M, Hausken T, Hatlebakk JG. Current status of fecal microbiota transplantation for irritable bowel syndrome. Neurogastroenterol Motil 2021; 33:e14157. [PMID: 34236740 DOI: 10.1111/nmo.14157] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common gastrointestinal functional disorder. Although IBS is a benign condition, it reduces the quality of life considerably. While there is currently no effective treatment for this disorder, fecal microbiota transplantation (FMT) seems to be promising. PURPOSE The aim of this review was to analysis possible factors affecting the success or failure of the randomized controlled trials (RCTs) of FMT for IBS and highlighting the gaps in our knowledge that need to be filled and of sketching a possible model for successful FMT in IBS patients. METHODS A systematic search was conducted of literature published in English from January 2015 to December 2020 using the keywords: fecal microbiota transplantation, randomized trials, and IBS. KEY RESULTS Seven randomized controlled trials (RCTs) on the efficacy of FMT for IBS were found in the literature. Four of the seven RCTs found various positive effects, while the other three did not find any effect. CONCLUSIONS AND INFERENCES The efficacy of FMT for IBS appears to be donor-dependent. The effective (super) donor would need to have a favorable microbiota signature, and 11 clinical criteria that are known to be associated with a favorable microbiota have been suggested for selecting FMT donors for IBS. Comparing the microbiota of the effective donors with those of healthy subjects would reveal the favorable microbiota signature required for a super-donor. However, the studies reviewed were not designed to compare efficacy of different donor types. The dose of the fecal transplant is also an important factor influencing the outcome of FMT for IBS. However, further studies designed to test the effect of fecal transplant dose are needed to answer this question. Administering the fecal transplant to either the small or large intestine seems to be effective, but the optimal route of administration remains to be determined. Moreover, whether single or repeated FMT is more effective is also still unclear. A 1-year follow-up of IBS patients who received FMT showed that adverse events of abdominal pain, diarrhea, and constipation were both mild and self-limiting.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Stord Hospital, Stord, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
| | - Jan Gunnar Hatlebakk
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
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Hang L, Zhou Y, Meng YY, Feng Y, Wang YS, Yuan JY. Progress in understanding of relationship between short chain fatty acids and irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2021; 29:1102-1109. [DOI: 10.11569/wcjd.v29.i19.1102] [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
Irritable bowel syndrome (IBS) is a functional intestinal disease whose pathogenesis has not yet been fully defined. The main clinical manifestations of IBS are irregular abdominal pain, abdominal distension, and changes in stool character and defecation habits. As one of the pathogeneses of IBS, intestinal flora imbalance plays an important role in the development of IBS. The vast majorities of short chain fatty acids (SCFAs) are produced through the interaction of intestinal flora with host diet in the colon. As one of the main metabolites of intestinal flora, SCFAs have the effects of intestinal barrier protection, immune regulation, anti-inflammation, and regulation of visceral sensitivity in the intestine. In recent years, with the increasing attention to SCFAs, studies on the relationship between SCFAs and IBS are emerging. This review summarizes the progress in the understanding of the relationship between SCFAs and IBS in recent five years.
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Affiliation(s)
- Lu Hang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yang-Yang Meng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ya Feng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yin-Shu Wang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jian-Ye Yuan
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Abstract
Glia, the non-neuronal cells of the nervous system, were long considered secondary cells only necessary for supporting the functions of their more important neuronal neighbors. Work by many groups over the past two decades has completely overturned this notion, revealing the myriad and vital functions of glia in nervous system development, plasticity, and health. The largest population of glia outside the brain is in the enteric nervous system, a division of the autonomic nervous system that constitutes a key node of the gut-brain axis. Here, we review the latest in the understanding of these enteric glia in mammals with a focus on their putative roles in human health and disease.
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Affiliation(s)
- Harry J. Rosenberg
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
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Aguilera M, Rossini V, Hickey A, Simnica D, Grady F, Felice VD, Moloney A, Pawley L, Fanning A, McCarthy L, O’Mahony SM, Cryan JF, Nally K, Shanahan F, Melgar S. Inflammasome Signaling Regulates the Microbial-Neuroimmune Axis and Visceral Pain in Mice. Int J Mol Sci 2021; 22:ijms22158336. [PMID: 34361102 PMCID: PMC8371481 DOI: 10.3390/ijms22158336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/21/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain–gut interactions, but their role in microbiota–neuro–immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut–neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.
