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Kumar R, Pathak NK, Sarkar JK, Tripathy U, Datta PK. Vibrational spectra of serotonin by terahertz time domain spectroscopy and DFT simulations. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 329:125541. [PMID: 39642626 DOI: 10.1016/j.saa.2024.125541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/11/2024] [Accepted: 11/29/2024] [Indexed: 12/09/2024]
Abstract
Serotonin is an important biogenic monoamine neurotransmitter that has major influences on mental health disorders; its structural and conformational changes have important roles in the biological functions of the human body. The decreased serotonin levels in the human body are majorly attributed to the causes of anxiety, depressive disorders, mood disorders, etc. Therefore, the quantification of serotonin in our bodies is of utmost importance in unearthing the origin of such physiological disorders. In this study, Terahertz-Time Domain Spectroscopy (THz-TDS) is employed to characterize the unique THz fingerprint of serotonin in the frequency range 0-3 THz. The characteristic THz absorption peaks of serotonin are observed at 0.54, 0.84, and 1.10 THz. In addition, Density Functional Theory (DFT) calculations are performed to investigate the vibrational properties of serotonin. For the vibrational assignment of modes, we have used Potential Energy Distribution (PED) analysis. Furthermore, studies have been conducted on the variation of serotonin concentration in a polyethylene (PE) host medium. The effect of the serotonin concentration in the PE host is studied using the complex refractive index (CRI) model. The sensitivity of detection of serotonin concentration is 0.015 for an increment of 2% concentration in PE medium. This work maps the spectral features of serotonin in the THz range, suggesting that THz-TDS can be used to understand and treat the physiological disorders related to serotonergic systems.
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Affiliation(s)
- Rajat Kumar
- Department of Physics, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Nitesh Kumar Pathak
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India
| | - Jayanta Kumar Sarkar
- Department of Physics, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Umakanta Tripathy
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India
| | - Prasanta Kumar Datta
- Department of Physics, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
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2
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Huang YP, Shi JY, Luo XT, Luo SC, Cheung PCK, Corke H, Yang QQ, Zhang BB. How do probiotics alleviate constipation? A narrative review of mechanisms. Crit Rev Biotechnol 2025; 45:80-96. [PMID: 38710624 DOI: 10.1080/07388551.2024.2336531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/06/2023] [Accepted: 11/25/2023] [Indexed: 05/08/2024]
Abstract
Constipation is a common gastrointestinal condition, which may occur at any age and affects countless people. The search for new treatments for constipation is ongoing as current drug treatments fail to provide fully satisfactory results. In recent years, probiotics have attracted much attention because of their demonstrated therapeutic efficacy and fewer side effects than pharmaceutical products. Many studies attempted to answer the question of how probiotics can alleviate constipation. It has been shown that different probiotic strains can alleviate constipation by different mechanisms. The mechanisms on probiotics in relieving constipation were associated with various aspects, including regulation of the gut microbiota composition, the level of short-chain fatty acids, aquaporin expression levels, neurotransmitters and hormone levels, inflammation, the intestinal environmental metabolic status, neurotrophic factor levels and the body's antioxidant levels. This paper summarizes the perception of the mechanisms on probiotics in relieving constipation and provides some suggestions on new research directions.
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Affiliation(s)
- Yu-Ping Huang
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
| | - Jie-Yan Shi
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
| | - Xin-Tao Luo
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
| | - Si-Chen Luo
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
| | - Peter C K Cheung
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, P.R. China
| | - Harold Corke
- Biotechnology and Food Engineering Program, Guangdong Technion-Israel Institute of Technology, Shantou, P.R. China
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Qiong-Qiong Yang
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
| | - Bo-Bo Zhang
- Department of Biology, College of Science, Shantou University, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, P.R. China
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3
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Azarfarin M, Moradikor N, Matin S, Dadkhah M. Association Between Stress, Neuroinflammation, and Irritable Bowel Syndrome: The Positive Effects of Probiotic Therapy. Cell Biochem Funct 2024; 42:e70009. [PMID: 39487668 DOI: 10.1002/cbf.70009] [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: 06/22/2024] [Revised: 09/23/2024] [Accepted: 10/14/2024] [Indexed: 11/04/2024]
Abstract
Stress refers to an organism's response to environmental threats in normal condition to maintain homeostasis in the body. In addition, strong inflammatory reactions induced by the hypothalamic-pituitary-adrenal (HPA) axis under stress condition during a long time. Reciprocally, chronic stress can induce the irritable bowel syndrome (IBS) which is a well-known gut disorder thereby play an important role in the promotion and pathophysiology of neuropsychiatric diseases. It has been demonstrated that leaky gut is a hallmark of IBS, leads to the entrance the microbiota into the bloodstream and consequent low-grade systemic inflammation. In the current review, we will discuss the mechanisms by which stress can influence the risk and severity of IBS and its relationship with neuroinflammation. Also, the role of probiotics in IBS co-existing with chronic stress conditions is highlighted.
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Affiliation(s)
- Maryam Azarfarin
- Department of Neuroscience, Faculty of Advanced Medical, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrollah Moradikor
- International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia
| | - Somaieh Matin
- Digestive Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Masoomeh Dadkhah
- Lung Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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4
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Safaei F, Shahrokh S, Naderi N, Rastegar R, Shamsi A. Unveiling the efficacy of paroxetine and gabapentin in ulcerative colitis patients in remission with co-existing IBS-like symptoms: a single-blinded randomized clinical trial. Front Med (Lausanne) 2024; 11:1468885. [PMID: 39635600 PMCID: PMC11614664 DOI: 10.3389/fmed.2024.1468885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024] Open
Abstract
Introduction This clinical trial is designed to explore the efficacy of paroxetine and gabapentin in alleviating functional gastrointestinal symptoms, anxiety, depression, and quality of life in patients with ulcerative colitis during the remission stage. Methods The study enrolled 97 patients with ulcerative colitis in remission who had reported functional gastrointestinal symptoms. Patients were measured in terms of quality of life, anxiety, depression, and IBS severity. One group received paroxetine at a dosage of 20 mg/day, and the other group received gabapentin at a dosage of 100 mg/day in the first month and 300 mg/day in the second and third months. The patients were followed up for 3 months. Results Anxiety (p < 0.001), depression (p = 0.012), and severity score levels (p = 0.045) among patients in the paroxetine group were significantly lower compared to the gabapentin group following the intervention. Paired evaluation in each treatment group revealed a significant reduction in the paroxetine group, while changes in the gabapentin group were not significant. Quality-of-life scores among patients in the paroxetine group were significantly higher compared to the gabapentin group following the intervention (p < 0.001). Conclusion The rate of improvement in gastrointestinal functional symptoms, anxiety, depression, and quality of life is significantly superior with paroxetine compared to gabapentin. Clinical trial registration https://irct.behdasht.gov.ir/trial/69397, identifier RCT20220417054557N1.
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Affiliation(s)
- Farahnaz Safaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nosratollah Naderi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Rastegar
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Shamsi
- Department of Psychiatry, Taleghani Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Boustany A, Feuerstadt P, Tillotson G. The 3 Ds: Depression, Dysbiosis, and Clostridiodes difficile. Adv Ther 2024; 41:3982-3995. [PMID: 39276186 PMCID: PMC11480130 DOI: 10.1007/s12325-024-02972-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 08/12/2024] [Indexed: 09/16/2024]
Abstract
This paper explores the intricate relationship between depression, gut dysbiosis, and Clostridioides difficile infections, collectively termed "The 3 Ds". Depression is a widespread mental disorder increasing in prevalence. It is recognized for its societal burden and complex pathophysiology, encompassing genetic, environmental, and microbiome-related factors. The consequent increased use of antidepressants has led to growing concerns about their effects on the gut microbiome. Various classes of antidepressants and antipsychotics show antimicrobial activity, potentially leading to shifts in the gut microbiome and contributing to the development of dysbiosis. Dysbiosis, in turn, can predispose individuals to opportunistic infections like C. difficile, a significant healthcare concern due to its high recurrence rates and severe impact on patients' quality of life. Further, the link between antidepressant use and an increased risk of C. difficile infection (CDI) is explored and, finally, the emergence of live biotherapeutic products as novel treatment options for recurrent CDI is discussed.
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Affiliation(s)
- Antoine Boustany
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Paul Feuerstadt
- Yale University School of Medicine, New Haven, CT, USA
- PACT-Gastroenterology Center, Hamden, CT, USA
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Asaji S, Funai Y, Seki Y, Tamai I, Shirasaka Y. Contributions of multiple transport mechanisms to intestinal uptake of serotonin. J Pharm Sci 2024; 113:3216-3226. [PMID: 39278593 DOI: 10.1016/j.xphs.2024.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 09/18/2024]
Abstract
This study aimed to analyze the contributions of multiple transport mechanisms to the intestinal uptake of serotonin (5-HT) by employing a variety of in vitro experimental techniques, focusing on organic cation transporters expressed in the gastrointestinal (GI) tract, such as SERT, PMAT, THTR2, OCT3, and OCTN2. Analysis of the concentration dependence of 5-HT uptake by Caco-2 cells revealed multi-affinity kinetics with high-affinity and low-affinity components, suggesting that multiple transporters are involved in the intestinal 5-HT uptake. Comparative analysis of transporters using Km values obtained in Xenopus oocyte expression systems suggested that SERT is responsible for the high-affinity transport, while PMAT, THTR2, and OCT3 contribute to the low-affinity transport. Further analysis indicated that the relative contributions of SERT and PMAT to the intestinal 5-HT uptake (0.01 µM) are approximately 94.9% and 1.1%, respectively. Interestingly, at the concentration of 10 µM, the reported steady-state concentration of 5-HT in the human colon, the contributions of SERT, PMAT, THTR2, and OCT3 were estimated to be approximately 37.0%, 1.0%, 18.2%, and 20.5%, respectively. In conclusion, the present study indicated that the contributions of multiple transporters to 5-HT uptake in the GI tract are dependent upon the colon luminal concentration of 5-HT.
