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Antoine D, Tao J, Singh S, Singh PK, Marin BG, Roy S. Neonatal exposure to morphine results in prolonged pain hypersensitivity during adolescence, driven by gut microbial dysbiosis and gut-brain axis-mediated inflammation. Brain Behav Immun 2025; 126:3-23. [PMID: 39900146 DOI: 10.1016/j.bbi.2025.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/17/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
Opioids, such as morphine, are used in the Neonatal Intensive Care Unit (NICU) for pain relief in neonates. However, the available evidence concerning the benefits and harms of opioid therapy in neonates remains limited. While previous studies have reported that neonatal morphine exposure (NME) results in long-term heightened pain sensitivity, the underlying mechanisms are not well understood. This study proposes that dysbiosis of the gut microbiome contributes to pain hypersensitivity following NME. Using an adolescent female murine model, pain sensitivity was evaluated using the tail flick and hot plate assays for thermal pain and the Von Frey assay for mechanical pain. Gut microbiome composition was assessed using 16S rRNA sequencing, while transcriptomic changes in midbrain samples were investigated using bulk RNA sequencing. NME induced prolonged hypersensitivity to thermal and mechanical pain in adolescence, accompanied by persistent gut microbial dysbiosis and sustained systemic inflammation, characterized by elevated circulating cytokine levels (e.g., IL-1α, IL-12p70, IFN-γ, IL-10). Transplantation of the microbiome from NME adolescents recapitulated pain hypersensitivity in naïve adolescent mice, while neonatal probiotic intervention with Bifidobacterium infantis (B. infantis) reversed the pain hypersensitivity by preventing gut dysbiosis and associated systemic inflammation. Furthermore, transcriptomic analysis of midbrain tissues revealed that NME upregulated several genes and key signaling pathways, including those related to immune activation and excitatory signaling, which were notably mitigated with neonatal B. infantis administration. Together, these findings highlight the critical role of the gut-brain axis in modulating pain sensitivity and suggest that targeting the gut microbiome offers a promising therapeutic strategy for managing neurobiological disorders following early opioid exposure.
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Affiliation(s)
- Danielle Antoine
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA; Department of Neuroscience, University of Miami Miller School of Medicine Miami FL USA
| | - Junyi Tao
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA
| | - Salma Singh
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA
| | - Praveen Kumar Singh
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA
| | - Barbara G Marin
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA; Department of Neuroscience, University of Miami Miller School of Medicine Miami FL USA
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine Miami FL USA.
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Lee SH, Han C, Shin C. IUPHAR Review: Microbiota-Gut-Brain Axis and its role in Neuropsychiatric Disorders. Pharmacol Res 2025; 216:107749. [PMID: 40306604 DOI: 10.1016/j.phrs.2025.107749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 04/20/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
The human gut microbiome, composed of a vast array of microorganisms that have co-evolved with humans, is crucial for the development and function of brain systems. Research has consistently shown bidirectional communication between the gut and the brain through neuronal, endocrine, and immunological, and chemical pathways. Recent neuroscience studies have linked changes in the microbiome and microbial metabolites to various neuropsychiatric disorders such as autism, depression, anxiety, schizophrenia, eating disorders, and neurocognitive disorders. Novel metagenome-wide association studies have confirmed these microbiome variations in large samples and expanded our understanding of the interactions between human genes and the gut microbiome. The causal relationship between gut microbiota and neuropsychiatric disorders is being elucidated through the establishment of large cohort studies incorporating microbiome data and advanced statistical techniques. Ongoing animal and human studies focused on the microbiota-gut-brain axis are promising for developing new prevention and treatment strategies for neuropsychiatric conditions. The scope of these studies has broadened from microbiome-modulating therapies including prebiotics, probiotics, synbiotics and postbiotics to more extensive approaches such as fecal microbiota transplantation. Recent systematic reviews and meta-analyses have strengthened the evidence base for these innovative treatments. Despite extensive research over the past decade, many intriguing aspects still need to be elucidated regarding the role and therapeutic interventions of the microbiota-gut-brain axis in neuropsychiatric disorders.
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Affiliation(s)
- Seung-Hoon Lee
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Changsu Han
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheolmin Shin
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
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Nakhal MM, Mydeen AB, Yassin LK, Almazrouei R, Alkamali R, Alsulaimi M, Elsaleh RI, BaniYas S, Al Houqani S, Al-Marzooq F, Hassane M, Voitetskii R, Statsenko Y, Allam M, Akour A, Hamad MIK. Antibiotics-induced dysbiosis impacts dendritic morphology of adult mouse cortical interneurons. Front Neuroanat 2025; 19:1557961. [PMID: 40124111 PMCID: PMC11925899 DOI: 10.3389/fnana.2025.1557961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction A growing body of evidence suggests that the gut microbiome may contribute to changes in brain morphology. The microbiota-gut-brain axis (MGBA) has been shown to influence neurogenesis, axon myelination, and synapse structure. However, it remains unclear whether the MGBA can influence the morphology and density of inhibitory GABAergic interneurons. The aim of this study was to determine whether antibiotic-induced dysbiosis (AID) is associated with alterations in dendritic morphology of GABAergic inhibitory interneurons in the medial entorhinal cortex (mEC), somatosensory cortex (SSC), motor cortex (MC), and hippocampus (Hp). Methods A cohort of six-month-old GAD-67-EGFP transgenic mice was treated with an antibiotic cocktail for two weeks, resulting in gut dysbiosis as validated by collecting stool samples at baseline and after treatment, then using next-generation sequencing of 16S ribosomal RNA. Results The results demonstrate that the proposed model effectively exhibited the defining features of gut dysbiosis, including a significant reduction in microbiome diversity, expansion of pathobionts, and loss of beneficial microbes. The AID group showed alterations in density and morphology of GABAergic interneurons in different brain areas. The mean dendritic length and mean dendritic segments of the SSC and Hp were found to be significantly decreased, while no such decrease was observed in the mEC or MC. Furthermore, the density of interneurons was decreased in the mEC, Hp, and SSC areas, while no change was observed in the MC area. Discussion The interneuron dysfunction plays a role in the pathogenesis of neurological disease. The findings of this study suggest that AID potentially influences the density and morphology of the interneurons, which may contribute to the development of neurological disorders.
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Affiliation(s)
- Mohammed M. Nakhal
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ayishal B. Mydeen
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Lydia K. Yassin
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Reem Almazrouei
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Rasha Alkamali
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mahra Alsulaimi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Rawan I. Elsaleh
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Shamsa BaniYas
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Shaikha Al Houqani
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Farah Al-Marzooq
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Maya Hassane
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Roman Voitetskii
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Yauhen Statsenko
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mushal Allam
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Amal Akour
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammad I. K. Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Meerschaert KA, Chiu IM. The gut-brain axis and pain signalling mechanisms in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2025; 22:206-221. [PMID: 39578592 DOI: 10.1038/s41575-024-01017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 11/24/2024]
Abstract
Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut-brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell-cell communication is integrated into this gut-brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain.
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Affiliation(s)
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
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Yassin LK, Nakhal MM, Alderei A, Almehairbi A, Mydeen AB, Akour A, Hamad MIK. Exploring the microbiota-gut-brain axis: impact on brain structure and function. Front Neuroanat 2025; 19:1504065. [PMID: 40012737 PMCID: PMC11860919 DOI: 10.3389/fnana.2025.1504065] [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: 09/30/2024] [Accepted: 01/30/2025] [Indexed: 02/28/2025] Open
Abstract
The microbiota-gut-brain axis (MGBA) plays a significant role in the maintenance of brain structure and function. The MGBA serves as a conduit between the CNS and the ENS, facilitating communication between the emotional and cognitive centers of the brain via diverse pathways. In the initial stages of this review, we will examine the way how MGBA affects neurogenesis, neuronal dendritic morphology, axonal myelination, microglia structure, brain blood barrier (BBB) structure and permeability, and synaptic structure. Furthermore, we will review the potential mechanistic pathways of neuroplasticity through MGBA influence. The short-chain fatty acids (SCFAs) play a pivotal role in the MGBA, where they can modify the BBB. We will therefore discuss how SCFAs can influence microglia, neuronal, and astrocyte function, as well as their role in brain disorders such as Alzheimer's disease (AD), and Parkinson's disease (PD). Subsequently, we will examine the technical strategies employed to study MGBA interactions, including using germ-free (GF) animals, probiotics, fecal microbiota transplantation (FMT), and antibiotics-induced dysbiosis. Finally, we will examine how particular bacterial strains can affect brain structure and function. By gaining a deeper understanding of the MGBA, it may be possible to facilitate research into microbial-based pharmacological interventions and therapeutic strategies for neurological diseases.