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Affiliation(s)
- Mònica Aguilera
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Valerio Rossini
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Ana Hickey
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- School of Biochemistry and Cell Biology, University College Cork, T12 YT20 Cork, Ireland
| | - Donjete Simnica
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Fiona Grady
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Valeria D. Felice
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20 Cork, Ireland
| | - Amy Moloney
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Lauren Pawley
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20 Cork, Ireland
| | - Aine Fanning
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Lorraine McCarthy
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Siobhan M. O’Mahony
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20 Cork, Ireland
| | - John F. Cryan
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20 Cork, Ireland
| | - Ken Nally
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- School of Biochemistry and Cell Biology, University College Cork, T12 YT20 Cork, Ireland
| | - Fergus Shanahan
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
| | - Silvia Melgar
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; (M.A.); (V.R.); (A.H.); (D.S.); (F.G.); (V.D.F.); (A.M.); (L.P.); (A.F.); (L.M.); (S.M.O.); (J.F.C.); (K.N.); (F.S.)
- Correspondence: ; Tel.: +353-21-4901384
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Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2021; 18:571-587. [PMID: 33731961 PMCID: PMC8324524 DOI: 10.1038/s41575-021-00423-7] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.
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Affiliation(s)
- Luisa Seguella
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Brian D Gulbransen
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA.
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Nutraceuticals and Enteric Glial Cells. Molecules 2021; 26:molecules26123762. [PMID: 34205534 PMCID: PMC8234579 DOI: 10.3390/molecules26123762] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/21/2022] Open
Abstract
Until recently, glia were considered to be a structural support for neurons, however further investigations showed that glial cells are equally as important as neurons. Among many different types of glia, enteric glial cells (EGCs) found in the gastrointestinal tract, have been significantly underestimated, but proved to play an essential role in neuroprotection, immune system modulation and many other functions. They are also said to be remarkably altered in different physiopathological conditions. A nutraceutical is defined as any food substance or part of a food that provides medical or health benefits, including prevention and treatment of the disease. Following the description of these interesting peripheral glial cells and highlighting their role in physiological and pathological changes, this article reviews all the studies on the effects of nutraceuticals as modulators of their functions. Currently there are only a few studies available concerning the effects of nutraceuticals on EGCs. Most of them evaluated molecules with antioxidant properties in systemic conditions, whereas only a few studies have been performed using models of gastrointestinal disorders. Despite the scarcity of studies on the topic, all agree that nutraceuticals have the potential to be an interesting alternative in the prevention and/or treatment of enteric gliopathies (of systemic or local etiology) and their associated gastrointestinal conditions.
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El-Salhy M, Patcharatrakul T, Gonlachanvit S. Fecal microbiota transplantation for irritable bowel syndrome: An intervention for the 21 st century. World J Gastroenterol 2021; 27:2921-2943. [PMID: 34168399 PMCID: PMC8192290 DOI: 10.3748/wjg.v27.i22.2921] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/03/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) affects about 12% of the global population. Although IBS does not develop into a serious disease or increase mortality, it results in a considerable reduction in the quality of life. The etiology of IBS is not known, but the intestinal microbiota appears to play a pivotal role in its pathophysiology. There is no effective treatment for IBS, and so the applied treatments clinically focus on symptom relief. Fecal microbiota transplantation (FMT), an old Chinese treatment, has been applied to IBS patients in seven randomized controlled trials (RCTs). Positive effects on IBS symptoms in various degrees were obtained in four of these RCTs, while there was no effect in the remaining three. Across the seven RCTs there were marked differences in the selection processes for the donor and treated patients, the transplant dose, the route of administration, and the methods used to measure how the patients responded to FMT. The present frontier discusses these differences and proposes: (1) criteria for selecting an effective donor (superdonor); (2) selection criteria for patients that are suitable for FMT; (3) the optimal FMT dose; and (4) the route of transplant administration. FMT appears to be safe, with only mild, self-limiting side effects of abdominal pain, cramping, tenderness, diarrhea, and constipation. Although it is early to speculate about the mechanisms underlying the effects of FMT, the available data suggest that changes in the intestinal bacteria accompanied by changes in fermentation patterns and fermentation products (specifically short-chain fatty acids) play an important role in improving the IBS symptoms seen after FMT. FMT appears to be a promising treatment for IBS, but further studies are needed before it can be applied in everyday clinical practice.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Stord Helse Fonna Hospital and University of Bergen, Stord 5416, Norway
| | - Tanisa Patcharatrakul
- Department of Medicine, King Chulalongkorn Memorial Hospital and Center of Excellence in Neurogastroenterology and Motility, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sutep Gonlachanvit
- Department of Medicine, King Chulalongkorn Memorial Hospital and Center of Excellence in Neurogastroenterology and Motility, Chulalongkorn University, Bangkok 10330, Thailand
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El-Salhy M, Casen C, Valeur J, Hausken T, Hatlebakk JG. Responses to faecal microbiota transplantation in female and male patients with irritable bowel syndrome. World J Gastroenterol 2021; 27:2219-2237. [PMID: 34025075 PMCID: PMC8117742 DOI: 10.3748/wjg.v27.i18.2219] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/13/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Faecal microbiota transplantation (FMT) seems to be a promising treatment for irritable bowel syndrome (IBS) patients. In Western countries (United States and Europe), there is a female predominance in IBS. A sex difference in the response to FMT has been reported recently in IBS patients.