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Affiliation(s)
- Suguru Asaji
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Yuta Funai
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Yuta Seki
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Ikumi Tamai
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Yoshiyuki Shirasaka
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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Zhang H, Xia Y, Wang G, Xiong Z, Wei G, Liao Z, Qian Y, Cai Z, Ai L. Lactobacillus plantarum AR495 improves colonic transport hyperactivity in irritable bowel syndrome through tryptophan metabolism. Food Funct 2024; 15:7416-7429. [PMID: 38899520 DOI: 10.1039/d4fo01087f] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Lactobacillus plantarum AR495 is a widely used probiotic for the treatment of various digestive diseases, including irritable bowel syndrome (IBS). However, the specific mechanisms of L. plantarum AR495 in alleviating IBS remain unclear. Abnormal intestinal tryptophan metabolism can cause disordered immune responses, gastrointestinal peristalsis, digestion and sensation, which is closely related to IBS pathogenesis. The aim of this study is to explore the effects and mechanisms of L. plantarum AR495 in regulating tryptophan metabolism. Primarily, tryptophan and its related metabolites in patients with IBS and healthy people were analyzed, and an IBS rat model of acetic acid enema plus restraint stress was established to explore the alleviation pathway of L. plantarum AR495 in tryptophan metabolism. It was found that the 5-HT pathway was significantly changed, and the 5-HTP and 5-HT metabolites were significantly increased in the feces of patients with IBS, which were consistent with the results obtained for the IBS rat model. Maladjusted 5-HT could increase intestinal peristalsis and lead to an increase in the fecal water content and shapeless stool in rats. On the contrary, these two metabolites could be restored to normal levels via intragastric administration of L. plantarum AR495. Further study of the metabolic pathway showed that L. plantarum AR495 could effectively reduce the abundance of 5-HT by inhibiting the expression of enterochromaffin cells rather than promoting its decomposition. In addition, the results showed that L. plantarum AR495 did not affect the expression of SERT. To sum up, L. plantarum AR495 could restore the normal levels of 5-HT by inhibiting the abnormal proliferation of enterochromaffin cells and the excessive activation of TPH1 to inhibit the intestinal peristalsis in IBS. These findings provide insights for the use of probiotics in the treatment of IBS and other diarrheal diseases.
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Affiliation(s)
- Hongyun Zhang
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
- Business school, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Yongjun Xia
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
| | - Guangqiang Wang
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
| | - Zhiqiang Xiong
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
| | - Guoliang Wei
- Business school, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Zhuan Liao
- Department of Gastroenterol, Digestive Endoscopy Center, Changhai Hospital, Shanghai, 200433, China
| | - Yangyan Qian
- Department of Gastroenterol, Digestive Endoscopy Center, Changhai Hospital, Shanghai, 200433, China
| | - Zongwei Cai
- State Key Laboratory of Environmental & Biological Analysis, Hong Kong Baptist University, Hong Kong Special Administrative region of China, China
| | - Lianzhong Ai
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
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Saei Ghare Naz M, Ghasemi V, Amirshekari S, Ramezani Tehrani F. Polycystic Ovary Syndrome and Irritable Bowel Syndrome: Is There a Common Pathway? Endocrinol Diabetes Metab 2024; 7:e00477. [PMID: 38494583 PMCID: PMC10944984 DOI: 10.1002/edm2.477] [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: 01/09/2024] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 03/19/2024] Open
Abstract
OBJECTIVE Little is known about how polycystic ovary syndrome (PCOS) is linked to irritable bowel syndrome (IBS). This study aimed to review the existing literature regarding the association between PCOS or its symptoms and complications with IBS. METHODS In this review, studies that investigated the proposed cross-link between features of PCOS and IBS were included. This review collectively focused on recent findings on the mechanism and novel insight regarding the association between IBS and PCOS in future clinical practice. An electronic search of PubMed, Scopus, Epistemonikos, Cochrane Library and Google Scholar was performed. We did not restrict the study setting and publication date. RESULTS The existing evidence has not completely answered the question of whether there is an association between PCOS and IBS and vice versa. Six case-control studies (793 women with PCOS and 547 women in the control group) directly assessed the association between PCOS and IBS. The prevalence of IBS among women with PCOS in these studies has ranged from 10% to 52% compared with 5%-50% in control groups. Evidence suggested the common pathways may have contributed to the interaction between IBS and PCOS, including metabolic syndrome, sex hormone fluctuation, dysregulation of neurotransmitters, psychological problems and environmental and lifestyle factors. To date, it is still ambiguous which of the mentioned components largely contributes to the pathogenesis of both. CONCLUSION Although limited evidence has shown a higher prevalence of IBS in women with PCOS, there are several potential, direct and common indirect pathways contributing to the development of both IBS and PCOS.
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Affiliation(s)
- Marzieh Saei Ghare Naz
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | | | - Shabahang Amirshekari
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Fahimeh Ramezani Tehrani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
- The Foundation for Research & Education ExcellenceVestavia HillsAlabamaUSA
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Sun Z, Huang S, Yan X, Zhang X, Hao Y, Jiang L, Dai Z. Living, Heat-Killed Limosilactobacillus mucosae and Its Cell-Free Supernatant Differentially Regulate Colonic Serotonin Receptors and Immune Response in Experimental Colitis. Nutrients 2024; 16:468. [PMID: 38398793 PMCID: PMC10893098 DOI: 10.3390/nu16040468] [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: 01/18/2024] [Revised: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Lactobacillus species have been shown to alleviate gut inflammation and oxidative stress. However, the effect of different lactobacilli components on gut inflammation has not been well studied. This study aims to identify the differences in the effect and mechanisms of different forms and components of Limosilactobacillus mucosae (LM) treatment in the alleviation of gut inflammation using a colitis mouse model that is induced by dextran sodium sulfate (DSS). Seventy-two C57BL/6 mice were divided into six groups: control, DSS, live LM+DSS (LM+DSS), heat-killed LM+DSS (HKLM+DSS), LM cell-free supernatant + DSS (LMCS+DSS), and MRS medium + DSS (MRS+DSS). The mice were treated with different forms and components of LM for two weeks before DSS treatment. After that, the mice were sacrificed for an assessment of their levels of inflammatory cytokines, serotonin (5-HT) receptors (HTRs), and tryptophan metabolites. The results showed that, compared to other treatments, LMCS was more effective (p < 0.05) in the alleviation of DSS-induced body weight loss and led to an increase in the disease activity index score. All three forms and components of LM increased (p < 0.05) the levels of indole-3-acetic acid but reduced (p < 0.05) the levels of 5-HT in the colon. HKLM or LMCS reduced (p < 0.05) the percentages of CD3+CD8+ cytotoxic T cells but increased (p < 0.05) the percentages of CD3+CD4+ T helper cells in the spleen. LM or HKLM increased (p < 0.05) abundances of CD4+Foxp3+ regulatory T cells in the spleen. The LM and LMCS treatments reduced (p < 0.05) the expression of the pro-inflammatory cytokines Il6 and Il17a. The mice in the HKLM+DSS group had higher (p < 0.05) mRNA levels of the anti-inflammatory cytokine Il10, the cell differentiation and proliferation markers Lgr5 and Ki67, the 5-HT degradation enzyme Maoa, and HTRs (Htr1a, Htr2a, and Htr2b) in the colon. All three forms and components of LM reduced the phosphorylation of STAT3. The above findings can help to optimize the functionality of probiotics and develop new dietary strategies that aid in the maintenance of a healthy gut.
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Affiliation(s)
- Zhiyuan Sun
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
| | - Siqi Huang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Xing Yan
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
| | - Xiuwen Zhang
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
| | - Youling Hao
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
| | - Lili Jiang
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, Beijing 100193, China; (Z.S.); (X.Y.); (X.Z.); (Y.H.); (L.J.)
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10
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Grondin JA, Khan WI. Emerging Roles of Gut Serotonin in Regulation of Immune Response, Microbiota Composition and Intestinal Inflammation. J Can Assoc Gastroenterol 2024; 7:88-96. [PMID: 38314177 PMCID: PMC10836984 DOI: 10.1093/jcag/gwad020] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2024] Open
Abstract
Although the exact etiology of inflammatory bowel diseases (IBD) is unknown, studies have shown that dysregulated immune responses, genetic factors, gut microbiota, and environmental factors contribute to their pathogenesis. Intriguingly, serotonin (5-hydroxytryptamine or 5-HT) seems to be a molecule with increasingly strong implications in the pathogenesis of intestinal inflammation, affecting host physiology, including autophagy and immune responses, as well as microbial composition and function. 5-HT may also play a role in mediating how environmental effects impact outcomes in IBD. In this review, we aim to explore the production and important functions of 5-HT, including its impact on the gut. In addition, we highlight the bidirectional impacts of 5-HT on the immune system, the gut microbiota, and the process of autophagy and how these effects contribute to the manifestation of intestinal inflammation. We also explore recent findings connecting 5-HT signalling and the influence of environmental factors, particularly diet, in the pathogenesis of IBD. Ultimately, we explore the pleiotropic effects of this ancient molecule on biology and health in the context of intestinal inflammation.
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Affiliation(s)
- Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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11
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Mitchell SB, Thorn TL, Lee MT, Kim Y, Comrie JMC, Bai ZS, Johnson EL, Aydemir TB. Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism. Am J Physiol Gastrointest Liver Physiol 2023; 325:G593-G607. [PMID: 37873588 PMCID: PMC10887856 DOI: 10.1152/ajpgi.00091.2023] [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: 05/01/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
Metal transporter SLC39A14/ZIP14 is localized on the basolateral side of the intestine, functioning to transport metals from blood to intestine epithelial cells. Deletion of Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose. Importantly, antibiotic treatment reverses the adipocyte phenotype of Slc39a14/Zip14 knockout (KO), suggesting a potential gut microbial role in the metabolic alterations in the Slc39a14/Zip14 KO mice. Here, we investigated the hypothesis that increased intestinal permeability and subsequent metabolic alterations in the absence of Zip14 could be in part due to alterations in gut microbial composition. Dietary metals have been shown to be involved in the regulation of gut microbial diversity and composition. However, studies linking the action of intestinal metal transporters to gut microbial regulation are lacking. We showed the influence of deletion of metal transporter Slc39a14/Zip14 on gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Slc39a14/Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract, a shift in gut microbial composition that partially overlapped with changes previously associated with obesity and inflammatory bowel disease (IBD), increased the fungi/bacteria ratio in the gut microbiome, altered the host metabolome, and shifted host energy metabolism toward glucose utilization. Collectively, our data suggest a potential predisease microbial susceptibility state dependent on host gene Slc39a14/Zip14 that contributes to intestinal permeability, a common trait of IBD, and metabolic disorders such as obesity and type 2 diabetes.NEW & NOTEWORTHY Metal dyshomeostasis, intestinal permeability, and gut dysbiosis are emerging signatures of chronic disorders, including inflammatory bowel diseases, type-2 diabetes, and obesity. Studies in reciprocal regulations between host intestinal metal transporters genes and gut microbiome are scarce. Our research revealed a potential predisease microbial susceptibility state dependent on the host metal transporter gene, Slc39a14/Zip14, that contributes to intestinal permeability providing new insight into understanding host metal transporter gene-microbiome interactions in developing chronic disease.