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Affiliation(s)
- Lidya K. Yassin
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammed M. Nakhal
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Alreem Alderei
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Afra Almehairbi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ayishal B. Mydeen
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Amal Akour
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammad I. K. Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Pratt ML, Plumb AN, Manjrekar A, Cardona LM, Chan CK, John JM, Sadler KE. Microbiome contributions to pain: a review of the preclinical literature. Pain 2025; 166:262-281. [PMID: 39258679 PMCID: PMC11723818 DOI: 10.1097/j.pain.0000000000003376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/28/2024] [Indexed: 09/12/2024]
Abstract
ABSTRACT Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments.
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Affiliation(s)
- McKenna L Pratt
- Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
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Sajjad J, Morael J, Melo TG, Foley T, Murphy A, Keane J, Popov J, Stanton C, Dinan TG, Clarke G, Cryan JF, Collins JM, O'Mahony SM. Differential cortical aspartate uptake across the oestrous cycle is associated with changes in gut microbiota in Wistar-Kyoto rats. Neurosci Lett 2025; 847:138096. [PMID: 39716584 DOI: 10.1016/j.neulet.2024.138096] [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: 11/04/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 12/25/2024]
Abstract
Pain and psychological stress are intricately linked, with sex differences evident in disorders associated with both systems. Glutamatergic signalling in the central nervous system is influenced by gonadal hormones via the hypothalamic-pituitary-adrenal axis and is central in pain research. Emerging evidence supports an important role for the gut microbiota in influencing pain signalling. Here, the functional activity of excitatory amino acid transporters (EAATs) in the anterior cingulate cortex (ACC) and lumbosacral spinal cord of male and female Wistar-Kyoto rats, an animal model of comorbid visceral hypersensitivity and enhanced stress responsivity, was investigated across the oestrous cycle. Correlations between the gut microbiota and changes in the functional activity of the central glutamatergic system were also investigated. EAAT function in the lumbosacral spinal cord was similar between males and females across the oestrous cycle. EAAT function was higher in the ACC of dioestrus females compared to proestrus and oestrus females. In males, aspartate uptake in the ACC positively correlated with Bacteroides, while aspartate uptake in the spinal cord positively correlated with the relative abundance of Lachnospiraceae NK4A136. Positive associations with aspartate uptake in the spinal cord were also observed for Alistipes and Bifidobacterium during oestrus, and Eubacterium coprostanoligenes during proestrus. Clostridium sensu stricto1 was negatively associated with aspartate uptake in the ACC in males and dioestrus females. These data indicate that glutamate metabolism in the ACC is oestrous stage-dependent and that short-chain fatty acid-producing bacteria are positively correlated with aspartate uptake in males and during specific oestrous stages in females.
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Affiliation(s)
- Jahangir Sajjad
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Jennifer Morael
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Thieza G Melo
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Tara Foley
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Amy Murphy
- Teagasc Food Research Centre, Moorepark, Cork, Ireland
| | - James Keane
- APC Microbiome Ireland, University College Cork, Ireland
| | - Jelena Popov
- APC Microbiome Ireland, University College Cork, Ireland
| | | | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - James M Collins
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland.
| | - Siobhain M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
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Rykalo N, Riehl L, Kress M. The gut microbiome and the brain. Curr Opin Support Palliat Care 2024; 18:282-291. [PMID: 39250732 DOI: 10.1097/spc.0000000000000717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
PURPOSE OF REVIEW The importance of the gut microbiome for human health and well-being is generally accepted, and elucidating the signaling pathways between the gut microbiome and the host offers novel mechanistic insight into the (patho)physiology and multifaceted aspects of healthy aging and human brain functions. RECENT FINDINGS The gut microbiome is tightly linked with the nervous system, and gut microbiota are increasingly emerging as important regulators of emotional and cognitive performance. They send and receive signals for the bidirectional communication between gut and brain via immunological, neuroanatomical, and humoral pathways. The composition of the gut microbiota and the spectrum of metabolites and neurotransmitters that they release changes with increasing age, nutrition, hypoxia, and other pathological conditions. Changes in gut microbiota (dysbiosis) are associated with critical illnesses such as cancer, cardiovascular, and chronic kidney disease but also neurological, mental, and pain disorders, as well as chemotherapies and antibiotics affecting brain development and function. SUMMARY Dysbiosis and a concomitant imbalance of mediators are increasingly emerging both as causes and consequences of diseases affecting the brain. Understanding the microbiota's role in the pathogenesis of these disorders will have major clinical implications and offer new opportunities for therapeutic interventions.
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Affiliation(s)
- Nadiia Rykalo
- Department of Physiology and Medical Physics, Institute of Physiology, Medical University Innsbruck, Austria
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9
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Kodila ZN, Shultz SR, Yamakawa GR, Mychasiuk R. Critical Windows: Exploring the Association Between Perinatal Trauma, Epigenetics, and Chronic Pain. Neuroscientist 2024; 30:574-596. [PMID: 37212380 PMCID: PMC11439237 DOI: 10.1177/10738584231176233] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Chronic pain is highly prevalent and burdensome, affecting millions of people worldwide. Although it emerges at any point in life, it often manifests in adolescence. Given that adolescence is a unique developmental period, additional strains associated with persistent and often idiopathic pain lead to significant long-term consequences. While there is no singular cause for the chronification of pain, epigenetic modifications that lead to neural reorganization may underpin central sensitization and subsequent manifestation of pain hypersensitivity. Epigenetic processes are particularly active during the prenatal and early postnatal years. We demonstrate how exposure to various traumas, such as intimate partner violence while in utero or adverse childhood experiences, can significantly influence epigenetic regulation within the brain and in turn modify pain-related processes. We provide compelling evidence that the burden of chronic pain is likely initiated early in life, often being transmitted from mother to offspring. We also highlight two promising prophylactic strategies, oxytocin administration and probiotic use, that have the potential to attenuate the epigenetic consequences of early adversity. Overall, we advance understanding of the causal relationship between trauma and adolescent chronic pain by highlighting epigenetic mechanisms that underlie this transmission of risk, ultimately informing how to prevent this rising epidemic.
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Affiliation(s)
- Zoe N. Kodila
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Sandy R. Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
- Health Sciences, Vancouver Island University, Nanaimo, Canada
| | - Glenn R. Yamakawa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
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Coluzzi F, Scerpa MS, Loffredo C, Borro M, Pergolizzi JV, LeQuang JA, Alessandri E, Simmaco M, Rocco M. Opioid Use and Gut Dysbiosis in Cancer Pain Patients. Int J Mol Sci 2024; 25:7999. [PMID: 39063241 PMCID: PMC11276997 DOI: 10.3390/ijms25147999] [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: 04/30/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.
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Affiliation(s)
- Flaminia Coluzzi
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maria Sole Scerpa
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Chiara Loffredo
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Marina Borro
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | | | | | - Elisa Alessandri
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maurizio Simmaco
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | - Monica Rocco
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
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11
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Lannon AS, Brocka M, Collins JM, Fitzgerald P, O'Mahony SM, Cryan JF, Moloney RD. A novel animal model for understanding secondary traumatic stress and visceral pain in male rats. Eur J Neurosci 2024; 60:3544-3556. [PMID: 38695253 DOI: 10.1111/ejn.16353] [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: 06/02/2023] [Revised: 03/15/2024] [Accepted: 03/30/2024] [Indexed: 07/06/2024]
Abstract
Empathetic relationships and the social transference of behaviours have been shown to occur in humans, and more recently through the development of rodent models, where both fear and pain phenotypes develop in observer animals. Clinically, observing traumatic events can induce 'trauma and stressor-related disorders' as defined in the DSM 5. These disorders are often comorbid with pain and gastrointestinal disturbances; however, our understanding of how gastrointestinal - or visceral - pain can be vicariously transmitted is lacking. Visceral pain originates from the internal organs, and despite its widespread prevalence, remains poorly understood. We established an observation paradigm to assess the impact of witnessing visceral pain. We utilised colorectal distension (CRD) to induce visceral pain behaviours in a stimulus rodent while the observer rodent observed. Twenty four hours post-observation, the observer rodent's visceral sensitivity was assessed using CRD. The observer rodents were found to have significant hyperalgesia as determined by lower visceral pain threshold and higher number of total pain behaviours compared with controls. The behaviours of the observer animals during the observation were found to be correlated with the behaviours of the stimulus animal employed. We found that observer animals had hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis, highlighted by reduced corticosterone at 90 minutes post-CRD. Using c-Fos immunohistochemistry we showed that observer animals also had increased activation of the anterior cingulate cortex, and decreased activation of the paraventricular nucleus, compared with controls. These results suggest that witnessing another animal in pain produces a behavioural phenotype and impacts the brain-gut axis.