AIM To investigate whether there was a sex difference in the response to FMT in the IBS patients who were included in our previous randomized controlled trial of the efficacy of FMT.
METHODS The study included 164 IBS patients who participated in our previous randomized controlled trial. These patients had moderate-to-severe IBS symptoms belonging to the IBS-D (diarrhoea-predominant), IBS-C (constipation-predominant) and IBS-M (mixed) subtypes, and had not responded to the National Institute for Health and Care Excellence (NICE)-modified diet. They belonged in three groups: placebo (own faeces), and active treated group (30-g or 60-g superdonor faeces). The patients completed the IBS severity scoring system (IBS-SSS), Fatigue Assessment Scale (FAS) and the IBS quality of life scale (IBS-QoL) questionnaires at the baseline and 2 wk, 1 mo and 3 mo after FMT. They also provided faecal samples at the baseline and 1 mo after FMT. The faecal bacteria profile and dysbiosis were determined using the 16S rRNA gene polymerase chain reaction DNA amplification covering V3-V9; probe labelling by single nucleotide extension and signal detection. The levels of short-chain fatty acids (SCFAs) were determined by gas chromatography and flame ionization.
RESULTS There was no sex difference in the response to FMT either in the placebo group or active treated group. There was no difference between females and males in either the placebo group or actively treated groups in the total score on the IBS-SSS, FAS or IBS-QoL, in dysbiosis, or in the faecal bacteria or SCFA level. However, the response rate was significantly higher in females with diarrhoea-predominant (IBS-D) than that of males at 1 mo, and 3 mo after FMT. Moreover, IBS-SSS total score was significantly lower in female patients with IBS-D than that of male patients both 1 mo and 3 mo after FMT.
CONCLUSION There was no sex difference in the response to FMT among IBS patients with moderate-to-severe symptoms who had previously not responded to NICE-modified diet. However, female patients with IBS-D respond better and have higher reduction of symptoms than males after FMT.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Stord Helse-Fonna Hospital, Stord 5416, Norway
- Department of Clinical Medicine, University of Bergen, Bergen 5020, Norway
- National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5020, Norway
| | | | - Jørgen Valeur
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo 0440, Norway
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, Bergen 5020, Norway
- National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5020, Norway
| | - Jan Gunnar Hatlebakk
- Department of Clinical Medicine, University of Bergen, Bergen 5020, Norway
- National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5020, Norway
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El‐Salhy M, Valeur J, Hausken T, Gunnar Hatlebakk J. Changes in fecal short-chain fatty acids following fecal microbiota transplantation in patients with irritable bowel syndrome. Neurogastroenterol Motil 2021; 33:e13983. [PMID: 32945066 PMCID: PMC7900992 DOI: 10.1111/nmo.13983] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Short-chain fatty acids (SCFAs) may play a role in the pathophysiology of irritable bowel syndrome (IBS). This study analyzed fecal SCFAs after performing fecal microbiota transplantation (FMT) in the IBS patients who were included in our previous study of the efficacy of FMT. METHODS This study included 142 of the 164 IBS patients who participated in our previous study. They were belonging to three groups: placebo (own feces), 30-g (superdonor feces), and 60-g (superdonor feces) FMT. The patients completed the IBS Severity Scoring System (IBS-SSS) Birmingham IBS Symptom, Fatigue Assessment Scale (FAS), the IBS Quality of Life (IBS-QoL) and Short-Form Nepean Dyspepsia Index (SF-NDI) questionnaires and delivered fecal samples at the baseline and 1 month after FMT. The SCFA levels were determined by vacuum distillation followed by gas chromatography. KEY RESULTS The fecal butyric acid level was significantly increased after FMT in both the 30-g and 60-g groups (both P ≤ 0.001). In the 60-g group, the levels of total SCFAs and isobutyric, isovaleric, and valeric acids increased after FMT. Butyric acid levels in the responders in both the 30-g and 60-g FMT groups were significantly inversely correlated with IBS-SSS and FAS scores (P = 0.001, r = -0.3 and P = 0.0001. r=- 0.3, respectively). There were no differences in the SCFA levels in the placebo group after FMT. CONCLUSION AND INFERENCES FMT increases the fecal SCFA levels in IBS patients. The increase in the butyric acid level is inversely correlated with symptoms in IBS patients following FMT, suggesting that SCFAs might play a role in the pathophysiology of IBS. www.clinicaltrials.gov (NCT03822299).