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Affiliation(s)
- Samuel B Mitchell
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Trista L Thorn
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Min-Ting Lee
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Yongeun Kim
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Janine M C Comrie
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Zi Shang Bai
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Elizabeth L Johnson
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
| | - Tolunay B Aydemir
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
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12
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Zhao J, Zhao F, Yuan J, Liu H, Wang Y. Gut microbiota metabolites, redox status, and the related regulatory effects of probiotics. Heliyon 2023; 9:e21431. [PMID: 38027795 PMCID: PMC10643359 DOI: 10.1016/j.heliyon.2023.e21431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/29/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Oxidative stress is a state of imbalance between oxidation and antioxidation. It is caused by excess levels of free radicals and leads to the damage of DNA, proteins, and lipids. The crucial role of gut microbiota in regulating oxidative stress has been widely demonstrated. Studies have suggested that the redox regulatory effects of gut microbiota are related to gut microbiota metabolites, including fatty acids, lipopolysaccharides, tryptophan metabolites, trimethylamine-N-oxide and polyphenolic metabolites. In recent years, the potential benefits of probiotics have been gaining increasing scientific interest owing to their ability to modulate gut microbiota and oxidative stress. In this review, we summarise the adverse health effects of oxidative stress and discuss the role of the gut microbiota and its metabolites in redox regulation. Based on the influence of gut microbiota metabolites, the roles of probiotics in preventing oxidative stress are highlighted.
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Affiliation(s)
| | | | - Junmeng Yuan
- College of Animal Science and Technology, Qingdao Agricultural University, 266109, Qingdao, China
| | - Huawei Liu
- College of Animal Science and Technology, Qingdao Agricultural University, 266109, Qingdao, China
| | - Yang Wang
- College of Animal Science and Technology, Qingdao Agricultural University, 266109, Qingdao, China
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13
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Jiang L, Li JC, Tang BS, Guo JF. Associations between gut microbiota and Parkinson disease: A bidirectional Mendelian randomization analysis. Eur J Neurol 2023; 30:3471-3477. [PMID: 37159496 DOI: 10.1111/ene.15848] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND AND PURPOSE Parkinson disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans. METHODS We performed two-sample bidirectional Mendelian randomization using summary statistics from the international consortium MiBioGen (N = 18,340), the Framingham Heart Study (N = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD age at onset (17,996 cases). RESULTS Twelve microbiota features presented suggestive associations with PD risk or age at onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio = 0.77, 95% confidence interval [CI] = 0.60-0.99, p = 0.040). Conversely, high levels of five short-chain fatty acid (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age at PD onset. Gut production of serotonin was associated with an earlier age at PD onset (beta = -0.64, 95% CI = -1.15 to -0.13, p = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition. CONCLUSIONS These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation.
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Affiliation(s)
- Li Jiang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jin-Chen Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- Bioinformatics Center and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Bei-Sha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- Bioinformatics Center and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ji-Feng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- Bioinformatics Center and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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14
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Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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15
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Xu L, Zeng X, Liu Y, Wu Z, Zheng X, Zhang X. Effect of Dendrobium officinale polysaccharides on central nervous system disease: Based on gut microbiota. Int J Biol Macromol 2023; 240:124440. [PMID: 37062382 DOI: 10.1016/j.ijbiomac.2023.124440] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/29/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023]
Abstract
Dendrobium officinale has anti-inflammatory effects and is one of the well-known functional foods. Dendrobium officinale polysaccharide (DOP) can reduce intestinal barrier disruption and excessive inflammatory response by regulating intestinal bacterial homeostasis as well as short-chain fatty acid levels. It can also inhibit the activation of astrocytes and microglia, further realizing the protective effect on neuronal apoptosis and apoptosis, thus exerting a significant alleviating effect on neurological diseases. There is now evidence that bidirectional communication between the central nervous system and the gastrointestinal tract may influence human neurology, cognition and behavior via the gut-brain axis. In this review, we review the structural characterization, bioactivity and possible bioactive mechanisms of DOP, so as to elucidate the advantages of DOP's action on CNS diseases, with the aim of providing new perspectives for its drug and functional food development as well as clinical applications.
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Affiliation(s)
- Lei Xu
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, PR China
| | - Xiaoxiong Zeng
- Department of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
| | - Yanan Liu
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, PR China
| | - Zufang Wu
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, PR China
| | - Xiaojie Zheng
- Department of Agriculture and Biotechnology, Wenzhou Vocational College of Science and Technology, Wenzhou 325006, PR China.
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, PR China.
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16
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Cleminson JR, Pasco JA, Bortolasci CC, Holloway-Kew KL, Hodge JM, Anderson KB, Kotowicz MA, Samarasinghe RM, Williams LJ. Lipopolysaccharide-binding protein and bone health: data from a population-based sample of men. Osteoporos Int 2023; 34:309-317. [PMID: 36409359 DOI: 10.1007/s00198-022-06602-9] [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: 03/22/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022]
Abstract
UNLABELLED We aimed to investigate the association between serum lipopolysaccharide-binding protein (LBP) and bone health in men. LBP was associated with lower bone density at the mid-forearm and the quantitative heel ultrasound measure, broadband ultrasound attenuation, for heavier participants. Data do not support clear associations between serum LBP and bone health. INTRODUCTION The objective of this study was to investigate the association between serum lipopolysaccharide-binding protein (LBP) and potential downstream effects on skeletal density, quality, and turnover in a population-based sample of men. METHODS This cross-sectional study utilised data from 1149 men (aged 20-96 year) enrolled in the Geelong Osteoporosis Study. Blood samples were obtained and lipopolysaccharide-binding protein (LBP), bone resorption marker, C-telopeptide (CTx), and formation marker, type 1 procollagen amino-terminal-propeptide (P1NP), were measured. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Stiffness Index (SI), broadband ultrasound attenuation (BUA), and speed of sound (SOS) were derived from quantitative heel ultrasound (QUS). Linear regression models were developed to test associations between log-transformed LBP (ln-LBP), BMD, QUS, and bone turnover, after adjusting for potential covariates. RESULTS Serum LBP ranged from 1.07-208.53 ng/mL (median 16.53 ng/mL). Those with higher levels were older, less mobile, and had lower BMD at the mid-forearm, otherwise, groups were similar. Before and after adjustment for age, ln-LBP was associated with lower BMD at the spine, total body, and mid-forearm. Further adjustment for weight attenuated associations at the spine and total body, yet the relationship at the mid-forearm was sustained (β - 0.014 ± 0.004, p = 0.001). SOS and SI were not associated with ln-LBP either before or after adjustment for age; however, weight was identified as an effect modifier in the relationship between ln-LBP and BUA. An association was observed for those weighing greater than 82.7 kg (β 3.366 ± 0.929, p < 0.001), after adjustment for potential covariates. Neither bone turnover marker was associated with ln-LBP. CONCLUSION Our data do not support a clear association between serum LBP and measures of bone health in this sample of men.
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Affiliation(s)
- Jasmine R Cleminson
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia.
| | - Julie A Pasco
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
- Department of Medicine-Western Health, The University of Melbourne, St Albans, Victoria, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
- Barwon Health, University Hospital, Geelong, VIC, Australia
| | - Chiara C Bortolasci
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
| | - Kara L Holloway-Kew
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
| | - Jason M Hodge
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
- Barwon Health, University Hospital, Geelong, VIC, Australia
- Geelong Centre for Emerging Infectious Diseases, Geelong, VIC, 3220, Australia
| | - Kara B Anderson
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
| | - Mark A Kotowicz
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
- Department of Medicine-Western Health, The University of Melbourne, St Albans, Victoria, Australia
- Barwon Health, University Hospital, Geelong, VIC, Australia
| | - Rasika M Samarasinghe
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
| | - Lana J Williams
- Deakin University, School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), PO Box 281, Geelong, Victoria, 3220, Australia
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17
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Hizay A, Dag K, Oz N, Comak-Gocer EM, Ozbey-Unlu O, Ucak M, Keles-Celik N. Lactobacillus acidophilus regulates abnormal serotonin availability in experimental ulcerative colitis. Anaerobe 2023; 80:102710. [PMID: 36708801 DOI: 10.1016/j.anaerobe.2023.102710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/06/2023] [Accepted: 01/24/2023] [Indexed: 01/26/2023]
Abstract
OBJECTIVES Probiotics are known to play a beneficial role in curing irritable bowel syndrome such as ulcerative colitis. Commensal Lactobacillus species are thought to play a protective role against ulcerative colitis, as they restore homeostasis in intestinal disorders. Abnormal serotonin availability has been described in ulcerative colitis, but the underlying mechanism is still unclear. The aim of this study was to determine the anti-inflammatory role of Lactobacillus acidophilus (L. acidophilus) and its effect on serotonin expression. METHODS Ulcerative colitis was created with the intrarectal administration of acetic acid. A total of 40 adult male rats were divided into five groups of eight rats as control, sham, experimental colitis, treatment (Colitis + L. acidophilus) and protective group (L. acidophilus + colitis). To evaluate the effects of L. acidophilus on serotonin expression in ulcerative colitis, this bacterial strain was administered orally to the rats with acetic acid-induced colitis. After oral administration of L. acidophilus for 14 days, serotonin content was biochemically measured and serotonin expression was evaluated immunohistochemically. RESULTS The expression of serotonin and its protein content was significantly increased in colitis compared to the control and sham groups. Abnormal serotonin availability in the rats with acetic acid-induced colitis was significantly reduced by the L. acidophilus. CONCLUSIONS In our study, it was observed that the amount of serotonin in the intestinal tissue increased excessively with ulcerative colitis. In addition, L.acidophilus has been found to reduce the abnormally increased amount of serotonin in the colon tissue, as well as reduce the inflammation in the intestinal tissue that occurs with ulcerative colitis. With our findings, it is predicted that probiotic application can be used as a treatment option in ulcerative colitis.