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Affiliation(s)
- Adam S Lannon
- School of Pharmacy, University College Cork, Ireland
- Department of Pharmacology and Therapeutics, University College Cork, Ireland
- APC Microbiome Ireland, University College Cork, Ireland
| | - Marta Brocka
- APC Microbiome Ireland, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - James M Collins
- APC Microbiome Ireland, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | | | - Siobhain M O'Mahony
- APC Microbiome Ireland, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Rachel D Moloney
- School of Pharmacy, University College Cork, Ireland
- Department of Pharmacology and Therapeutics, University College Cork, Ireland
- APC Microbiome Ireland, University College Cork, Ireland
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Huang CT, Wang LK, Lue JH, Chen SH, Tsai YJ. Lactobacillus Plantarum intake mitigates neuropathic pain behavior via enhancing macrophage M2 polarization in a rat model of peripheral neuropathy. Biomed Pharmacother 2024; 175:116769. [PMID: 38776678 DOI: 10.1016/j.biopha.2024.116769] [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: 03/15/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024] Open
Abstract
Pro-inflammatory macrophages (M1-polarized) play a crucial role in neuroinflammation and neuropathic pain following nerve injury. Redirecting macrophage polarization toward anti-inflammatory (M2-polarized) phenotypes offers a promising therapeutic strategy. Recognized for their anti-inflammatory and immunomodulatory properties, probiotics are becoming a focal point of research. This study investigated the effects of Lactobacillus plantarum on macrophage polarization, nerve protection, and neuropathic pain behavior following chronic constriction injury (CCI) of the median nerve. Rats received daily oral doses of L. plantarum for 28 days before and 14 days after CCI. Subsequently, behavioral and electrophysiological assessments were performed. The M1 marker CD86 levels, M2 marker CD206 levels, and concentrations of pro-inflammatory and anti-inflammatory cytokines in the injured median nerve were assessed. L. plantarum administration effectively reduced neuropathic pain behavior and the Firmicutes to Bacteroidetes ratio after CCI. Moreover, L. plantarum treatment increased serum short-chain fatty acids (SCFAs) levels, preserved myelination of the injured median nerve, and suppressed injury-induced discharges. In CCI rats treated with L. plantarum, there was a reduction in CD86 and pro-inflammatory cytokine levels, accompanied by an increase in CD206 and the release of anti-inflammatory cytokines. Furthermore, receptors for anti-inflammatory cytokines were localized on Schwann cells, and their expression was significantly upregulated in the injured nerves of CCI rats receiving L. plantarum. In conclusion, L. plantarum shifts macrophage phenotypes from M1 to M2 by promoting the production of SCFAs and enhancing the release of anti-inflammatory cytokines. Ultimately, this process preserves nerve fiber integrity and impedes the onset of neuropathic pain.
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Affiliation(s)
- Chun-Ta Huang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Li-Kai Wang
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan, Republic of China
| | - June-Horng Lue
- Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Seu-Hwa Chen
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Yi-Ju Tsai
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, Republic of China.
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13
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Browning BD, Kirkland AE, Green R, Engevik M, Alekseyenko AV, Leggio L, Tomko RL, Squeglia LM. The adolescent and young adult microbiome and its association with substance use: a scoping review. Alcohol Alcohol 2024; 59:agad055. [PMID: 37665023 PMCID: PMC10979412 DOI: 10.1093/alcalc/agad055] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/18/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
AIMS The microbiome is a critical factor in health throughout human development. The aims of this scoping review are to (i) elucidate the differences between the youth (post-natal day 21-65 for rodents, 2-7 years for non-human primates, and 10-25 years for humans) microbiome with other life stages and (ii) identify youth-specific microbial changes associated with substance use. METHODS Peer-reviewed studies published up to May 2023 were identified in PubMed and SCOPUS and included gut and oral microbiome studies from rodents, non-human primates, and humans (N = 1733). Twenty-six articles were determined eligible based on inclusion criteria (aim 1: n = 19, aim 2: n = 7). RESULTS The adolescent and young adult oral and gut microbiomes are distinct compared to other life stages, within both non-human and human models. While there is limited research in this area, the microbiome appears to be vulnerable to substance use exposure earlier in life, including substances commonly initiated and escalated during adolescence and young adulthood (i.e. alcohol, cannabis, and tobacco). CONCLUSIONS Studies across the lifespan indicate that adolescence and young adulthood are distinct periods of development, where the microbiome is sensitive to exposures, including substance use. There is a need for more studies focused on the adolescent and young adult microbiome and substance use, as well as focused on the oral microbiome during this developmental period. Understanding the gut and oral microbiome during adolescence and young adulthood may provide insight into the pathophysiology of substance use disorders.
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Affiliation(s)
- Brittney D Browning
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St., Charleston, SC 29425, United States
- Department of Neuroscience, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, United States
| | - Anna E Kirkland
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St., Charleston, SC 29425, United States
| | - Rejoyce Green
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St., Charleston, SC 29425, United States
| | - Melinda Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston SC, 29425, United States
| | - Alexander V Alekseyenko
- Department of Public Health Sciences, Biomedical Informatics Center, Medical University of South Carolina, 135 Cannon St., Charleston, SC 29425, United States
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, Maryland, USA
| | - Rachel L Tomko
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St., Charleston, SC 29425, United States
| | - Lindsay M Squeglia
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St., Charleston, SC 29425, United States
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14
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Riehl L, Fürst J, Kress M, Rykalo N. The importance of the gut microbiome and its signals for a healthy nervous system and the multifaceted mechanisms of neuropsychiatric disorders. Front Neurosci 2024; 17:1302957. [PMID: 38249593 PMCID: PMC10797776 DOI: 10.3389/fnins.2023.1302957] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/13/2023] [Indexed: 01/23/2024] Open
Abstract
Increasing evidence links the gut microbiome and the nervous system in health and disease. This narrative review discusses current views on the interaction between the gut microbiota, the intestinal epithelium, and the brain, and provides an overview of the communication routes and signals of the bidirectional interactions between gut microbiota and the brain, including circulatory, immunological, neuroanatomical, and neuroendocrine pathways. Similarities and differences in healthy gut microbiota in humans and mice exist that are relevant for the translational gap between non-human model systems and patients. There is an increasing spectrum of metabolites and neurotransmitters that are released and/or modulated by the gut microbiota in both homeostatic and pathological conditions. Dysbiotic disruptions occur as consequences of critical illnesses such as cancer, cardiovascular and chronic kidney disease but also neurological, mental, and pain disorders, as well as ischemic and traumatic brain injury. Changes in the gut microbiota (dysbiosis) and a concomitant imbalance in the release of mediators may be cause or consequence of diseases of the central nervous system and are increasingly emerging as critical links to the disruption of healthy physiological function, alterations in nutrition intake, exposure to hypoxic conditions and others, observed in brain disorders. Despite the generally accepted importance of the gut microbiome, the bidirectional communication routes between brain and gut are not fully understood. Elucidating these routes and signaling pathways in more detail offers novel mechanistic insight into the pathophysiology and multifaceted aspects of brain disorders.
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Affiliation(s)
| | | | | | - Nadiia Rykalo
- Institute of Physiology, Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
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15
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Lai TT, Liou CW, Tsai YH, Lin YY, Wu WL. Butterflies in the gut: the interplay between intestinal microbiota and stress. J Biomed Sci 2023; 30:92. [PMID: 38012609 PMCID: PMC10683179 DOI: 10.1186/s12929-023-00984-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023] Open
Abstract
Psychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host's complex behavior.
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Affiliation(s)
- Tzu-Ting Lai
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Chia-Wei Liou
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Yu-Hsuan Tsai
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Yuan-Yuan Lin
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Wei-Li Wu
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan.
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16
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Fyntanidou B, Amaniti A, Soulioti E, Zagalioti SC, Gkarmiri S, Chorti A, Loukipoudi L, Ioannidis A, Dalakakis I, Menni AE, Shrewsbury AD, Kotzampassi K. Probiotics in Postoperative Pain Management. J Pers Med 2023; 13:1645. [PMID: 38138872 PMCID: PMC10745134 DOI: 10.3390/jpm13121645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Postoperative pain is the unpleasant sensory and emotional experience after surgery, its origin being both the inflammatory reaction induced by the surgical trauma on the abdominal wall and the splanchnic pain induced by the activation of nociceptors of the viscera, which are highly sensitive to distension, ischemia, and inflammation. Nowadays, it is well recognized that there is a close relationship between the gut microbiome and pain perception, and that microbiome is highly affected by both anesthesia and surgical manipulation. Thus, efforts to restore the disturbed microbiome via supplementation with beneficial bacteria, namely probiotics, seem to be effective. In this article, the knowledge gained mainly from experimental research on this topic is analyzed, the concluding message being that each probiotic strain works in its own way towards pain relief.