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Affiliation(s)
- Magdy El‐Salhy
- Department of MedicineStord HospitalStordNorway,Department of Clinical MedicineUniversity of BergenBergenNorway
| | - Jørgen Valeur
- Unger‐Vetlesen InstituteLovisenberg Diaconal HospitalOsloNorway,Department of GastroenterologyOslo University Hospital UllevålOsloNorway
| | - Trygve Hausken
- Department of Clinical MedicineUniversity of BergenBergenNorway,Department of MedicineNational Centre for Functional Gastrointestinal DisordersHaukeland University HospitalBergenNorway
| | - Jan Gunnar Hatlebakk
- Department of Clinical MedicineUniversity of BergenBergenNorway,Department of MedicineNational Centre for Functional Gastrointestinal DisordersHaukeland University HospitalBergenNorway
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Lagomarsino VN, Kostic AD, Chiu IM. Mechanisms of microbial-neuronal interactions in pain and nociception. NEUROBIOLOGY OF PAIN 2020; 9:100056. [PMID: 33392418 PMCID: PMC7772816 DOI: 10.1016/j.ynpai.2020.100056] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023]
Abstract
Molecular mechanisms of how microorganisms communicate with sensory afferent neurons. How pathogenic microorganisms directly communicate with nociceptor neurons to inflict pain on the host. Symbiotic bacterial communication with gut-extrinsic sensory afferent neurons. Plausible roles on how gut symbionts directly mediate pain and nociception. Nociceptor sensory neurons innervate barrier tissues that are constantly exposed to microbial stimuli. During infection, pathogenic microorganisms can breach barrier surfaces and produce pain by directly activating nociceptors. Microorganisms that live in symbiotic relationships with their hosts, commensals and mutualists, have also been associated with pain, but the molecular mechanisms of how symbionts act on nociceptor neurons to modulate pain remain largely unknown. In this review, we will discuss the known molecular mechanisms of how microbes directly interact with sensory afferent neurons affecting nociception in the gut, skin and lungs. We will touch on how bacterial, viral and fungal pathogens signal to the host to inflict or suppress pain. We will also discuss recent studies examining how gut symbionts affect pain. Specifically, we will discuss how gut symbionts may interact with sensory afferent neurons either directly, through secretion of metabolites or neurotransmitters, or indirectly,through first signaling to epithelial cells or immune cells, to regulate visceral, neuropathic and inflammatory pain. While this area of research is still in its infancy, more mechanistic studies to examine microbial-sensory neuron crosstalk in nociception may allow us to develop new therapies for the treatment of acute and chronic pain.
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Affiliation(s)
- Valentina N Lagomarsino
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.,Joslin Diabetes Center, Boston, MA 02115, USA.,Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Aleksandar D Kostic
- Joslin Diabetes Center, Boston, MA 02115, USA.,Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
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Chao G, Zhang S. The characteristics of intestinal flora of IBS-D with different syndromes. Immun Inflamm Dis 2020; 8:615-628. [PMID: 32940426 PMCID: PMC7654421 DOI: 10.1002/iid3.348] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 08/27/2020] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To study the distribution of fecal microbiota in diarrhea-predominant irritable bowel syndrome (IBS-D) patients of spleen-kidney-yang deficiency and liver depression and spleen deficiency, to make an objective foundation for dialectics of different type of IBS-D. And to provide the clinical doctors an experimental basis for medication by regulating dysbacteriosis. METHODS We collected feces from the control group, spleen-kidney-yang deficiency IBS-D group, and liver-depression and spleen-deficiency IBS-D group. After the extraction of fecal DNA, global DNA was isolated from every sample, and 16S ribosomal RNA was sequenced, and then we analyzed the results for bacteria such as Alpha diversity, community composition, LEfSe, and partial least squares discriminant analysis. RESULTS We compared the changes among the fecal bacteria in the intestine of the IBS-D patients and healthy controls and found the specificity of spleen-kidney-yang deficiency syndrome and liver-depression and spleen-deficiency syndrome. The control group has the highest flora diversity (control group > liver-depression and spleen-deficiency > spleen-kidney-yang deficiency group). The control group, spleen-kidney-yang deficiency group, and liver-depression and spleen-deficiency group are different in phylum (Actinobacteria, Fusobacteria), class (Actinobacteria, Fusobacteria), order (Enterobacteriales, Bifidobacteriales, Fusobacteriales), and family (Bifidobacteriaceae, Ruminococcaceae, Enterobacteriaceae, Acidaminococcaceae, Veillonellaceae, Fusobacteriaceae). Bifidobacteriaceae and Ruminococcaceae in the control group, Enterobacteriales, Fusobacteriales, Acidaminococcaceae, and Phascolarctobacterium in the spleen-kidney-yang deficiency group, and streptococcus are the specific bacteria in the liver-depression and spleen-deficiency group. Intestinal flora disturbance is closely related to IBS-D. CONCLUSIONS There is a correlation between traditional Chinese medicine syndrome type and intestinal flora. The control group, the spleen-kidney-yang deficiency group, and the liver-depression and spleen-deficiency group have specific bacteria.