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Affiliation(s)
- Arzu Hizay
- Department of Anatomy, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Kubra Dag
- Department of Anatomy, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Nuriye Oz
- Department of Anatomy, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Emine Mine Comak-Gocer
- Department of Nutrition and Dietetics, Akdeniz University, Faculty of Health Sciences, Antalya, Turkey.
| | - Ozlem Ozbey-Unlu
- Department of Histology and Embryology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Melike Ucak
- Department of Histology and Embryology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Nigar Keles-Celik
- Department of Anatomy, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
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18
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Grozić A, Coker K, Dussik CM, Sabir MS, Sabir Z, Bradley A, Zhang L, Park J, Yale S, Kaneko I, Hockley M, Harris LA, Lunsford TN, Sandrin TR, Jurutka PW. Identification of putative transcriptomic biomarkers in irritable bowel syndrome (IBS): Differential gene expression and regulation of TPH1 and SERT by vitamin D. PLoS One 2022; 17:e0275683. [PMID: 36264926 PMCID: PMC9584396 DOI: 10.1371/journal.pone.0275683] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and affects approximately 4% of the global population. The diagnosis of IBS can be made based on symptoms using the validated Rome criteria and ruling out commonly occurring organic diseases. Although biomarkers exist for "IBS mimickers" such as celiac disease and inflammatory bowel disease (IBD), no such test exists for IBS. DNA microarrays of colonic tissue have been used to identify disease-associated variants in other gastrointestinal (GI) disorders. In this study, our objective was to identify biomarkers and unique gene expression patterns that may define the pathological state of IBS. Mucosal tissue samples were collected from the sigmoid colon of 29 participants (11 IBS and 18 healthy controls). DNA microarray analysis was used to assess gene expression profiling. Extraction and purification of RNA were then performed and used to synthesize cDNA. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was employed to identify differentially expressed genes in patients diagnosed with IBS compared to healthy, non-IBS patient-derived cDNA. Additional testing probed vitamin D-mediated regulation of select genes associated with serotonergic metabolism. DNA microarray analyses led to the identification of 858 differentially expressed genes that may characterize the IBS pathological state. After screening a series of genes using a combination of gene ontological analysis and RT-qPCR, this spectrum of potential IBS biomarkers was narrowed to 23 genes, some of which are regulated by vitamin D. Seven putative IBS biomarkers, including genes involved in serotonin metabolism, were identified. This work further supports the hypothesis that IBS pathophysiology is evident within the human transcriptome and that vitamin D modulates differential expression of genes in IBS patients. This suggests that IBS pathophysiology may also involve vitamin D deficiency and/or an irregularity in serotonin metabolism.
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Affiliation(s)
- Aleksandra Grozić
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Keaton Coker
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Christopher M. Dussik
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Marya S. Sabir
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Zhela Sabir
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Arianna Bradley
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Lin Zhang
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Jin Park
- Biodesign Institute, Arizona State University, Tempe, AZ, United States of America
| | - Steven Yale
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL, United States of America
| | - Ichiro Kaneko
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, United States of America
| | - Maryam Hockley
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
| | - Lucinda A. Harris
- Mayo Clinic Division of Gastroenterology & Hepatology, Alix School of Medicine, Mayo Clinic, Scottsdale, AZ, United States of America
| | - Tisha N. Lunsford
- Mayo Clinic Division of Gastroenterology & Hepatology, Alix School of Medicine, Mayo Clinic, Scottsdale, AZ, United States of America
| | - Todd R. Sandrin
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
- Julie Ann Wrigley Global Futures Laboratory, Arizona State University, Tempe, AZ, United States of America
| | - Peter W. Jurutka
- School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, United States of America
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, United States of America
- * E-mail:
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19
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Li B, Li M, Luo Y, Li R, Li W, Liu Z. Engineered 5-HT producing gut probiotic improves gastrointestinal motility and behavior disorder. Front Cell Infect Microbiol 2022; 12:1013952. [PMID: 36339343 PMCID: PMC9630942 DOI: 10.3389/fcimb.2022.1013952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/04/2022] [Indexed: 12/03/2022] Open
Abstract
Slow transit constipation is an intractable constipation with unknown aetiology and uncertain pathogenesis. The gut microbiota maintains a symbiotic relationship with the host and has an impact on host metabolism. Previous studies have reported that some gut microbes have the ability to produce 5-hydroxytryptamine (5-HT), an important neurotransmitter. However, there are scarce data exploiting the effects of gut microbiota-derived 5-HT in constipation-related disease. We genetically engineered the probiotic Escherichia coli Nissle 1917 (EcN-5-HT) for synthesizing 5-HT in situ. The ability of EcN-5-HT to secrete 5-HT in vitro and in vivo was confirmed. Then, we examined the effects of EcN-5-HT on intestinal motility in a loperamide-induced constipation mouse model. After two weeks of EcN-5-HT oral gavage, the constipation-related symptoms were relieved and gastrointestinal motility were enhanced. Meanwhile, administration of EcN-5-HT alleviated the constipation related depressive-like behaviors. We also observed improved microbiota composition during EcN-5-HT treatment. This work suggests that gut microbiota-derived 5-HT might promise a potential therapeutic strategy for constipation and related behavioral disorders.
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Affiliation(s)
- Bei Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Min Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Yanan Luo
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Rong Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Wei Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
- *Correspondence: Wei Li, ; Zhi Liu,
| | - Zhi Liu
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
- *Correspondence: Wei Li, ; Zhi Liu,
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20
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Hatamnejad MR, Baradaran Ghavami S, Shirvani M, Asghari Ahmadabad M, Shahrokh S, Farmani M, Sherkat G, Asadzadeh Aghdaei H, Zali MR. Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice. Front Immunol 2022; 13:980189. [PMID: 36275739 PMCID: PMC9583131 DOI: 10.3389/fimmu.2022.980189] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/22/2022] [Indexed: 11/21/2022] Open
Abstract
IBD, a chronic inflammatory disease, has been manifested as a growing health problem. No Crohn's and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them to rectify functional bowel consequences such as pain and alleviate psychiatric comorbidities. On the other side, SSRIs' prescription is accompanied by adverse effects such as sleep disturbances. Prolonged intermittent hypoxia throughout sleep disturbance such as sleep apnea provokes periodic reductions in the partial oxygen pressure gradient in the gut lumen. It promotes gut microbiota to dysbiosis, which induces intestinal inflammation. This phenomenon and evidence representing the higher amount of serotonin associated with Crohn's disease challenged our previous knowledge. Can SSRIs worsen the IBD course? Evidence answered the question with the claim on anti-inflammatory properties (central and peripheral) of SSRIs and illuminated the other substantial elements (compared to serotonin elevation) responsible for IBD pathogenesis. However, later clinical evidence was not all in favor of the benefits of SSRIs. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the interfering molecular mechanism justifying both supporting and disproving clinical evidence. Biphasic dose-dependent serotonin behavior accompanying SSRI shifting function when used up for the long-term can be assumed as the parameters leading to IBD patients' adverse outcomes. Despite more research being needed to elucidate the effect of SSRI consumption in IBD patients, periodic prescriptions of SSRIs at monthly intervals can be recommended.
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Affiliation(s)
- Mohammad Reza Hatamnejad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Shirvani
- Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Medicine Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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21
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Melatonin shapes bacterial clearance function of porcine macrophages during enterotoxigenic Escherichia coli infection. ANIMAL NUTRITION 2022; 11:242-251. [PMID: 36263406 PMCID: PMC9556787 DOI: 10.1016/j.aninu.2022.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/28/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022]
Abstract
Due to the immature gastrointestinal immune system, weaning piglets are highly susceptible to pathogens, e.g., enterotoxigenic Escherichia coli (ETEC). Generally, pathogens activate the immune cells (e.g., macrophages) and shape intracellular metabolism (including amino acid metabolism); nevertheless, the metabolic cues of tryptophan (especially melatonin pathway) in directing porcine macrophage function during ETEC infection remain unclear. Therefore, this study aimed to investigate the changes in the serotonin pathway of porcine macrophages during ETEC infection and the effect of melatonin on porcine macrophage functions. Porcine macrophages (3D4/21 cells) were infected with ETEC, and the change of serotonin pathway was analysed by reverse transcription PCR and metabolomic analysis. The effect of melatonin on porcine macrophage function was also studied with proteomic analysis. In order to investigate the effect of melatonin on bacterial clearance function of porcine macrophages during ETEC infection, methods such as bacterial counting, reverse transcription PCR and western blotting were used to detect the corresponding indicators. The results showed that ETEC infection blocked melatonin production in porcine macrophages (P < 0.05) which is largely associated with the heat-stable enterotoxin b (STb) of ETEC (P < 0.05). Interestingly, melatonin altered porcine macrophage functions, including bacteriostatic and bactericidal activities based on proteomic analysis. In addition, melatonin pre-treatment significantly reduced extracellular lactate dehydrogenase (LDH) activity (P < 0.05), indicating that melatonin also attenuated ETEC-triggered macrophage death. Moreover, melatonin pre-treatment resulted in the decrease of viable ETEC in 3D4/21 cells (P < 0.05), suggesting that melatonin enhances bacterial clearance of porcine macrophages. These results suggest that melatonin is particularly important in shaping porcine macrophage function during ETEC infection.
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22
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The Role of Serotonin Neurotransmission in Gastrointestinal Tract and Pharmacotherapy. Molecules 2022; 27:molecules27051680. [PMID: 35268781 PMCID: PMC8911970 DOI: 10.3390/molecules27051680] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/01/2022] [Indexed: 02/06/2023] Open
Abstract
5-Hydroxytryptamine (5-HT, serotonin) is a neurotransmitter in both the central nervous system and peripheral structures, acting also as a hormone in platelets. Although its concentration in the gut covers >90% of all organism resources, serotonin is mainly known as a neurotransmitter that takes part in the pathology of mental diseases. Serotonin modulates not only CNS neurons, but also pain transmission and platelet aggregation. In the periphery, 5-HT influences muscle motility in the gut, bronchi, uterus, and vessels directly and through neurons. Serotonin synthesis starts from hydroxylation of orally delivered tryptophan, followed by decarboxylation. Serotonin acts via numerous types of receptors and clinically plays a role in several neural, mental, and other chronic disorders, such as migraine, carcinoid syndrome, and some dysfunctions of the alimentary system. 5-HT acts as a paracrine hormone and growth factor. 5-HT receptors in both the brain and gut are targets for drugs modifying serotonin neurotransmission. The aim of the present article is to review the 5-HT receptors in the gastrointestinal (GI) tract to determine the role of serotonin in GI physiology and pathology, including known GI diseases and the role of serotonin in GI pharmacotherapy.
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23
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Abstract
Hypertension is a worldwide problem with major impacts on health including morbidity and mortality, as well as consumption of health care resources. Nearly 50% of American adults have high blood pressure, and this rate is rising. Even with multiple antihypertensive drugs and aggressive lifestyle modifications, blood pressure is inadequately controlled in about 1 of 5 hypertensive individuals. This review highlights a hypothesis for hypertension that suggests alternative mechanisms for blood pressure elevation and maintenance. A better understanding of these mechanisms could open avenues for more successful treatments. The hypothesis accounts for recent understandings of the involvement of gut physiology, gut microbiota, and neuroinflammation in hypertension. It includes bidirectional communication between gut microbiota and gut epithelium in the gut-brain axis that is involved in regulation of autonomic nervous system activity and blood pressure control. Dysfunction of this gut-brain axis, including dysbiosis of gut microbiota, gut epithelial dysfunction, and deranged input to the brain, contributes to hypertension via inflammatory mediators, metabolites, bacteria in the circulation, afferent information alterations, etc resulting in neuroinflammation and unbalanced autonomic nervous system activity that elevates blood pressure. This in turn negatively affects gut function and its microbiota exacerbating the problem. We focus this review on the gut-brain axis hypothesis for hypertension and possible contribution to racial disparities in hypertension. A novel idea, that immunoglobulin A-coated bacteria originating in the gut with access to the brain could be involved in hypertension, is raised. Finally, minocycline, with its anti-inflammatory and antimicrobial properties, is evaluated as a potential antihypertensive drug acting on this axis.