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Affiliation(s)
- Barbara Fyntanidou
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Aikaterini Amaniti
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Eleftheria Soulioti
- Second Department of Anesthesiology, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece;
| | - Sofia-Chrysovalantou Zagalioti
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Sofia Gkarmiri
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Angeliki Chorti
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Lamprini Loukipoudi
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Aris Ioannidis
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Ioannis Dalakakis
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Alexandra-Eleftheria Menni
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Anne D. Shrewsbury
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Katerina Kotzampassi
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
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17
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Gomes P, Laroute V, Beaufrand C, Daveran-Mingot ML, Aubry N, Liebgott C, Ballet N, Legrain-Raspaud S, Theodorou V, Mercier-Bonin M, Cocaign-Bousquet M, Eutamene H. Lactococcus lactis CNCM I-5388 versus NCDO2118 by its GABA hyperproduction ability, counteracts faster stress-induced intestinal hypersensitivity in rats. FASEB J 2023; 37:e23264. [PMID: 37850915 DOI: 10.1096/fj.202301588r] [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: 08/05/2023] [Revised: 09/21/2023] [Accepted: 10/04/2023] [Indexed: 10/19/2023]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by its main symptom, visceral hypersensitivity (VH), which is aggravated by stress. Gut-brain interactions and gut bacteria may alleviate IBS symptoms, including VH. γ-amino butyric acid (GABA), produced notably by lactic acid bacteria (LAB), shows promising result in IBS symptoms treatment. In bacteria, GABA is generated through glutamate decarboxylase (GAD) metabolism of L-glutamic acid, maintaining intracellular pH. In mammals, GABA acts as an inhibitory neurotransmitter, modulating pain, stress, and anxiety. Therefore, utilizing GABA-producing LAB as a therapeutic approach might be beneficial. Our previous work showed that a GABA-producing Lactococcus lactis strain, NCDO2118, reduced VH induced by acute stress in rats after a 10-day oral treatment. Here, we identified the strain CNCM I-5388, with a four-fold higher GABA production rate under the same conditions as NCDO2118. Both strains shared 99.1% identical GAD amino acid sequences and in vitro analyses revealed the same optimal pH for GAD activity; however, CNCM I-5388 exhibited 17 times higher intracellular GAD activity and increased resistance to acidic pH. Additionally, in vivo experiments have demonstrated that CNCM I-5388 has faster anti-VH properties in rats compared with NCDO2118, starting from the fifth day of treatment. Finally, CNCM I-5388 anti-VH effects partially persisted after 5-day treatment interruption and after a single oral treatment. These findings highlight CNCM I-5388 as a potential therapeutic agent for managing VH in IBS patients.
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Affiliation(s)
- Pedro Gomes
- Toulouse Biotechnology Institute (TBI), Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Valérie Laroute
- Toulouse Biotechnology Institute (TBI), Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France
| | - Catherine Beaufrand
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | | | - Nathalie Aubry
- Toulouse Biotechnology Institute (TBI), Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France
| | - Chloé Liebgott
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | | | | | - Vassilia Theodorou
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Muriel Mercier-Bonin
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Muriel Cocaign-Bousquet
- Toulouse Biotechnology Institute (TBI), Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France
| | - Hélène Eutamene
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
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18
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Dalziel JE, Zobel G, Dewhurst H, Hurst C, Olson T, Rodriguez-Sanchez R, Mace L, Parkar N, Thum C, Hannaford R, Fraser K, MacGibbon A, Bassett SA, Dekker J, Anderson RC, Young W. A Diet Enriched with Lacticaseibacillus rhamnosus HN001 and Milk Fat Globule Membrane Alters the Gut Microbiota and Decreases Amygdala GABA a Receptor Expression in Stress-Sensitive Rats. Int J Mol Sci 2023; 24:10433. [PMID: 37445611 DOI: 10.3390/ijms241310433] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/12/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Brain signalling pathways involved in subclinical anxiety and depressed mood can be modulated via the gut brain axis (GBA), providing the potential for diet and dietary components to affect mood. We investigated behavioural, physiological and gut microbiome responses to the Lacticaseibacillus rhamnosus strain HN001 (LactoB HN001™), which has been shown to reduce postpartum anxiety and depression, and a milk fat globule membrane-enriched product, Lipid 70 (SurestartTM MFGM Lipid 70), which has been implicated in memory in stress-susceptible Wistar Kyoto rats. We examined behaviour in the open field, elevated plus maze and novel object recognition tests in conjunction with the expression of host genes in neuro-signalling pathways, and we also assessed brain lipidomics. Treatment-induced alterations in the caecal microbiome and short-chain fatty acid (SCFA) profiles were also assessed. Neither ingredient induced behavioural changes or altered the brain lipidome (separately or when combined). However, with regard to brain gene expression, the L. rhamnosus HN001 + Lipid 70 combination produced a synergistic effect, reducing GABAA subunit expression in the amygdala (Gabre, Gat3, Gabrg1) and hippocampus (Gabrd). Treatment with L. rhamnosus HN001 alone altered expression of the metabotropic glutamate receptor (Grm4) in the amygdala but produced only minor changes in gut microbiota composition. In contrast, Lipid 70 alone did not alter brain gene expression but produced a significant shift in the gut microbiota profile. Under the conditions used, there was no observed effect on rat behaviour for the ingredient combination. However, the enhancement of brain gene expression by L. rhamnosus HN001 + Lipid 70 implicates synergistic actions on region-specific neural pathways associated with fear, anxiety, depression and memory. A significant shift in the gut microbiota profile also occurred that was mainly attributable to Lipid 70.
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Affiliation(s)
- Julie E Dalziel
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Gosia Zobel
- Ethical Agriculture, AgResearch, Hamilton 3240, New Zealand
| | - Hilary Dewhurst
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Charlotte Hurst
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Trent Olson
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | | | - Louise Mace
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Nabil Parkar
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Caroline Thum
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Rina Hannaford
- Digital Agriculture, AgResearch, Palmerston North 4442, New Zealand
| | - Karl Fraser
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Alastair MacGibbon
- Fonterra Research and Development Centre Co., Ltd., Palmerston North 4442, New Zealand
| | - Shalome A Bassett
- Fonterra Research and Development Centre Co., Ltd., Palmerston North 4442, New Zealand
| | - James Dekker
- Fonterra Research and Development Centre Co., Ltd., Palmerston North 4442, New Zealand
| | - Rachel C Anderson
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
| | - Wayne Young
- Smart Foods & Bioproducts, AgResearch, Palmerston North 4442, New Zealand
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19
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Gut microbiota in chronic pain: Novel insights into mechanisms and promising therapeutic strategies. Int Immunopharmacol 2023. [DOI: 10.1016/j.intimp.2023.109685] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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20
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Understanding the Connection between Gut Homeostasis and Psychological Stress. J Nutr 2023; 153:924-939. [PMID: 36806451 DOI: 10.1016/j.tjnut.2023.01.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/24/2022] [Accepted: 01/17/2023] [Indexed: 02/03/2023] Open
Abstract
Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.
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21
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Tian S, Zhang H, Chen S, Wu P, Chen M. Global research progress of visceral hypersensitivity and irritable bowel syndrome: bibliometrics and visualized analysis. Front Pharmacol 2023; 14:1175057. [PMID: 37201020 PMCID: PMC10185792 DOI: 10.3389/fphar.2023.1175057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/18/2023] [Indexed: 05/20/2023] Open
Abstract
Background: Irritable bowel syndrome (IBS) is a group of functional intestinal disorders characterized by abdominal pain, bloating, and changes in bowel habits, and/or stool characteristics. Recent studies have shown that there has been a significant advancement in the study of visceral hypersensitivity in IBS. Through the use of bibliometrics, this study aims to provide a comprehensive overview of the knowledge structure and research hotpots of visceral hypersensitivity in IBS. Methods: Publications related to visceral hypersensitivity in IBS from 2012 to 2022 were searched on the web of science core collection (WoSCC) database. CiteSpace.6.1. R2 and Vosviewer 1.6.17 were used to perform bibliometric analysis. Results: A total of 974 articles led by China and the United States from 52 countries were included. Over the past decade, the number of articles on visceral hypersensitivity and IBS has steadily increased year by year. China, the United States, and Belgium are the main countries in this field. Univ Oklahoma, Univ Gothenburg, and Zhejiang University are the main research institutions. Simren, Magnus, Greenwood-van meerveld, Beverley, and Tack, Jan are the most published authors in this research field. The research on the causes, genes, and pathways involved in visceral hypersensitivity in IBS and the mechanism of IBS are the main topics and hotspots in this field. This study also found that gut microbiota may be related to the occurrence of visceral hypersensitivity, and probiotics may be a new method for the treatment of visceral hypersensitivity and pain, which may become a new direction for research in this field. Conclusion: This is the first bibliometric study to comprehensively summarize the research trends and developments of visceral hypersensitivity in IBS. This information provides the research frontier and hot topics in this field in recent years, which will provide a reference for scholars studying this field.