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Affiliation(s)
- Guanqun Chao
- Department of General practice, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shuo Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Mishima Y, Ishihara S. Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome. Int J Mol Sci 2020; 21:ijms21228664. [PMID: 33212919 PMCID: PMC7698457 DOI: 10.3390/ijms21228664] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term “brain–gut–microbiome axis” has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.
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Dai X, Hou H, Zhang W, Liu T, Li Y, Wang S, Wang B, Cao H. Microbial Metabolites: Critical Regulators in NAFLD. Front Microbiol 2020; 11:567654. [PMID: 33117316 PMCID: PMC7575719 DOI: 10.3389/fmicb.2020.567654] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease throughout the world. The relationship between gut microbiota and NAFLD has been extensively investigated. The gut microbiota is involved in the regulation of NAFLD by participating in the fermentation of indigestible food, interacting with the intestinal mucosal immune system, and influencing the intestinal barrier function, leading to signaling alteration. Meanwhile, the microbial metabolites not only affect the signal transduction pathway in the gut but also reach the liver far away from gut. In this review, we focus on the effects of certain key microbial metabolites such as short-chain fatty acids, trimethylamine-N-oxide, bile acids, and endogenous ethanol and indole in NAFLD, and also summarize several potential therapies targeting the gut-liver axis and modulation of gut microbiota metabolites including antibiotics, prebiotics, probiotics, bile acid regulation, and fecal microbiota transplantation. Understanding the complex interactions between microbial metabolites and NAFLD may provide crucial insight into the pathogenesis and treatment of NAFLD.
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Affiliation(s)
- Xin Dai
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Huiqin Hou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Wanru Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yun Li
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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Fecal transplantation and butyrate improve neuropathic pain, modify immune cell profile, and gene expression in the PNS of obese mice. Proc Natl Acad Sci U S A 2020; 117:26482-26493. [PMID: 33020290 DOI: 10.1073/pnas.2006065117] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Obesity affects over 2 billion people worldwide and is accompanied by peripheral neuropathy (PN) and an associated poorer quality of life. Despite high prevalence, the molecular mechanisms underlying the painful manifestations of PN are poorly understood, and therapies are restricted to use of painkillers or other drugs that do not address the underlying disease. Studies have demonstrated that the gut microbiome is linked to metabolic health and its alteration is associated with many diseases, including obesity. Pathologic changes to the gut microbiome have recently been linked to somatosensory pain, but any relationships between gut microbiome and PN in obesity have yet to be explored. Our data show that mice fed a Western diet developed indices of PN that were attenuated by concurrent fecal microbiome transplantation (FMT). In addition, we observed changes in expression of genes involved in lipid metabolism and calcium handling in cells of the peripheral nerve system (PNS). FMT also induced changes in the immune cell populations of the PNS. There was a correlation between an increase in the circulating short-chain fatty acid butyrate and pain improvement following FMT. Additionally, butyrate modulated gene expression and immune cells in the PNS. Circulating butyrate was also negatively correlated with distal pain in 29 participants with varied body mass index. Our data suggest that the metabolite butyrate, secreted by the gut microbiome, underlies some of the effects of FMT. Targeting the gut microbiome, butyrate, and its consequences may represent novel viable approaches to prevent or relieve obesity-associated neuropathies.
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Lin L, Feng B, Zhou R, Liu Y, Li L, Wang K, Yu Y, Liu C, Long X, Gu X, Li B, Wang X, Yang X, Cong Y, Zuo X, Li Y. Acute stress disrupts intestinal homeostasis via GDNF-RET. Cell Prolif 2020; 53:e12889. [PMID: 32808420 PMCID: PMC7574880 DOI: 10.1111/cpr.12889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/11/2020] [Accepted: 07/26/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D). MATERIALS AND METHODS GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro. RESULTS GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner. CONCLUSIONS We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.