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Affiliation(s)
- Elaine M Richards
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Jing Li
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Bruce R Stevens
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Carl J Pepine
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Mohan K Raizada
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
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24
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Nieves KM, Hirota SA, Flannigan KL. Xenobiotic receptors and the regulation of intestinal homeostasis: harnessing the chemical output of the intestinal microbiota. Am J Physiol Gastrointest Liver Physiol 2022; 322:G268-G281. [PMID: 34941453 DOI: 10.1152/ajpgi.00160.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The commensal bacteria that reside in the gastrointestinal tract exist in a symbiotic relationship with the host, driving the development of the immune system and maintaining metabolic and tissue homeostasis in the local environment. The intestinal microbiota has the capacity to generate a wide array of chemical metabolites to which the cells of the intestinal mucosa are exposed. Host cells express xenobiotic receptors, such as the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR), that can sense and respond to chemicals that are generated by nonhost pathways. In this review, we outline the physiological and immunological processes within the intestinal environment that are regulated by microbial metabolites through the activation of the AhR and the PXR, with a focus on ligands generated by the stepwise catabolism of tryptophan.
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Affiliation(s)
- Kristoff M Nieves
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Kyle L Flannigan
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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25
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Mavanji V, Pomonis B, Kotz CM. Orexin, serotonin, and energy balance. WIREs Mech Dis 2022; 14:e1536. [PMID: 35023323 PMCID: PMC9286346 DOI: 10.1002/wsbm.1536] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/27/2021] [Accepted: 08/23/2021] [Indexed: 12/02/2022]
Abstract
The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non‐goal‐oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high‐intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy‐homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin‐serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin–serotonin cross‐talk; the role of serotonin receptors, transporters and uptake‐inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin‐function; single‐nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin–serotonin field. This article is categorized under:
Metabolic Diseases > Molecular and Cellular Physiology
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Affiliation(s)
- Vijayakumar Mavanji
- Research Service, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA
| | - Brianna Pomonis
- Research Service, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA
| | - Catherine M Kotz
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA.,Geriatric Research Education and Clinical Center, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA
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26
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Ali T, Ishtiaq A, Mushtaq I, Ayaz N, Jan MI, Khan W, Khan U, Murtaza I. Mentha longifolia Alleviates Exogenous Serotonin-Induced Diabetic Hypoglycemia and Relieves Renal Toxicity via ROS Regulation. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2021; 76:501-506. [PMID: 34716886 DOI: 10.1007/s11130-021-00932-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/15/2021] [Indexed: 06/13/2023]
Abstract
Diabetic kidney disease is one of the most common microvascular complications of diabetes mellitus with consequences of diabetic nephropathy. Here we amined to evaluate the nephroprotective potential of methanolic Mentha longifolia (MML) against serotonin-induced hypoglycemia allied toxicity in the rat model of diabetes. Diabetes was induced in rats via alloxan administration and validated by blood glucose level measurement. After that, the animals were treated with serotonin and methanolic extract of Mentha longifolia. Surprisingly, serotonin treatment significantly reduced the glucose levels to hypoglycemic conditions, accompanied by impaired redox defense system, abnormal kidney histopathology, dyslipidemia, and altered level of liver toxicity markers. Interestingly these changes were rescued by the methanolic extract of M. longifolia. The present study suggests that impaired serotonin levels during diabetic conditions may accelerate hypoglycemic allied free radical-dependent abnormalities; however, medicinal plants like M. longifolia can reduce these deleterious effects by scavenging free radicals and their associated toxicity.
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Affiliation(s)
- Tahir Ali
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan.
| | - Ayesha Ishtiaq
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Iram Mushtaq
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Neelum Ayaz
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Muhammad Ishtiaq Jan
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Wajiha Khan
- COMSATS University Abbottabad Campus, Mansehra, KPK, Pakistan
| | - Uzma Khan
- Hazara University, Mansehra, KPK, Pakistan
| | - Iram Murtaza
- Signal Transduction Laboratory, Department of Biochemistry, Quaid-I-Azam University, Islamabad, Pakistan.
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27
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Simonato M, Dall’Acqua S, Zilli C, Sut S, Tenconi R, Gallo N, Sfriso P, Sartori L, Cavallin F, Fiocco U, Cogo P, Agostinis P, Aldovini A, Bruttomesso D, Marcolongo R, Comai S, Baritussio A. Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomedicines 2021; 9:biomedicines9111724. [PMID: 34829952 PMCID: PMC8615774 DOI: 10.3390/biomedicines9111724] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 02/04/2023] Open
Abstract
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
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Affiliation(s)
- Manuela Simonato
- PCare Laboratory, Fondazione Istituto di Ricerca Pediatrica, Citta’ della Speranza, 35127 Padova, Italy;
| | - Stefano Dall’Acqua
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (S.D.); (S.S.)
| | | | - Stefania Sut
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (S.D.); (S.S.)
| | - Romano Tenconi
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | - Nicoletta Gallo
- Department of Laboratory Medicine, Policlinico Azienda Ospedaliera di Padova, 35128 Padova, Italy;
| | - Paolo Sfriso
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | - Leonardo Sartori
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | | | - Ugo Fiocco
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | - Paola Cogo
- Department of Medicine, University Hospital Santa Maria della Misericordia, University of Udine, 33100 Udine, Italy;
| | - Paolo Agostinis
- Department of Medicine, Ospedale Sant’Antonio Abate, Azienda Sanitaria del Friuli Centrale, 33100 Udine, Italy;
| | - Anna Aldovini
- Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, USA;
- Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Daniela Bruttomesso
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | - Renzo Marcolongo
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
| | - Stefano Comai
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (S.D.); (S.S.)
- Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy
- Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada
- Division of Neuroscience, IRCSS San Raffaele Scientific Institute, 20132 Milan, Italy
- Correspondence: ; Tel.: +39-049-827-5098
| | - Aldo Baritussio
- Department of Medicine, University of Padova, 35128 Padova, Italy; (R.T.); (P.S.); (L.S.); (U.F.); (D.B.); (R.M.); (A.B.)
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28
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Snarska J, Fiedorowicz E, Rozmus D, Wroński K, Latacz M, Kordulewska N, Płomiński J, Grzybowski R, Savelkoul HFJ, Kostyra E, Cieślińska A. TPH1 gene polymorphism rs211105 is associated with serotonin and tryptophan hydroxylase 1 concentrations in acute pancreatitis patients. BMC Gastroenterol 2021; 21:426. [PMID: 34772352 PMCID: PMC8588706 DOI: 10.1186/s12876-021-02012-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/02/2021] [Indexed: 11/25/2022] Open
Abstract
Background The role of serotonin and its metabolic pathway in proper functioning of the pancreas has not been thoroughly investigated yet in acute pancreatitis (AP) patients. Tryptophan hydroxylase (TPH) as the rate-limiting enzyme of serotonin synthesis has been considered for possible associations in various diseases. Single-nucleotide polymorphisms (SNPs) in TPH genes have been already described in associations with psychiatric and digestive system disorders. This study aimed to explore the association of a rs211105 (T/G) polymorphism in TPH1 gene with tryptophan hydroxylase 1 concentrations in blood serum in a population of acute pancreatitis patients, and to investigate this association with acute pancreatitis susceptibility. Results Our data showed an association between the presence of the T allele at the position rs211105 (OR = 2.47, 95 % CI 0.94–6.50, p = 0.06) under conditions of a decreased AP incidence. For TT and GT genotypes in the control group, the lowest concentration of TPH was associated with higher serotonin levels (TT: Rs = − 0.415, p = 0.0018; GT: Rs = − 0.457, p = 0.0066), while for the AP group the highest levels of TPH among the TT genotype were associated with lower levels of serotonin (TT: Rs = − 0.749, p < 0.0001, and in the GG genotype higher levels of TPH were associated with higher levels of serotonin (GG: Rs = − 0.738, p = 0.037). Conclusions Here, a new insight in the potential role of a selected genetic factor in pancreatitis development was shown. Not only the metabolic pathway of serotonin, but also factors affecting serotonin synthesis may be interesting and important points in acute pancreatitis.
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Affiliation(s)
- Jadwiga Snarska
- Department of General Surgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Ewa Fiedorowicz
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Dominika Rozmus
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Konrad Wroński
- General and Colorectal Surgery Clinic, University Clinical Hospital of the Military Medical Academy - Central Veterans Hospital in Lodz, Lodz, Poland
| | - Maria Latacz
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Natalia Kordulewska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Janusz Płomiński
- Department and Clinic of Orthopaedics and Traumatology, Collegium Medicum, University of Warmia and Mazury, 10-719, Olsztyn, Poland
| | - Roman Grzybowski
- Department and Clinic of Orthopaedics and Traumatology, Collegium Medicum, University of Warmia and Mazury, 10-719, Olsztyn, Poland
| | - Huub F J Savelkoul
- Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University and Research, Wageningen, Netherlands
| | - Elżbieta Kostyra
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Anna Cieślińska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
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29
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Haq S, Wang H, Grondin J, Banskota S, Marshall JK, Khan II, Chauhan U, Cote F, Kwon YH, Philpott D, Brumell JH, Surette M, Steinberg GR, Khan WI. Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn's disease. SCIENCE ADVANCES 2021; 7:eabi6442. [PMID: 34739317 PMCID: PMC8570609 DOI: 10.1126/sciadv.abi6442] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn’s disease (CD). Factors that lead to the development of impaired autophagy during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin [5-hydroxytryptamine;(5-HT)] and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.
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Affiliation(s)
- Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Huaqing Wang
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jensine Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Suhrid Banskota
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John K. Marshall
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Irfan I. Khan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Usha Chauhan
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Francine Cote
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Dana Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - John H. Brumell
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Ontario and Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michael Surette
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R. Steinberg
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Waliul I. Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Hamilton, Ontario, Canada
- Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
- Corresponding author.