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Affiliation(s)
- Siyu Tian
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Hang Zhang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Siqi Chen
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Pengning Wu
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Min Chen
- Department of Colorectal Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Min Chen,
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22
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Ren M, Lotfipour S. Antibiotic Knockdown of Gut Bacteria Sex-Dependently Enhances Intravenous Fentanyl Self-Administration in Adult Sprague Dawley Rats. Int J Mol Sci 2022; 24:409. [PMID: 36613853 PMCID: PMC9820294 DOI: 10.3390/ijms24010409] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/20/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Communication between the brain and gut bacteria impacts drug- and addiction-related behaviors. To investigate the role of gut microbiota on fentanyl reinforcement and reward, we depleted gut bacteria in adult Sprague Dawley male and female rats using an oral, nonabsorbable antibiotic cocktail and allowed rats to intravenously self-administer fentanyl on an escalating schedule of reinforcement. We found that antibiotic treatment enhanced fentanyl self-administration in males, but not females, at the lowest schedule of reinforcement (i.e., fixed ratio 1). Both males and females treated with antibiotics self-administered greater amounts of fentanyl at higher schedules of reinforcement. We then replete microbial metabolites via short-chain fatty acid administration to evaluate a potential mechanism in gut-brain communication and found that restoring metabolites decreases fentanyl self-administration back to controls at higher fixed ratio schedules of reinforcement. Our findings highlight an important relationship between the knockdown and rescue of gut bacterial metabolites and fentanyl self-administration in adult rats, which provides support for a significant relationship between the gut microbiome and opioid use. Further work in this field may lead to effective, targeted treatment interventions in opioid-related disorders.
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Affiliation(s)
- Michelle Ren
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Shahrdad Lotfipour
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA
- Department of Emergency Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
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The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders. Cells 2022; 12:cells12010054. [PMID: 36611848 PMCID: PMC9818777 DOI: 10.3390/cells12010054] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/25/2022] Open
Abstract
Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut-brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic-environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed "gut dysbiosis" (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic-pituitary-adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood-brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs.
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Yang J, Deng Y, Cai Y, Liu Y, Peng L, Luo Z, Li D. Mapping trends and hotspot regarding gastrointestinal microbiome and neuroscience: A bibliometric analysis of global research (2002-2022). Front Neurosci 2022; 16:1048565. [PMID: 36466165 PMCID: PMC9714683 DOI: 10.3389/fnins.2022.1048565] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/28/2022] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Scholars have long understood that gastrointestinal microorganisms are intimately related to human disorders. The literature on research involving the gut microbiome and neuroscience is emerging. This study exposed the connections between gut microbiota and neuroscience methodically and intuitively using bibliometrics and visualization. This study's objectives were to summarize the knowledge structure and identify emerging trends and potential hotspots in this field. MATERIALS AND METHODS On October 18, 2022, a literature search was conducted utilizing the Web of Science Core Collection (WoSCC) database for studies on gut microbiota and neuroscience studies from 2002 to 2022 (August 20, 2022). VOSviewer and CiteSpace V software was used to conduct the bibliometrics and visualization analysis. RESULTS From 2002 to 2022 (August 20, 2022), 2,275 publications in the WoSCC database satisfied the criteria. The annual volume of publications has rapidly emerged in recent years (2016-2022). The most productive nation (n = 732, 32.18%) and the hub of inter-country cooperation (links: 38) were the United States. University College Cork had the most research papers published in this area, followed by McMaster University and Harvard Medical School. Cryan JF, Dinan TG, and Clarke G were key researchers with considerable academic influence. The journals with the most publications are "Neurogastroenterology and Motility" and "Brain Behavior and Immunity." The most cited article and co-cited reference was Cryan JF's 2012 article on the impact of gut microbiota on the brain and behavior. The current research hotspot includes gastrointestinal microbiome, inflammation, gut-brain axis, Parkinson's disease (PD), and Alzheimer's disease (AD). The research focus would be on the "gastrointestinal microbiome, inflammation: a link between obesity, insulin resistance, and cognition" and "the role of two important theories of the gut-brain axis and microbial-gut-brain axis in diseases." Burst detection analysis showed that schizophrenia, pathology, and psychiatric disorder may continue to be the research frontiers. CONCLUSION Research on "gastrointestinal microbiome, inflammation: a link between obesity, insulin resistance, and cognition" and "the role of two important theories of the gut-brain axis and microbial-gut-brain axis in diseases" will continue to be the hotspot. Schizophrenia and psychiatric disorder will be the key research diseases in the field of gut microbiota and neuroscience, and pathology is the key research content, which is worthy of scholars' attention.
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Affiliation(s)
- Jingjing Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Yihui Deng
- Hunan University of Chinese Medicine, Changsha, China
| | - Yuzhe Cai
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Yixuan Liu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Lanyu Peng
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Zheng Luo
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Dingxiang Li
- Hunan University of Chinese Medicine, Changsha, China
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Ustianowska K, Ustianowski Ł, Machaj F, Gorący A, Rosik J, Szostak B, Szostak J, Pawlik A. The Role of the Human Microbiome in the Pathogenesis of Pain. Int J Mol Sci 2022; 23:13267. [PMID: 36362056 PMCID: PMC9659276 DOI: 10.3390/ijms232113267] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 08/22/2023] Open
Abstract
Understanding of the gut microbiome's role in human physiology developed rapidly in recent years. Moreover, any alteration of this microenvironment could lead to a pathophysiological reaction of numerous organs. It results from the bidirectional communication of the gastrointestinal tract with the central nervous system, called the gut-brain axis. The signals in the gut-brain axis are mediated by immunological, hormonal, and neural pathways. However, it is also influenced by microorganisms in the gut. The disturbances in the gut-brain axis are associated with gastrointestinal syndromes, but recently their role in the development of different types of pain was reported. The gut microbiome could be the factor in the central sensitization of chronic pain by regulating microglia, astrocytes, and immune cells. Dysbiosis could lead to incorrect immune responses, resulting in the development of inflammatory pain such as endometriosis. Furthermore, chronic visceral pain, associated with functional gastrointestinal disorders, could result from a disruption in the gut microenvironment. Any alteration in the gut-brain axis could also trigger migraine attacks by affecting cytokine expression. Understanding the gut microbiome's role in pain pathophysiology leads to the development of analgetic therapies targeting microorganisms. Probiotics, FODMAP diet, and fecal microbiota transplantation are reported to be beneficial in treating visceral pain.
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Affiliation(s)
- Klaudia Ustianowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Łukasz Ustianowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Filip Machaj
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
- Department of Medical Biology, Medical University of Warsaw, 00-575 Warsaw, Poland
| | - Anna Gorący
- Independent Laboratory of Invasive Cardiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA
| | - Bartosz Szostak
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Joanna Szostak
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
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26
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Ho AHY, Wong S, Lui R. Topic: Nutrition and the Gut-Liver-Brain Axis. CURRENT HEPATOLOGY REPORTS 2022; 21:99-110. [DOI: 10.1007/s11901-022-00589-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/24/2022] [Indexed: 04/14/2025]
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Medicinal Plants and Their Impact on the Gut Microbiome in Mental Health: A Systematic Review. Nutrients 2022; 14:nu14102111. [PMID: 35631252 PMCID: PMC9144835 DOI: 10.3390/nu14102111] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/29/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Various neurocognitive and mental health-related conditions have been associated with the gut microbiome, implicating a microbiome–gut–brain axis (MGBA). The aim of this systematic review was to identify, categorize, and review clinical evidence supporting medicinal plants for the treatment of mental disorders and studies on their interactions with the gut microbiota. Methods: This review included medicinal plants for which clinical studies on depression, sleeping disorders, anxiety, or cognitive dysfunction as well as scientific evidence of interaction with the gut microbiome were available. The studies were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Eighty-five studies met the inclusion criteria and covered thirty mental health-related medicinal plants with data on interaction with the gut microbiome. Conclusion: Only a few studies have been specifically designed to assess how herbal preparations affect MGBA-related targets or pathways. However, many studies provide hints of a possible interaction with the MGBA, such as an increased abundance of health-beneficial microorganisms, anti-inflammatory effects, or MGBA-related pathway effects by gut microbial metabolites. Data for Panax ginseng, Schisandra chinensis, and Salvia rosmarinus indicate that the interaction of their constituents with the gut microbiota could mediate mental health benefits. Studies specifically assessing the effects on MGBA-related pathways are still required for most medicinal plants.