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Affiliation(s)
- Lin Lin
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Bingcheng Feng
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Ruchen Zhou
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yi Liu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Lixiang Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Kairuo Wang
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yanbo Yu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Chao Liu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xin Long
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xiang Gu
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Bing Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xiaojie Wang
- Department of dermatologyPeking University People’s HospitalBeijingChina
| | - Xiaoyun Yang
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yingzi Cong
- Department of Microbiology and ImmunologyUniversity of Texas Medical BranchGalvestonTexasUSA
| | - Xiuli Zuo
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yanqing Li
- Department of GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
- Laboratory of Translational GastroenterologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
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A Brief Review of Nutraceutical Ingredients in Gastrointestinal Disorders: Evidence and Suggestions. Int J Mol Sci 2020; 21:ijms21051822. [PMID: 32155799 PMCID: PMC7084955 DOI: 10.3390/ijms21051822] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 02/27/2020] [Accepted: 03/04/2020] [Indexed: 12/12/2022] Open
Abstract
The dietary effect on gut health has long been recognized through the empirical practice of soothing gastric discomfort with certain types of food, and recently the correlation between specific diets with lower incidences of several gastrointestinal diseases has been revealed. Ingredients from those considered beneficial foods have been isolated and studied, and some of them have already been put into the supplement market. In this review, we focus on latest studies of these food-derived ingredients for their proposed preventive and therapeutic roles in gastrointestinal disorders, with the attempt of drawing evidence-based suggestions on consuming these products.
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Accarie A, Vanuytsel T. Animal Models for Functional Gastrointestinal Disorders. Front Psychiatry 2020; 11:509681. [PMID: 33262709 PMCID: PMC7685985 DOI: 10.3389/fpsyt.2020.509681] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.
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Affiliation(s)
- Alison Accarie
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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Butyrate inhibits visceral allodynia and colonic hyperpermeability in rat models of irritable bowel syndrome. Sci Rep 2019; 9:19603. [PMID: 31862976 PMCID: PMC6925246 DOI: 10.1038/s41598-019-56132-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/06/2019] [Indexed: 12/11/2022] Open
Abstract
Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and gut hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is a rat irritable bowel syndrome (IBS) model. As butyrate is known to suppress the release of proinflammatory cytokine, we hypothesized that butyrate alleviates these colonic changes in IBS models. The visceral pain was assessed by electrophysiologically measuring the threshold of abdominal muscle contractions in response to colonic distention. Colonic permeability was determined by measuring the absorbance of Evans blue in colonic tissue. Colonic instillation of sodium butyrate (SB; 0.37-2.9 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral allodynia and colonic hyperpermeability dose-dependently. Additionally, the visceral changes induced by repeated WAS (1 h for 3 days) or CRF (50 µg/kg) were also blocked by SB. These effects of SB in the LPS model were eliminated by compound C, an AMPK inhibitor, or GW9662, a PPAR-γ antagonist, NG-nitro-L-arginine methyl ester, a NO synthesis inhibitor, naloxone or sulpiride. SB attenuated visceral allodynia and colonic hyperpermeability in animal IBS models. These actions may be AMPK and PPAR-γ dependent and also mediated by the NO, opioid and central dopamine D2 pathways. Butyrate may be effective for the treatment of IBS.
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Butyric acid, a gut bacteria metabolite, lowers arterial blood pressure via colon-vagus nerve signaling and GPR41/43 receptors. Pflugers Arch 2019; 471:1441-1453. [PMID: 31728701 PMCID: PMC6882756 DOI: 10.1007/s00424-019-02322-y] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/26/2019] [Accepted: 10/07/2019] [Indexed: 01/01/2023]
Abstract
Butyric acid (BA) is a short-chain fatty acid (SCFA) produced by gut bacteria in the colon. We hypothesized that colon-derived BA may affect hemodynamics. Arterial blood pressure (BP) and heart rate (HR) were recorded in anesthetized, male, 14-week-old Wistar rats. A vehicle, BA, or 3-hydroxybutyrate, an antagonist of SCFA receptors GPR41/43 (ANT) were administered intravenously (IV) or into the colon (IC). Reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries was tested ex vivo. The concentration of BA in stools, urine, portal, and systemic blood was measured with liquid chromatography coupled with mass spectrometry. BA administered IV decreased BP with no significant effect on HR. The ANT reduced, whereas L-NAME, a nitric oxide synthase inhibitor, did not affect the hypotensive effect of BA. In comparison to BA administered intravenously, BA administered into the colon produced a significantly longer decrease in BP and a decrease in HR, which was associated with a 2–3-fold increase in BA colon content. Subphrenic vagotomy and IC pretreatment with the ANT significantly reduced the hypotensive effect. Ex vivo, BA dilated MA and GMA. In conclusion, an increase in the concentration of BA in the colon produces a significant hypotensive effect which depends on the afferent colonic vagus nerve signaling and GPR41/43 receptors. BA seems to be one of mediators between gut microbiota and the circulatory system.