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30
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Shao J, Li Z, Gao Y, Zhao K, Lin M, Li Y, Wang S, Liu Y, Chen L. Construction of a "Bacteria-Metabolites" Co-Expression Network to Clarify the Anti-Ulcerative Colitis Effect of Flavonoids of Sophora flavescens Aiton by Regulating the "Host-Microbe" Interaction. Front Pharmacol 2021; 12:710052. [PMID: 34721011 PMCID: PMC8553221 DOI: 10.3389/fphar.2021.710052] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/09/2021] [Indexed: 12/30/2022] Open
Abstract
Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate–induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and “bacteria and metabolites” co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus, Roseburia, norank_f__Muribaculaceae, Anaerotruncus, Candidatus_Saccharimona, and Parasutterella, which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC.
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Affiliation(s)
- Jing Shao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhaocheng Li
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanping Gao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kairui Zhao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Minling Lin
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yadi Li
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shumei Wang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Liu
- The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, China.,School of Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lei Chen
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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31
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Taverniti V, Cesari V, Gargari G, Rossi U, Biddau C, Lecchi C, Fiore W, Arioli S, Toschi I, Guglielmetti S. Probiotics Modulate Mouse Gut Microbiota and Influence Intestinal Immune and Serotonergic Gene Expression in a Site-Specific Fashion. Front Microbiol 2021; 12:706135. [PMID: 34539604 PMCID: PMC8441017 DOI: 10.3389/fmicb.2021.706135] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Probiotic microorganisms may benefit the host by influencing diverse physiological processes, whose nature and underlying mechanisms are still largely unexplored. Animal models are a unique tool to understand the complexity of the interactions between probiotic microorganisms, the intestinal microbiota, and the host. In this regard, in this pilot study, we compared the effects of 5-day administration of three different probiotic bacterial strains (Bifidobacterium bifidum MIMBb23sg, Lactobacillus helveticus MIMLh5, and Lacticaseibacillus paracasei DG) on three distinct murine intestinal sites (ileum, cecum, and colon). All probiotics preferentially colonized the cecum and colon. In addition, probiotics reduced in the ileum and increased in the cecum and colon the relative abundance of numerous bacterial taxonomic units. MIMBb23sg and DG increased the inducible nitric oxide synthase (iNOS) in the ileum, which is involved in epithelial homeostasis. In addition, MIMBb23sg upregulated cytokine IL-10 in the ileum and downregulated the cyclooxygenase COX-2 in the colon, suggesting an anti-inflammatory/regulatory activity. MIMBb23sg significantly affected the expression of the main gene involved in serotonin synthesis (TPH1) and the gene coding for the serotonin reuptake protein (SERT) in the ileum and colon, suggesting a potential propulsive effect toward the distal part of the gut, whereas the impact of MIMLh5 and DG on serotonergic genes suggested an effect toward motility control. The three probiotics decreased the expression of the permeability marker zonulin in gut distal sites. This preliminary in vivo study demonstrated the safety of the tested probiotic strains and their common ability to modulate the intestinal microbiota. The probiotics affected host gene expression in a strain-specific manner. Notably, the observed effects in the gut were site dependent. This study provides a rationale for investigating the effects of probiotics on the serotonergic system, which is a topic still widely unexplored.
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Affiliation(s)
- Valentina Taverniti
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Valentina Cesari
- Department of Agricultural and Environmental Sciences, Università degli Studi di Milano, Milan, Italy
| | - Giorgio Gargari
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Umberto Rossi
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Cristina Biddau
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Cristina Lecchi
- Department of Veterinary Medicine, Università degli Studi di Milano, Milan, Italy
| | | | - Stefania Arioli
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Ivan Toschi
- Department of Agricultural and Environmental Sciences, Università degli Studi di Milano, Milan, Italy
| | - Simone Guglielmetti
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
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32
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Haq S, Grondin JA, Khan WI. Tryptophan-derived serotonin-kynurenine balance in immune activation and intestinal inflammation. FASEB J 2021; 35:e21888. [PMID: 34473368 PMCID: PMC9292703 DOI: 10.1096/fj.202100702r] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023]
Abstract
Endogenous tryptophan metabolism pathways lead to the production of serotonin (5‐hydroxytryptamine; 5‐HT), kynurenine, and several downstream metabolites which are involved in a multitude of immunological functions in both health and disease states. Ingested tryptophan is largely shunted to the kynurenine pathway (95%) while only minor portions (1%–2%) are sequestered for 5‐HT production. Though often associated with the functioning of the central nervous system, significant production of 5‐HT, kynurenine and their downstream metabolites takes place within the gut. Accumulating evidence suggests that these metabolites have essential roles in regulating immune cell function, intestinal inflammation, as well as in altering the production and suppression of inflammatory cytokines. In addition, both 5‐HT and kynurenine have a considerable influence on gut microbiota suggesting that these metabolites impact host physiology both directly and indirectly via compositional changes. It is also now evident that complex interactions exist between the two pathways to maintain gut homeostasis. Alterations in 5‐HT and kynurenine are implicated in the pathogenesis of many gastrointestinal dysfunctions, including inflammatory bowel disease. Thus, these pathways present numerous potential therapeutic targets, manipulation of which may aid those suffering from gastrointestinal disorders. This review aims to update both the role of 5‐HT and kynurenine in immune regulation and intestinal inflammation, and analyze the current knowledge of the relationship and interactions between 5‐HT and kynurenine pathways.
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Affiliation(s)
- Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Laboratory Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada
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33
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5-HT Receptors and the Development of New Antidepressants. Int J Mol Sci 2021; 22:ijms22169015. [PMID: 34445721 PMCID: PMC8396477 DOI: 10.3390/ijms22169015] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023] Open
Abstract
Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.
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34
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Kuwahara A, Matsuda K, Kuwahara Y, Asano S, Inui T, Marunaka Y. Microbiota-gut-brain axis: enteroendocrine cells and the enteric nervous system form an interface between the microbiota and the central nervous system. Biomed Res 2021; 41:199-216. [PMID: 33071256 DOI: 10.2220/biomedres.41.199] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The microbiota-gut-brain axis transmits bidirectional communication between the gut and the central nervous system and links the emotional and cognitive centers of the brain with peripheral gut functions. This communication occurs along the axis via local, paracrine, and endocrine mechanisms involving a variety of gut-derived peptide/amine produced by enteroendocrine cells. Neural networks, such as the enteric nervous system, and the central nervous system, including the autonomic nervous system, also transmit information through the microbiota-gut-brain axis. Recent advances in research have described the importance of the gut microbiota in influencing normal physiology and contributing to disease. We are only beginning to understand this bidirectional communication system. In this review, we summarize the available data supporting the existence of these interactions, highlighting data related to the contribution of enteroendocrine cells and the enteric nervous system as an interface between the gut microbiota and brain.
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Affiliation(s)
- Atsukazu Kuwahara
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University
| | - Kyoko Matsuda
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University
| | - Yuko Kuwahara
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University
| | - Shinji Asano
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University
| | | | - Yoshinori Marunaka
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University.,Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.,Research Institute for Clinical Physiology, Kyoto Industrial Health Association
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35
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Serotonin Exposure Improves Stress Resistance, Aggregation, and Biofilm Formation in the Probiotic Enterococcus faecium NCIMB10415. MICROBIOLOGY RESEARCH 2021. [DOI: 10.3390/microbiolres12030043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The role of the microbiota–gut–brain axis in maintaining a healthy status is well recognized. In this bidirectional flux, the influence of host hormones on gut bacteria is crucial. However, data on commensal/probiotics are scarce since most reports analyzed the effects of human bioactive compounds on opportunistic strains, highlighting the risk of increased pathogenicity under stimulation. The present investigation examined the modifications induced by 5HT, a tryptophan-derived molecule abundant in the intestine, on the probiotic Enterococcus faecium NCIMB10415. Specific phenotypic modifications concerning the probiotic potential and possible effects of treated bacteria on dendritic cells were explored together with the comparative soluble proteome evaluation. Increased resistance to bile salts and ampicillin in 5HT-stimulated conditions relate with overexpression of specific proteins (among which Zn-beta-lactamases, a Zn-transport protein and a protein involved in fatty acid incorporation into the membrane). Better auto-aggregating properties and biofilm-forming aptitude are consistent with enhanced QS peptide transport. Concerning interaction with the host, E. faecium NCIMB10415 enhanced dendritic cell maturation, but no significant differences were observed between 5HT-treated and untreated bacteria; meanwhile, after 5HT exposure, some moonlight proteins possibly involved in tissue adhesion were found in higher abundance. Finally, the finding in stimulated conditions of a higher abundance of VicR, a protein involved in two-component signal transduction system (VicK/R), suggests the existence of a possible surface receptor (VicK) for 5HT sensing in the strain studied. These overall data indicate that E. faecium NCIMB10415 modifies its physiology in response to 5HT by improving bacterial interactions and resistance to stressors.
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36
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Grifka-Walk HM, Jenkins BR, Kominsky DJ. Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism. Front Immunol 2021; 12:653208. [PMID: 34149693 PMCID: PMC8213022 DOI: 10.3389/fimmu.2021.653208] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Tryptophan (Trp) is an essential amino acid primarily derived from the diet for use by the host for protein synthesis. The intestinal tract is lined with cells, both host and microbial, that uptake and metabolize Trp to also generate important signaling molecules. Serotonin (5-HT), kynurenine and its downstream metabolites, and to a lesser extent other neurotransmitters are generated by the host to signal onto host receptors and elicit physiological effects. 5-HT production by neurons in the CNS regulates sleep, mood, and appetite; 5-HT production in the intestinal tract by enterochromaffin cells regulates gastric motility and inflammation in the periphery. Kynurenine can signal onto the aryl hydrocarbon receptor (AHR) to elicit pleiotropic responses from several cell types including epithelial and immune cells, or can be further metabolized into bioactive molecules to influence neurodegenerative disease. There is a remarkable amount of cross-talk with the microbiome with regard to tryptophan metabolites as well. The gut microbiome can regulate the production of host tryptophan metabolites and can use dietary or recycled trp to generate bioactive metabolites themselves. Trp derivatives like indole are able to signal onto xenobiotic receptors, including AHR, to elicit tolerogenic effects. Here, we review studies that demonstrate that tryptophan represents a key intra-kingdom signaling molecule.
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Affiliation(s)
| | | | - Douglas J. Kominsky
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, United States
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37
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Banskota S, Brim H, Kwon YH, Singh G, Sinha SR, Wang H, Khan WI, Ashktorab H. Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice. Molecules 2021; 26:3351. [PMID: 34199466 PMCID: PMC8199624 DOI: 10.3390/molecules26113351] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.
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Affiliation(s)
- Suhrid Banskota
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4K1, Canada; (S.B.); (Y.H.K.); (H.W.)