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28
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Jiang Z, Li M, McClements DJ, Liu X, Liu F. Recent advances in the design and fabrication of probiotic delivery systems to target intestinal inflammation. Food Hydrocoll 2022. [DOI: 10.1016/j.foodhyd.2021.107438] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Gut microbiota and its role in stress-induced hyperalgesia: gender-specific responses linked to different changes in serum metabolites. Pharmacol Res 2022; 177:106129. [DOI: 10.1016/j.phrs.2022.106129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022]
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Meynier M, Baudu E, Rolhion N, Defaye M, Straube M, Daugey V, Modoux M, Wawrzyniak I, Delbac F, Villéger R, Méleine M, Borras Nogues E, Godfraind C, Barnich N, Ardid D, Poirier P, Sokol H, Chatel JM, Langella P, Livrelli V, Bonnet M, Carvalho FA. AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms. Gut Microbes 2022; 14:2022997. [PMID: 35090380 PMCID: PMC8803069 DOI: 10.1080/19490976.2021.2022997] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/12/2021] [Accepted: 12/10/2021] [Indexed: 02/04/2023] Open
Abstract
Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL-22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL-22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL-22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
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Affiliation(s)
- Maëva Meynier
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Elodie Baudu
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Nathalie Rolhion
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
- Paris Centre for Microbiome Medicine FHU, Paris, France
| | - Manon Defaye
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
- Department of Physiology and Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Marjolène Straube
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
| | - Valentine Daugey
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Morgane Modoux
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
| | - Ivan Wawrzyniak
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Frédéric Delbac
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Romain Villéger
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
| | - Mathieu Méleine
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Esther Borras Nogues
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Catherine Godfraind
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Neuropathology Unit, Clermont-Ferrand, France
| | - Nicolas Barnich
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
| | - Denis Ardid
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Philippe Poirier
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Laboratoire de Parasitologie et de Mycologie, Clermont-Ferrand, France
| | - Harry Sokol
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
- Paris Centre for Microbiome Medicine FHU, Paris, France
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Jean-Marc Chatel
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Philippe Langella
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Valérie Livrelli
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Laboratoire de Parasitologie et de Mycologie, Clermont-Ferrand, France
| | - Mathilde Bonnet
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
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31
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Gut Bacteria and Neuropsychiatric Disorders. Microorganisms 2021; 9:microorganisms9122583. [PMID: 34946184 PMCID: PMC8708963 DOI: 10.3390/microorganisms9122583] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 12/11/2022] Open
Abstract
Bacteria in the gut microbiome plays an intrinsic part in immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. Apart from physiological and structural changes brought about by gut bacteria on entero-epithelial cells and mucus layers, a vast number of signals generated in the gastro-intestinal tract (GIT) reaches the brain via the vagus nerve. Research on the gut–brain axis (GBA) has mostly been devoted to digestive functions and satiety. Less papers have been published on the role gut microbiota play in mood, cognitive behavior and neuropsychiatric disorders such as autism, depression and schizophrenia. Whether we will be able to fully decipher the connection between gut microbiota and mental health is debatable, especially since the gut microbiome is diverse, everchanging and highly responsive to external stimuli. Nevertheless, the more we discover about the gut microbiome and the more we learn about the GBA, the greater the chance of developing novel therapeutics, probiotics and psychobiotics to treat gastro-intestinal disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), but also improve cognitive functions and prevent or treat mental disorders. In this review we focus on the influence gut bacteria and their metabolites have on neuropsychiatric disorders.
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32
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Xu X, Chen R, Zhan G, Wang D, Tan X, Xu H. Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia? Front Cell Infect Microbiol 2021; 11:760076. [PMID: 34722345 PMCID: PMC8552036 DOI: 10.3389/fcimb.2021.760076] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic community has also recognized the existence of the microbiota-gut-brain axis. Chronic pain has always been an urgent difficulty for human beings, which often causes anxiety, depression, and other mental symptoms, seriously affecting people's quality of life. Hyperalgesia is one of the main adverse reactions of chronic pain. The mechanism of gut microbiota in hyperalgesia has been extensively studied, providing a new target for pain treatment. Enterochromaffin cells, as the chief sentinel for sensing gut microbiota and its metabolites, can play an important role in the interaction between the gut microbiota and hyperalgesia through paracrine or neural pathways. Therefore, this systematic review describes the role of gut microbiota in the pathological mechanism of hyperalgesia, learns about the role of enterochromaffin cell receptors and secretions in hyperalgesia, and provides a new strategy for pain treatment by targeting enterochromaffin cells through restoring disturbed gut microbiota or supplementing probiotics.
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Affiliation(s)
- Xiaolin Xu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rongmin Chen
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Gaofeng Zhan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danning Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Tan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Xu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
Preclinical evidence has firmly established bidirectional interactions among the brain, the gut, and the gut microbiome. Candidate signaling molecules and at least three communication channels have been identified. Communication within this system is nonlinear, is bidirectional with multiple feedback loops, and likely involves interactions between different channels. Alterations in gut-brain-microbiome interactions have been identified in rodent models of several digestive, psychiatric, and neurological disorders. While alterations in gut-brain interactions have clearly been established in irritable bowel syndrome, a causative role of the microbiome in irritable bowel syndrome remains to be determined. In the absence of specific microbial targets for more effective therapies, current approaches are limited to dietary interventions and centrally targeted pharmacological and behavioral approaches. A more comprehensive understanding of causative influences within the gut-brain-microbiome system and well-designed randomized controlled trials are needed to translate these exciting preclinical findings into effective therapies. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Emeran A Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience and Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; emayer@.ucla.edu
| | - Karina Nance
- G. Oppenheimer Center for Neurobiology of Stress and Resilience and Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; emayer@.ucla.edu
| | - Shelley Chen
- G. Oppenheimer Center for Neurobiology of Stress and Resilience and Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; emayer@.ucla.edu
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Tramullas M, Collins JM, Fitzgerald P, Dinan TG, O' Mahony SM, Cryan JF. Estrous cycle and ovariectomy-induced changes in visceral pain are microbiota-dependent. iScience 2021; 24:102850. [PMID: 34381975 PMCID: PMC8333168 DOI: 10.1016/j.isci.2021.102850] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/07/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
Visceral hypersensitivity (VH) is a hallmark of many functional gastrointestinal disorders including irritable bowel syndrome and is categorized by a dull, diffuse sensation of abdominal pain. Recently, the gut microbiota has been implicated in VH in male mice, but the effects in females have yet to be explored fully. To this end, we now show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls. However, we show that although sensitivity to CRD is estrous cycle stage-dependent in conventional mice, it is not in germ-free mice. Further, ovariectomy (OVX) induced VH in conventional but not germ-free mice, and induced weight gain regardless of microbiota status. Finally, we show that estrogen-replacement ameliorated OVX-induced VH. Taken together, this study provides evidence for a major role of female sex hormones and the gut microbiota in sensation of visceral pain in females.
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Affiliation(s)
| | - James M Collins
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
| | - Siobhain M O' Mahony
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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Luck B, Horvath TD, Engevik KA, Ruan W, Haidacher SJ, Hoch KM, Oezguen N, Spinler JK, Haag AM, Versalovic J, Engevik MA. Neurotransmitter Profiles Are Altered in the Gut and Brain of Mice Mono-Associated with Bifidobacterium dentium. Biomolecules 2021; 11:1091. [PMID: 34439760 PMCID: PMC8392031 DOI: 10.3390/biom11081091] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/29/2021] [Accepted: 07/18/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Accumulating evidence indicates that the gut microbiota can synthesize neurotransmitters as well as impact host-derived neurotransmitter levels. In the past, it has been challenging to decipher which microbes influence neurotransmitters due to the complexity of the gut microbiota. METHODS To address whether a single microbe, Bifidobacterium dentium, could regulate important neurotransmitters, we examined Bifidobacteria genomes and explored neurotransmitter pathways in secreted cell-free supernatant using LC-MS/MS. To determine if B. dentium could impact neurotransmitters in vivo, we mono-associated germ-free mice with B. dentium ATCC 27678 and examined fecal and brain neurotransmitter concentrations. RESULTS We found that B. dentium possessed the enzymatic machinery to generate γ-aminobutyric acid (GABA) from glutamate, glutamine, and succinate. Consistent with the genome analysis, we found that B. dentium secreted GABA in a fully defined microbial media and elevated fecal GABA in B. dentium mono-associated mice compared to germ-free controls. We also examined the tyrosine/dopamine pathway and found that B. dentium could synthesize tyrosine, but could not generate L-dopa, dopamine, norepinephrine, or epinephrine. In vivo, we found that B. dentium mono-associated mice had elevated levels of tyrosine in the feces and brain. CONCLUSIONS These data indicate that B. dentium can contribute to in vivo neurotransmitter regulation.