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van Thiel IAM, Botschuijver S, de Jonge WJ, Seppen J. Painful interactions: Microbial compounds and visceral pain. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165534. [PMID: 31634534 DOI: 10.1016/j.bbadis.2019.165534] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 08/12/2019] [Accepted: 08/13/2019] [Indexed: 12/18/2022]
Abstract
Visceral pain, characterized by abdominal discomfort, originates from organs in the abdominal cavity and is a characteristic symptom in patients suffering from irritable bowel syndrome, vulvodynia or interstitial cystitis. Most organs in which visceral pain originates are in contact with the external milieu and continuously exposed to microbes. In order to maintain homeostasis and prevent infections, the immune- and nervous system in these organs cooperate to sense and eliminate (harmful) microbes. Recognition of microbial components or products by receptors expressed on cells from the immune and nervous system can activate immune responses but may also cause pain. We review the microbial compounds and their receptors that could be involved in visceral pain development.
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Affiliation(s)
- I A M van Thiel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, location AMC, Meibergdreef 69, 1105 BK Amsterdam, the Netherlands
| | - S Botschuijver
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, location AMC, Meibergdreef 69, 1105 BK Amsterdam, the Netherlands
| | - W J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, location AMC, Meibergdreef 69, 1105 BK Amsterdam, the Netherlands
| | - J Seppen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, location AMC, Meibergdreef 69, 1105 BK Amsterdam, the Netherlands.
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40
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Zhang J, Song L, Wang Y, Liu C, Zhang L, Zhu S, Liu S, Duan L. Beneficial effect of butyrate-producing Lachnospiraceae on stress-induced visceral hypersensitivity in rats. J Gastroenterol Hepatol 2019; 34:1368-1376. [PMID: 30402954 PMCID: PMC7379616 DOI: 10.1111/jgh.14536] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/30/2018] [Accepted: 10/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Emerging evidence indicates that psychological stress is involved in the pathogenesis of irritable bowel syndrome, which is characterized by visceral hypersensitivity and may be accompanied by gut dysbiosis. However, how such stress contributes to the development of visceral hypersensitivity is incompletely understood. Here, we aimed to investigate the influence that stress-induced microbial changes exert on visceral sensitivity, as well as the possible underlying mechanisms associated with this effect. METHODS Male Sprague-Dawley rats underwent chronic water avoidance stress (WAS) to induce visceral hypersensitivity. Visceral sensitivity, colonic tight junction protein expression, and short-chain fatty acids of cecal contents were measured. Fecal samples were collected to characterize microbiota profiles. In a separate study, oral gavage of Roseburia in WAS rats was conducted to verify its potential role in the effectiveness on visceral hypersensitivity. RESULTS Repeated WAS caused visceral hypersensitivity, altered fecal microbiota composition and function, and decreased occludin expression in the colon. Stressed rats exhibited reduced representation of pathways involved in the metabolism of butyrate and reduced abundance of several operational taxonomic units associated with butyrate-producing bacteria, such as Lachnospiraceae. Consistently, supplementation with Roseburia hominis, a species belonging to Lachnospiraceae, significantly increased cecal butyrate content. Moreover, Roseburia supplementation alleviated visceral hypersensitivity and prevented the decreased expression of occludin. CONCLUSIONS Reduction in the abundance of butyrate-producing Lachnospiraceae, which is beneficial for the intestinal barrier, was involved in the formation of visceral hypersensitivity. R. hominis is a potential probiotic for treating stress-induced visceral hypersensitivity.