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Hassan Brim
- Department of Pathology, Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA;
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4K1, Canada; (S.B.); (Y.H.K.); (H.W.)
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Gulshan Singh
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA; (G.S.); (S.R.S.)
| | - Sidhartha R. Sinha
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA; (G.S.); (S.R.S.)
| | - Huaqing Wang
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4K1, Canada; (S.B.); (Y.H.K.); (H.W.)
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Waliul I. Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4K1, Canada; (S.B.); (Y.H.K.); (H.W.)
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Hassan Ashktorab
- Department of Medicine, Gastroenterology Division, Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA
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38
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Aggarwal S, Ranjha R, Paul J. Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases. World J Gastrointest Pathophysiol 2021; 12:25-39. [PMID: 34084590 PMCID: PMC8160600 DOI: 10.4291/wjgp.v12.i3.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease (IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell’s function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.
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Affiliation(s)
- Surbhi Aggarwal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi 110016, India
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
| | - Raju Ranjha
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
- Field Unit Raipur, ICMR-National Institute of Malaria Research, Raipur 492015, Chhattisgarh, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
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39
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Altomare A, Di Rosa C, Imperia E, Emerenziani S, Cicala M, Guarino MPL. Diarrhea Predominant-Irritable Bowel Syndrome (IBS-D): Effects of Different Nutritional Patterns on Intestinal Dysbiosis and Symptoms. Nutrients 2021; 13:1506. [PMID: 33946961 PMCID: PMC8146452 DOI: 10.3390/nu13051506] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain associated with defecation or a change in bowel habits. Gut microbiota, which acts as a real organ with well-defined functions, is in a mutualistic relationship with the host, harvesting additional energy and nutrients from the diet and protecting the host from pathogens; specific alterations in its composition seem to play a crucial role in IBS pathophysiology. It is well known that diet can significantly modulate the intestinal microbiota profile but it is less known how different nutritional approach effective in IBS patients, such as the low-FODMAP diet, could be responsible of intestinal microbiota changes, thus influencing the presence of gastrointestinal (GI) symptoms. The aim of this review was to explore the effects of different nutritional protocols (e.g., traditional nutritional advice, low-FODMAP diet, gluten-free diet, etc.) on IBS-D symptoms and on intestinal microbiota variations in both IBS-D patients and healthy subjects. To date, an ideal nutritional protocol does not exist for IBS-D patients but it seems crucial to consider the effect of the different nutritional approaches on the intestinal microbiota composition to better define an efficient strategy to manage this functional disorder.
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Affiliation(s)
- Annamaria Altomare
- Gastroenterology Unit, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy; (A.A.); (S.E.); (M.C.); (M.P.L.G.)
- Unit of Food Science and Human Nutrition, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy;
| | - Claudia Di Rosa
- Unit of Food Science and Human Nutrition, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy;
| | - Elena Imperia
- Unit of Food Science and Human Nutrition, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy;
| | - Sara Emerenziani
- Gastroenterology Unit, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy; (A.A.); (S.E.); (M.C.); (M.P.L.G.)
| | - Michele Cicala
- Gastroenterology Unit, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy; (A.A.); (S.E.); (M.C.); (M.P.L.G.)
| | - Michele Pier Luca Guarino
- Gastroenterology Unit, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21, 00128 Rome, Italy; (A.A.); (S.E.); (M.C.); (M.P.L.G.)
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40
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Fraser-Miller SJ, Rooney JS, Lau M, Gordon KC, Schultz M. Can Coupling Multiple Complementary Methods Improve the Spectroscopic Based Diagnosis of Gastrointestinal Illnesses? A Proof of Principle Ex Vivo Study Using Celiac Disease as the Model Illness. Anal Chem 2021; 93:6363-6374. [PMID: 33844904 DOI: 10.1021/acs.analchem.0c04963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Spectroscopic methods are a promising approach for providing a point-of-care diagnostic method for gastrointestinal mucosa associated illnesses. Such a tool is desired to aid immediate decision making and to provide a faster pathway to appropriate treatment. In this pilot study, Raman, near-infrared, low frequency Raman, and autofluoresence spectroscopic methods were explored alone and in combination for the diagnosis of celiac disease. Duodenal biopsies (n = 72) from 24 participants were measured ex vivo using the full suite of studied spectroscopic methods. Exploratory principal component analysis (PCA) highlighted the origin of spectral differences between celiac and normal tissue with celiac biopsies tending to have higher protein relative to lipid signals and lower carotenoid spectral signals than the samples with normal histology. Classification of the samples based on the histology and overall diagnosis was carried out for all combinations of spectroscopic methods. Diagnosis based classification (majority rule of class per participant) yielded sensitivities of 0.31 to 0.77 for individual techniques, which was increased up to 0.85 when coupling multiple techniques together. Likewise, specificities of 0.50 to 0.67 were obtained for individual techniques, which was increased up to 0.78 when coupling multiple techniques together. It was noted that the use of antidepressants contributed to false positives, which is believed to be associated with increased serotonin levels observed in the gut mucosa in both celiac disease and the use of selective serotonin reuptake inhibitors (SSRIs); however, future work with greater numbers is required to confirm this observation. Inclusion of two additional spectroscopic methods could improve the accuracy of diagnosis (0.78) by 7% over Raman alone (0.73). This demonstrates the potential for further exploration and development of a multispectroscopic system for disease diagnosis.
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Affiliation(s)
- Sara J Fraser-Miller
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Jeremy S Rooney
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Michael Lau
- Southern Community Laboratories, Dunedin 9016, New Zealand
| | - Keith C Gordon
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Michael Schultz
- Gastroenterology Research Unit, Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.,Mercy Hospital, Dunedin 9010, New Zealand.,Gastroenterology Department, Southern District Health Board, Dunedin 9016, New Zealand
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41
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Chen Q, He Z, Zhuo Y, Li S, Yang W, Hu L, Zhong H. Rubidium chloride modulated the fecal microbiota community in mice. BMC Microbiol 2021; 21:46. [PMID: 33588762 PMCID: PMC7885239 DOI: 10.1186/s12866-021-02095-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 01/19/2021] [Indexed: 12/24/2022] Open
Abstract
Background The microbiota plays an important role in host health. Although rubidium (Rb) has been used to study its effects on depression and cancers, the interaction between microbial commensals and Rb is still unexplored. To gain the knowledge of the relationship between Rb and microbes, 51 mice receiving RbCl-based treatment and 13 untreated mice were evaluated for their characteristics and bacterial microbiome changes. Results The 16S ribosomal RNA gene sequencing of fecal microbiota showed that RbCl generally maintained fecal microbial community diversity, while the shifts in fecal microbial composition were apparent after RbCl exposure. RbCl significantly enhanced the abundances of Rikenellaceae, Alistipes, Clostridium XlVa and sulfate-reducing bacteria including Deltaproteobacteria, Desulfovibrionales, Desulfovibrionaceae and Desulfovibrio, but significantly inhibited the abundances of Tenericutes, Mollicutes, Anaeroplasmatales, Anaeroplasmataceae and Anaeroplasma lineages. With regarding to the archaea, we only observed two less richness archaea Sulfolobus and Acidiplasma at the genus level. Conclusions Changes of fecal microbes may in part contribute to the anticancer or anti-depressant effects of RbCl. These findings further validate that the microbiome could be a target for therapeutic intervention. Supplementary Information The online version contains supplementary material available at 10.1186/s12866-021-02095-4.
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Affiliation(s)
- Qian Chen
- School of Life Sciences, Central South University, Changsha, 410013, China
| | - Zhiguo He
- School of Minerals Processing and Bioengineering, Key Laboratory of Biohydrometallurgy of Ministry of Education, Central South University, Changsha, 410083, China
| | - Yuting Zhuo
- School of Life Sciences, Central South University, Changsha, 410013, China
| | - Shuzhen Li
- School of Minerals Processing and Bioengineering, Key Laboratory of Biohydrometallurgy of Ministry of Education, Central South University, Changsha, 410083, China
| | - Wenjing Yang
- School of Minerals Processing and Bioengineering, Key Laboratory of Biohydrometallurgy of Ministry of Education, Central South University, Changsha, 410083, China
| | - Liang Hu
- School of Minerals Processing and Bioengineering, Key Laboratory of Biohydrometallurgy of Ministry of Education, Central South University, Changsha, 410083, China
| | - Hui Zhong
- School of Life Sciences, Central South University, Changsha, 410013, China.
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42
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Lyte JM, Keane J, Eckenberger J, Anthony N, Shrestha S, Marasini D, Daniels KM, Caputi V, Donoghue AM, Lyte M. Japanese quail (Coturnix japonica) as a novel model to study the relationship between the avian microbiome and microbial endocrinology-based host-microbe interactions. MICROBIOME 2021; 9:38. [PMID: 33531080 PMCID: PMC7856774 DOI: 10.1186/s40168-020-00962-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/06/2020] [Indexed: 05/09/2023]
Abstract
BACKGROUND Microbial endocrinology, which is the study of neuroendocrine-based interkingdom signaling, provides a causal mechanistic framework for understanding the bi-directional crosstalk between the host and microbiome, especially as regards the effect of stress on health and disease. The importance of the cecal microbiome in avian health is well-recognized, yet little is understood regarding the mechanisms underpinning the avian host-microbiome relationship. Neuroendocrine plasticity of avian tissues that are focal points of host-microbiome interaction, such as the gut and lung, has likewise received limited attention. Avian in vivo models that enable the study of the neuroendocrine dynamic between host and microbiome are needed. As such, we utilized Japanese quail (Coturnix japonica) that diverge in corticosterone response to stress to examine the relationship between stress-related neurochemical concentrations at sites of host-microbe interaction, such as the gut, and the cecal microbiome. RESULTS Our results demonstrate that birds which contrast in corticosterone response to stress show profound separation in cecal microbial community structure as well as exhibit differences in tissue neurochemical concentrations and structural morphologies of the gut. Changes in neurochemicals known to be affected by the microbiome were also identified in tissues outside of the gut, suggesting a potential relationship in birds between the cecal microbiome and overall avian physiology. CONCLUSIONS The present study provides the first evidence that the structure of the avian cecal microbial community is shaped by selection pressure on the bird for neuroendocrine response to stress. Identification of unique region-dependent neurochemical changes in the intestinal tract following stress highlights environmental stressors as potential drivers of microbial endocrinology-based mechanisms of avian host-microbiome dialogue. Together, these results demonstrate that tissue neurochemical concentrations in the avian gut may be related to the cecal microbiome and reveal the Japanese quail as a novel avian model in which to further examine the mechanisms underpinning these relationships. Video abstract.