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Affiliation(s)
- Berkley Luck
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Thomas D. Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Kristen A. Engevik
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Wenly Ruan
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
- Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Sigmund J. Haidacher
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Kathleen M. Hoch
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Numan Oezguen
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Jennifer K. Spinler
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Anthony M. Haag
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - James Versalovic
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Melinda A. Engevik
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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Liu YW, Wang YP, Yen HF, Liu PY, Tzeng WJ, Tsai CF, Lin HC, Lee FY, Jeng OJ, Lu CL, Tsai YC. Lactobacillus plantarum PS128 Ameliorated Visceral Hypersensitivity in Rats Through the Gut-Brain Axis. Probiotics Antimicrob Proteins 2021; 12:980-993. [PMID: 31691208 DOI: 10.1007/s12602-019-09595-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain and alterations in bowel habits. Current treatments for IBS are unsatisfactory due to its multifactorial pathogenesis involving the microbiota-gut-brain axis. Lactobacillus plantarum PS128 (PS128) was reported to exhibit neuromodulatory activity which may be beneficial for improving IBS. This study aimed to investigate the effect of PS128 on visceral hypersensitivity (VH) and the gut-brain axis using a 5-hydroxytryptophan (5-HTP)-induced VH rat model without colonic inflammation induction, mimicking the characteristics of IBS. Male Sprague-Dawley rats were administered with PS128 (109 CFU in 0.2 mL saline/rat/day) or saline (0.2 mL saline/rat/day) for 14 days. Colorectal distension (CRD) with simultaneous electromyography recording was performed 30 min before and 30 min after the 5-HTP injection. Levels of neuropeptides and neurotrophins were analyzed. PS128 significantly reduced VH induced by the 5-HTP injection and CRD. Neurotransmitter protein levels, substance P, CGRP, BDNF, and NGF, were decreased in the dorsal root ganglion but increased in the spinal cord in response to the 5-HTP injection; PS128 reversed these changes. The hypothalamic-pituitary-adrenal axis was modulated by PS128 with decreased corticosterone concentration in serum and the expression of mineralocorticoid receptors in the amygdala. Oral administration of PS128 inhibited 5-HTP-induced VH during CRD. The ameliorative effect on VH suggests the potential application of PS128 for IBS.
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Affiliation(s)
- Yen-Wenn Liu
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Microbiome Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Yen-Po Wang
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan.,Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Hsu-Fang Yen
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Pei-Yi Liu
- Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Wen-Jian Tzeng
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Chia-Fen Tsai
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | - Han-Chieh Lin
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | | | - Ching-Liang Lu
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan. .,Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan.
| | - Ying-Chieh Tsai
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,Microbiome Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.
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Simon E, Călinoiu LF, Mitrea L, Vodnar DC. Probiotics, Prebiotics, and Synbiotics: Implications and Beneficial Effects against Irritable Bowel Syndrome. Nutrients 2021; 13:nu13062112. [PMID: 34203002 PMCID: PMC8233736 DOI: 10.3390/nu13062112] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is still a common functional gastrointestinal disease that presents chronic abdominal symptoms but with a pathophysiology that is not yet fully elucidated. Moreover, the use of the synergistic combination of prebiotics and probiotics, known as synbiotics, for IBS therapy is still in the early stages. Advancements in technology led to determining the important role played by probiotics in IBS, whereas the present paper focuses on the detailed review of the various pathophysiologic mechanisms of action of probiotics, prebiotics, and synbiotics via multidisciplinary domains involving the gastroenterology (microbiota modulation, alteration of gut barrier function, visceral hypersensitivity, and gastrointestinal dysmotility) immunology (intestinal immunological modulation), and neurology (microbiota–gut–brain axis communication and co-morbidities) in mitigating the symptoms of IBS. In addition, this review synthesizes literature about the mechanisms involved in the beneficial effects of prebiotics and synbiotics for patients with IBS, discussing clinical studies testing the efficiency and outcomes of synbiotics used as therapy for IBS.
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Affiliation(s)
- Elemer Simon
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
| | - Lavinia Florina Călinoiu
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
| | - Laura Mitrea
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
| | - Dan Cristian Vodnar
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
- Correspondence: ; Tel.: +40-747-341-881
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Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci 2021; 22:ijms22062973. [PMID: 33804088 PMCID: PMC8000752 DOI: 10.3390/ijms22062973] [Citation(s) in RCA: 246] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.
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Banfi D, Moro E, Bosi A, Bistoletti M, Cerantola S, Crema F, Maggi F, Giron MC, Giaroni C, Baj A. Impact of Microbial Metabolites on Microbiota-Gut-Brain Axis in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:1623. [PMID: 33562721 PMCID: PMC7915037 DOI: 10.3390/ijms22041623] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the "gut-brain axis" and renamed the "microbiota-gut-brain axis", considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota-gut-brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as "postbiotics", such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.
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Affiliation(s)
- Davide Banfi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy; (S.C.); (M.C.G.)
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Fabrizio Maggi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy; (S.C.); (M.C.G.)
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
- Centre of Neuroscience, University of Insubria, 21100 Varese, Italy
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
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Lactobacillus rhamnosus GG soluble mediators ameliorate early life stress-induced visceral hypersensitivity and changes in spinal cord gene expression. Neuronal Signal 2020; 4:NS20200007. [PMID: 33343931 PMCID: PMC7726314 DOI: 10.1042/ns20200007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 10/26/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023] Open
Abstract
Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal disorders, and there is growing evidence that the gut microbiota may play a role in its pathophysiology. It has previously been shown that early life stress-induced visceral sensitivity is reduced by various probiotic strains of bacteria (including Lactobacillus rhamnosus GG (LGG)) alone or in combination with prebiotic fibres in rat models. However, the exact mechanisms underpinning such effects remain unresolved. Here, we investigated if soluble mediators derived from LGG can mimic the bacteria's effects on visceral hypersensitivity and the microbiota-gut-brain axis. Rats were exposed to maternal separation (MS) from postnatal days 2-12. From weaning onwards both non-separated (NS) and MS offspring were provided drinking water with or without supplementation of standardized preparations of the LGG soluble mediators (LSM). Our results show that MS led to increased visceral sensitivity and exaggerated corticosterone plasma levels following restraint stress in adulthood, and both of these effects were ameliorated through LSM supplementation. Differential regulation of various genes in the spinal cord of MS versus NS rats was observed, 41 of which were reversed by LSM supplementation. At the microbiota composition level MS led to changes in beta diversity and abundance of specific bacteria including parabacteroides, which were ameliorated by LSM. These findings support probiotic soluble mediators as potential interventions in the reduction of symptoms of visceral hypersensitivity.
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Rea K, Dinan TG, Cryan JF. Gut Microbiota: A Perspective for Psychiatrists. Neuropsychobiology 2020; 79:50-62. [PMID: 31726457 DOI: 10.1159/000504495] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/31/2019] [Indexed: 11/19/2022]
Abstract
There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.
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Affiliation(s)
- Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland, .,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland,
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Ouabbou S, He Y, Butler K, Tsuang M. Inflammation in Mental Disorders: Is the Microbiota the Missing Link? Neurosci Bull 2020; 36:1071-1084. [PMID: 32592144 PMCID: PMC7475155 DOI: 10.1007/s12264-020-00535-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/18/2020] [Indexed: 01/15/2023] Open
Abstract
Research suggests that inflammation is important in the pathophysiology of mental disorders. In addition, a growing body of evidence has led to the concept of the microbiota-gut-brain axis. To understand the potential interactions, we begin by exploring the liaison between the immune system and mental disorders, then we describe the evidence that the microbiota impact the immune response in the developing brain. Next, we review the literature that has documented microbiome alterations in major mental disorders. We end with a summary of therapeutic applications, ranging from psycho-biotics to immunomodulatory drugs that could affect the microbiota-gut-brain axis, and potential treatments to alleviate the adverse effects of antipsychotics. We conclude that there is promising evidence to support the position that the microbiota plays an important role in the immunological pathophysiology of mental disorders with an emphasis on psychotic disorders and mood disorders. However, more research is needed to elucidate the mechanisms.
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Affiliation(s)
- Sophie Ouabbou
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, and Hunan Key Laboratory of Psychiatry and Mental Health, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
- Cellular and Molecular Biology Research Centre, University of Costa Rica, San José, 11501, Costa Rica
| | - Ying He
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, and Hunan Key Laboratory of Psychiatry and Mental Health, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Keith Butler
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Ming Tsuang
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Health, Boston, MA, 02115, USA
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Oh D, Cheon KA. Alteration of Gut Microbiota in Autism Spectrum Disorder: An Overview. Soa Chongsonyon Chongsin Uihak 2020; 31:131-145. [PMID: 32665757 PMCID: PMC7350540 DOI: 10.5765/jkacap.190039] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/25/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
The microbiota-gut-brain axis, which refers to the bidirectional communication pathway between gut bacteria and the central nervous system, has a profound effect on important brain processes, from the synthesis of neurotransmitters to the modulation of complex behaviors such as sociability and anxiety. Previous studies have revealed that the gut microbiota is potentially related to not only gastrointestinal disturbances, but also social impairment and repetitive behavior-core symptoms of autism spectrum disorder (ASD). Although studies have been conducted to characterize the microbial composition in patients with ASD, the results are heterogeneous. Nevertheless, it is clear that there is a difference in the composition of the gut microbiota between ASD and typically developed individuals, and animal studies have repeatedly suggested that the gut microbiota plays an important role in ASD pathophysiology. This possibility is supported by abnormalities in metabolites produced by the gut microbiota and the association between altered immune responses and the gut microbiota observed in ASD patients. Based on these findings, various attempts have been made to use the microbiota in ASD treatment. The results reported to date suggest that microbiota-based therapies may be effective for ASD, but largescale, well-designed studies are needed to confirm this.