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Affiliation(s)
- Jindong Zhang
- Department of GastroenterologyPeking University Third HospitalBeijingChina
| | - Lijin Song
- Department of GastroenterologyPeking University Third HospitalBeijingChina
| | - Yujing Wang
- State Key Laboratory of Microbial Resources, Institute of MicrobiologyChinese Academy of SciencesBeijingChina
| | - Chang Liu
- State Key Laboratory of Microbial Resources, Institute of MicrobiologyChinese Academy of SciencesBeijingChina
| | - Lu Zhang
- Department of GastroenterologyPeking University Third HospitalBeijingChina
| | - Shiwei Zhu
- Department of GastroenterologyPeking University Third HospitalBeijingChina
| | - Shuangjiang Liu
- State Key Laboratory of Microbial Resources, Institute of MicrobiologyChinese Academy of SciencesBeijingChina
| | - Liping Duan
- Department of GastroenterologyPeking University Third HospitalBeijingChina
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Grundmann D, Loris E, Maas-Omlor S, Huang W, Scheller A, Kirchhoff F, Schäfer KH. Enteric Glia: S100, GFAP, and Beyond. Anat Rec (Hoboken) 2019; 302:1333-1344. [PMID: 30951262 DOI: 10.1002/ar.24128] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 02/10/2019] [Accepted: 02/18/2019] [Indexed: 12/15/2022]
Abstract
Since several years, the enteric nervous system (ENS) is getting more and more in the focus of gastrointestinal research. While the main interest was credited for years to the enteric neurons and their functional properties, less attention has been paid on the enteric glial cells (EGCs). Although the similarity of EGCs to central nervous system (CNS) astrocytes has been demonstrated a long time ago, EGCs were investigated in more detail only recently. Similar to the CNS, there is not "the" EGC, but also a broad range of diversity. Based on morphology and protein expression, such as glial fibrillary acidic protein (GFAP), S100, or Proteolipid-protein-1 (PLP1), several distinct glial types can be differentiated. Their heterogeneity in morphology, localization, and transcription as well as interaction with surrounding cells indicate versatile functional properties of these cells for gut function in health and disease. Although NG2 is found in a subset of CNS glial cells, it did not colocalize with the glial marker S100 or GFAP in the ENS. Instead, it in part colocalize with PDGFRα, as it does in the CNS, which do stain fibroblast-like cells in the gastrointestinal tract. Moreover, there seem to be species dependent differences. While GFAP is always found in the rodent ENS, this is completely different for the human gut. Only the compromised human ENS shows a significant amount of GFAP-positive glial cells. So, in general we can conclude that the EGC population is species specific and as complex as CNS glia. Anat Rec, 302:1333-1344, 2019. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- David Grundmann
- Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany
| | - Eva Loris
- Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany
| | - Silke Maas-Omlor
- Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany
| | - Wenhui Huang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
| | - Anja Scheller
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
| | - Frank Kirchhoff
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
| | - Karl-Herbert Schäfer
- Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany.,Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Liu S. Neurotrophic factors in enteric physiology and pathophysiology. Neurogastroenterol Motil 2018; 30:e13446. [PMID: 30259610 PMCID: PMC6166659 DOI: 10.1111/nmo.13446] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 07/15/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
Neurotrophic factors are traditionally recognized for their roles in differentiation, growth, and survival of specific neurons in the central and peripheral nervous system. Some neurotrophic factors are essential for the development and migration of the enteric nervous system along the fetal and post-natal gut. Over the last two decades, several non-developmental functions of neurotrophic factors have been characterized. In the adult gastrointestinal tract, neurotrophic factors regulate gut sensation, motility, epithelial barrier function, and protect enteric neurons and glial cells from damaging insults in the microenvironment of the gut. In this issue of Neurogastroenterology and Motility, Fu et al demonstrate that brain-derived neurotrophic factor plays a role in the pathogenesis of distention-induced abdominal pain in bowel obstruction. In light of this interesting finding, this mini-review highlights some of the recent advances in understanding of the physiological and pathophysiological roles of neurotrophic factors in the adult gut.
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Affiliation(s)
- Sumei Liu
- Department of Biology, College of Science and Health University of Wisconsin‐La Crosse La Crosse Wisconsin
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43
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Starobova H, S. W. A. H, Lewis RJ, Vetter I. Transcriptomics in pain research: insights from new and old technologies. Mol Omics 2018; 14:389-404. [DOI: 10.1039/c8mo00181b] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Physiological and pathological pain involves a complex interplay of multiple cell types and signaling pathways.
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Affiliation(s)
- H. Starobova
- Centre for Pain Research
- Institute for Molecular Bioscience
- University of Queensland
- St Lucia
- Australia
| | - Himaya S. W. A.
- Centre for Pain Research
- Institute for Molecular Bioscience
- University of Queensland
- St Lucia
- Australia
| | - R. J. Lewis
- Centre for Pain Research
- Institute for Molecular Bioscience
- University of Queensland
- St Lucia
- Australia
| | - I. Vetter
- Centre for Pain Research
- Institute for Molecular Bioscience
- University of Queensland
- St Lucia
- Australia
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