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Affiliation(s)
- Joshua M. Lyte
- Poultry Production and Product Safety Research, Agricultural Research Service, United States Department of Agriculture, Fayetteville, AR 72701 USA
| | - James Keane
- Department of Computer Science, Cork Institute of Technology, Cork, Ireland
| | - Julia Eckenberger
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
| | - Nicholas Anthony
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701 USA
| | - Sandip Shrestha
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701 USA
| | - Daya Marasini
- Weems Design Studio Inc., Suwanee, Georgia, USA/ Contractor to Centers for Disease control and Prevention, Atlanta, GA 30333 USA
| | - Karrie M. Daniels
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
| | | | - Annie M. Donoghue
- Poultry Production and Product Safety Research, Agricultural Research Service, United States Department of Agriculture, Fayetteville, AR 72701 USA
| | - Mark Lyte
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
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Fanciulli G, Ruggeri RM, Grossrubatscher E, Calzo FL, Wood TD, Faggiano A, Isidori A, Colao A. Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications. Rev Endocr Metab Disord 2020; 21:599-612. [PMID: 32152781 DOI: 10.1007/s11154-020-09547-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient's quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.
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Affiliation(s)
- Giuseppe Fanciulli
- Department of Medical, Surgical and Experimental Sciences, University of Sassari - Endocrine Unit, AOU Sassari, Sassari, Italy
| | - Rosaria M Ruggeri
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, Messina, Italy
| | | | - Fabio Lo Calzo
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - Troy D Wood
- Department of Chemistry, University at Buffalo, Buffalo, NY, USA
| | | | - Andrea Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
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Zhou L, Hao N, Li X, Chen J, Yang R, Song C, Sun Y, Zhang Q. Nattokinase mitigated dextran sulfate sodium-induced chronic colitis by regulating microbiota and suppressing tryptophan metabolism via inhibiting IDO-1. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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45
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Betari N, Sahlholm K, Morató X, Godoy-Marín H, Jáuregui O, Teigen K, Ciruela F, Haavik J. Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole- In Vitro and In Vivo Investigations. Front Pharmacol 2020; 11:593416. [PMID: 33324221 PMCID: PMC7726444 DOI: 10.3389/fphar.2020.593416] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/16/2020] [Indexed: 01/06/2023] Open
Abstract
Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism.
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Affiliation(s)
- Nibal Betari
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Kristoffer Sahlholm
- Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.,Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Morató
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.,Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.,Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Héctor Godoy-Marín
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.,Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Olga Jáuregui
- Scientific and Technological Centers of University of Barcelona (CCiTUB), Barcelona, Spain
| | - Knut Teigen
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Francisco Ciruela
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.,Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Division of Psychiatry, Bergen Center of Brain Plasticity, Haukeland University Hospital, Bergen, Norway
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Giuffrè M, Moretti R, Campisciano G, da Silveira ABM, Monda VM, Comar M, Di Bella S, Antonello RM, Luzzati R, Crocè LS. You Talking to Me? Says the Enteric Nervous System (ENS) to the Microbe. How Intestinal Microbes Interact with the ENS. J Clin Med 2020; 9:3705. [PMID: 33218203 PMCID: PMC7699249 DOI: 10.3390/jcm9113705] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022] Open
Abstract
Mammalian organisms form intimate interfaces with commensal and pathogenic gut microorganisms. Increasing evidence suggests a close interaction between gut microorganisms and the enteric nervous system (ENS), as the first interface to the central nervous system. Each microorganism can exert a different effect on the ENS, including phenotypical neuronal changes or the induction of chemical transmitters that interact with ENS neurons. Some pathogenic bacteria take advantage of the ENS to create a more suitable environment for their growth or to promote the effects of their toxins. In addition, some commensal bacteria can affect the central nervous system (CNS) by locally interacting with the ENS. From the current knowledge emerges an interesting field that may shape future concepts on the pathogen-host synergic interaction. The aim of this narrative review is to report the current findings regarding the inter-relationships between bacteria, viruses, and parasites and the ENS.
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Affiliation(s)
- Mauro Giuffrè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
- Italian Liver Foundation, 34129 Trieste, Italy
| | - Rita Moretti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Giuseppina Campisciano
- Department of Advanced Microbiology Diagnosis and Translational Research, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (G.C.); (M.C.)
| | | | | | - Manola Comar
- Department of Advanced Microbiology Diagnosis and Translational Research, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (G.C.); (M.C.)
| | - Stefano Di Bella
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Roberta Maria Antonello
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Roberto Luzzati
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Lory Saveria Crocè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
- Italian Liver Foundation, 34129 Trieste, Italy
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Wang XN, Liu JQ, Shi ZQ, Sun FY, Liu LF, Xin GZ. Orthogonal label and label-free dual pretreatment for targeted profiling of neurotransmitters in enteric nervous system. Anal Chim Acta 2020; 1139:68-78. [PMID: 33190711 DOI: 10.1016/j.aca.2020.09.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 09/14/2020] [Indexed: 01/23/2023]
Abstract
Neurotransmitter (NT) abnormalities in the enteric nervous system have been reported as crucial roles to regulate the intestinal inflammation and gut immune homeostasis. Capturing quantitative changes at the NT metabolome provides an opportunity to develop an understanding of neuroimmune-mediated inflammation. Given the wide diversity of chemical characterizations in the NTs, only partial coverage of the NT metabolome can be simultaneously quantified in a single-run analysis. Herein, we summarized the distribution of functional groups of compound entries in the NT metabolome. Based on this information, an orthogonal dansyl-labeling and label-free dual pretreatment approach was separately designed to target phenol and amine NTs and tertiary amine and choline NTs. By combining the dansyl-labeled and unlabeled NTs within a single vial, a comprehensive and practical approach was optimized for quantifying high coverage of NT metabolome in a single-run analysis on the reversed-phase C18 column. Method validation indicated good linearity with correlation coefficients (R2) > 0.99, intra- and interday accuracy with relative error < ±20%, and precision with relative standard deviations of ≤15%. With this method, we could simultaneously monitor the alterations of cholines, amines, amino acids, tryptophan and phenylalanine biological pathways in dextran sulphate sodium-induced colitis mice. The measured levels of NT metabolome ranged from 0.0007 to 3.540 μg/mg in intestinal contents and 0.013-154.54 μg/mL in serum samples. The NT metabolism was disrupted by colitis, characterized by the changed NT levels in serum and excessive amino acid NTs accumulation in the intestinal contents. We envisage that the orthogonal approach is of great significance for the comprehensive determination of targeted metabolomics. NTs have the potential to be biomarkers for clinical metabolomics.
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Affiliation(s)
- Xin-Nan Wang
- State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, China
| | - Jian-Qun Liu
- Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, No. 818 Xingwan Road, Nanchang, 330004, Jiangxi Province, China
| | - Zi-Qi Shi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Fang-Yuan Sun
- State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, China
| | - Li-Fang Liu
- State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, China.
| | - Gui-Zhong Xin
- State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, China.
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Belkacemi L, Darmani NA. Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function. Pharmacol Res 2020; 161:105124. [PMID: 32814171 DOI: 10.1016/j.phrs.2020.105124] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 07/20/2020] [Accepted: 08/05/2020] [Indexed: 12/19/2022]
Abstract
Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency.
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Affiliation(s)
- Louiza Belkacemi
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766, USA
| | - Nissar A Darmani
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766, USA.
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Bosi A, Banfi D, Bistoletti M, Giaroni C, Baj A. Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease. Int J Tryptophan Res 2020; 13:1178646920928984. [PMID: 32577079 PMCID: PMC7290275 DOI: 10.1177/1178646920928984] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 05/02/2020] [Indexed: 12/12/2022] Open
Abstract
The ‘microbiota-gut-brain axis’ plays a fundamental role in maintaining host homeostasis, and different immune, hormonal, and neuronal signals participate to this interkingdom communication system between eukaryota and prokaryota. The essential aminoacid tryptophan, as a precursor of several molecules acting at the interface between the host and the microbiota, is fundamental in the modulation of this bidirectional communication axis. In the gut, tryptophan undergoes 3 major metabolic pathways, the 5-HT, kynurenine, and AhR ligand pathways, which may be directly or indirectly controlled by the saprophytic flora. The importance of tryptophan metabolites in the modulation of the gastrointestinal tract is suggested by several preclinical and clinical studies; however, a thorough revision of the available literature has not been accomplished yet. Thus, this review attempts to cover the major aspects on the role of tryptophan metabolites in host-microbiota cross-talk underlaying regulation of gut functions in health conditions and during disease states, with particular attention to 2 major gastrointestinal diseases, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), both characterized by psychiatric disorders. Research in this area opens the possibility to target tryptophan metabolism to ameliorate the knowledge on the pathogenesis of both diseases, as well as to discover new therapeutic strategies based either on conventional pharmacological approaches or on the use of pre- and probiotics to manipulate the microbial flora.
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Affiliation(s)
- Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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50
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Gao K, Mu CL, Farzi A, Zhu WY. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Adv Nutr 2020; 11:709-723. [PMID: 31825083 PMCID: PMC7231603 DOI: 10.1093/advances/nmz127] [Citation(s) in RCA: 474] [Impact Index Per Article: 94.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/10/2019] [Accepted: 11/04/2019] [Indexed: 12/15/2022] Open
Abstract
The gut-brain axis (GBA) is a bilateral communication network between the gastrointestinal (GI) tract and the central nervous system. The essential amino acid tryptophan contributes to the normal growth and health of both animals and humans and, importantly, exerts modulatory functions at multiple levels of the GBA. Tryptophan is the sole precursor of serotonin, which is a key monoamine neurotransmitter participating in the modulation of central neurotransmission and enteric physiological function. In addition, tryptophan can be metabolized into kynurenine, tryptamine, and indole, thereby modulating neuroendocrine and intestinal immune responses. The gut microbial influence on tryptophan metabolism emerges as an important driving force in modulating tryptophan metabolism. Here, we focus on the potential role of tryptophan metabolism in the modulation of brain function by the gut microbiota. We start by outlining existing knowledge on tryptophan metabolism, including serotonin synthesis and degradation pathways of the host, and summarize recent advances in demonstrating the influence of the gut microbiota on tryptophan metabolism. The latest evidence revealing those mechanisms by which the gut microbiota modulates tryptophan metabolism, with subsequent effects on brain function, is reviewed. Finally, the potential modulation of intestinal tryptophan metabolism as a therapeutic option for brain and GI functional disorders is also discussed.
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Affiliation(s)
- Kan Gao
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China,National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Chun-long Mu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China,National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria
| | - Wei-yun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China,National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China,Address correspondence to WZ (e-mail: )
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