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Affiliation(s)
- Donghun Oh
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea.,Division of Child and Adolescent Psychiatry, Severance Children's Hospital, Seoul, Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Keun-Ah Cheon
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea.,Division of Child and Adolescent Psychiatry, Severance Children's Hospital, Seoul, Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea
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Kim M, Chung SK, Yang JC, Park JI, Nam SH, Park TW. Development of the Korean Form of the Premonitory Urge for Tics Scale: A Reliability and Validity Study. Soa Chongsonyon Chongsin Uihak 2020; 31:146-153. [PMID: 32665758 PMCID: PMC7350545 DOI: 10.5765/jkacap.200013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 03/30/2020] [Accepted: 04/16/2020] [Indexed: 12/26/2022] Open
Abstract
Objectives This study aimed to evaluate the reliability and validity of the Korean Form of the Premonitory Urge for Tics Scale (K-PUTS). Methods Thirty-eight patients with Tourette's disorder who visited Jeonbuk National University Hospital were assessed with the K-PUTS. Together with the PUTS, the Yale Global Tic Severity Scale (YGTSS), the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the attention-deficit/hyperactivity disorder (ADHD) rating scale (ARS), and the Adult ADHD Self-Report Scale (ASRS) were implemented to evaluate concurrent and discriminant validity. Results The internal consistency of items on the PUTS was high, with a Cronbach's α of 0.79. The test-retest reliability of the PUTS, which was administered at 2 weeks to 2 months intervals, showed high reliability with a Pearson correlation coefficient of 0.60. There was a significant positive correlation between the overall PUTS score and the YGTSS score, showing concurrent validity. There was no correlation between the PUTS, CY-BOCS, and ASRS scores, demonstrating the discriminant validity of the PUTS. Factor analysis for construct validity revealed three factors: "presumed functional relationship between the tic and the urge to tic," "the quality of the premonitory urge," and "just right phenomena." Conclusion The results of this study indicate that the K-PUTS is a reliable and valid scale for rating premonitory urge of tics.
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Affiliation(s)
- Mira Kim
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea
| | - Sang-Keun Chung
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.,Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
| | - Jong-Chul Yang
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.,Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
| | - Jong-Il Park
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.,Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
| | - Seok Hyun Nam
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea
| | - Tae Won Park
- Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.,Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
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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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Evrensel A, Ünsalver BÖ, Ceylan ME. Immune-Kynurenine Pathways and the Gut Microbiota-Brain Axis in Anxiety Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1191:155-167. [PMID: 32002928 DOI: 10.1007/978-981-32-9705-0_10] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body's serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.
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Affiliation(s)
- Alper Evrensel
- Department of Psychiatry, Uskudar University, Umraniye, Istanbul, Turkey.
| | - Barış Önen Ünsalver
- Vocational School of Health Services, Department of Medical Documentation and Secretariat, Uskudar University, Istanbul, Turkey
| | - Mehmet Emin Ceylan
- Departments of Psychology and Philosophy, Uskudar University, Istanbul, Turkey
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Zhu S, Jiang Y, Xu K, Cui M, Ye W, Zhao G, Jin L, Chen X. The progress of gut microbiome research related to brain disorders. J Neuroinflammation 2020; 17:25. [PMID: 31952509 PMCID: PMC6969442 DOI: 10.1186/s12974-020-1705-z] [Citation(s) in RCA: 273] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/07/2020] [Indexed: 02/06/2023] Open
Abstract
There is increasing evidence showing that the dynamic changes in the gut microbiota can alter brain physiology and behavior. Cognition was originally thought to be regulated only by the central nervous system. However, it is now becoming clear that many non-nervous system factors, including the gut-resident bacteria of the gastrointestinal tract, regulate and influence cognitive dysfunction as well as the process of neurodegeneration and cerebrovascular diseases. Extrinsic and intrinsic factors including dietary habits can regulate the composition of the microbiota. Microbes release metabolites and microbiota-derived molecules to further trigger host-derived cytokines and inflammation in the central nervous system, which contribute greatly to the pathogenesis of host brain disorders such as pain, depression, anxiety, autism, Alzheimer’s diseases, Parkinson’s disease, and stroke. Change of blood–brain barrier permeability, brain vascular physiology, and brain structure are among the most critical causes of the development of downstream neurological dysfunction. In this review, we will discuss the following parts:
Overview of technical approaches used in gut microbiome studies Microbiota and immunity Gut microbiota and metabolites Microbiota-induced blood–brain barrier dysfunction Neuropsychiatric diseases
■ Stress and depression ■ Pain and migraine ■ Autism spectrum disorders Neurodegenerative diseases
■ Parkinson’s disease ■ Alzheimer’s disease ■ Amyotrophic lateral sclerosis ■ Multiple sclerosis Cerebrovascular disease
■ Atherosclerosis ■ Stroke ■ Arteriovenous malformation Conclusions and perspectives
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Affiliation(s)
- Sibo Zhu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Yanfeng Jiang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Kelin Xu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,School of Data Science, Fudan University, Shanghai, China
| | - Mei Cui
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Genming Zhao
- School of Data Science, Fudan University, Shanghai, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China. .,Fudan University Taizhou Institute of Health Sciences, Taizhou, China. .,Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China.
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48
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Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1684198. [PMID: 31871540 PMCID: PMC6906814 DOI: 10.1155/2019/1684198] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/30/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To this purpose, patients diagnosed according to Fukuda's criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations. Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction. Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction. Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients. This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients. The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients. No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient, whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.
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49
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Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99:1877-2013. [PMID: 31460832 DOI: 10.1152/physrev.00018.2018] [Citation(s) in RCA: 2695] [Impact Index Per Article: 449.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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Affiliation(s)
- John F. Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kenneth J. O'Riordan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitlin S. M. Cowan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kiran V. Sandhu
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Thomaz F. S. Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcus Boehme
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Martin G. Codagnone
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Sofia Cussotto
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Christine Fulling
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Anna V. Golubeva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Katherine E. Guzzetta
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Minal Jaggar
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitriona M. Long-Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joshua M. Lyte
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Jason A. Martin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Alicia Molinero-Perez
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emanuela Morelli
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Enrique Morillas
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Rory O'Connor
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joana S. Cruz-Pereira
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Veronica L. Peterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Nathaniel L. Ritz
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Eoin Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Simon Spichak
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emily M. Teichman
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcel van de Wouw
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Ana Paula Ventura-Silva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Shauna E. Wallace-Fitzsimons
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Niall Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
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50
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Bassett SA, Young W, Fraser K, Dalziel JE, Webster J, Ryan L, Fitzgerald P, Stanton C, Dinan TG, Cryan JF, Clarke G, Hyland N, Roy NC. Metabolome and microbiome profiling of a stress-sensitive rat model of gut-brain axis dysfunction. Sci Rep 2019; 9:14026. [PMID: 31575902 PMCID: PMC6773725 DOI: 10.1038/s41598-019-50593-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 09/09/2019] [Indexed: 12/16/2022] Open
Abstract
Stress negatively impacts gut and brain health. Individual differences in response to stress have been linked to genetic and environmental factors and more recently, a role for the gut microbiota in the regulation of stress-related changes has been demonstrated. However, the mechanisms by which these factors influence each other are poorly understood, and there are currently no established robust biomarkers of stress susceptibility. To determine the metabolic and microbial signatures underpinning physiological stress responses, we compared stress-sensitive Wistar Kyoto (WKY) rats to the normo-anxious Sprague Dawley (SD) strain. Here we report that acute stress-induced strain-specific changes in brain lipid metabolites were a prominent feature in WKY rats. The relative abundance of Lactococcus correlated with the relative proportions of many brain lipids. In contrast, plasma lipids were significantly elevated in response to stress in SD rats, but not in WKY rats. Supporting these findings, we found that the greatest difference between the SD and WKY microbiomes were the predicted relative abundance of microbial genes involved in lipid and energy metabolism. Our results provide potential insights for developing novel biomarkers of stress vulnerability, some of which appear genotype specific.
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Affiliation(s)
- Shalome A Bassett
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand
| | - Wayne Young
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Karl Fraser
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Julie E Dalziel
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand. .,Riddet Institute, Massey University, Palmerston North, New Zealand.
| | - Jim Webster
- Farm Systems North, AgResearch Ltd., Ruakura Research Centre, Hamilton, New Zealand
| | - Leigh Ryan
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand
| | - Patrick Fitzgerald
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Catherine Stanton
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Niall Hyland
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Physiology, University College Cork, Cork, Ireland
| | - Nicole C Roy
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
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