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Filipovic T, Filipović A, Nikolic D, Gimigliano F, Stevanov J, Hrkovic M, Bosanac I. Fibromyalgia: Understanding, Diagnosis and Modern Approaches to Treatment. J Clin Med 2025; 14:955. [PMID: 39941626 PMCID: PMC11818761 DOI: 10.3390/jcm14030955] [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: 01/06/2025] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 02/16/2025] Open
Abstract
Fibromyalgia (FM) is a chronic condition characterized by generalized musculoskeletal pain associated with other symptoms, especially sleep and mood disorders, fatigue, and cognitive dysfunctions. The etiopathogenesis of FM is not sufficiently known, and regardless of numerous research, the clinical presentation is nonspecific, which makes it difficult to approve a timely diagnosis and, subsequently, an adequate therapeutic approach. Genetic, hormonal, immunological, and environmental factors are cited as potential factors in the development of this condition. Diagnosis is based on a clinical approach and known diagnostic criteria, while additional methods, such as radiographic, magnetic resonance, or laboratory analyses, can be useful to exclude other conditions. The heterogeneity of FM significantly impacts both diagnosis and treatment, as it presents a wide spectrum of symptoms that vary in severity, combinations, and underlying contributing factors. This variability is a challenge for clinicians and requires a holistic, comprehensive, multidisciplinary, patient-centered approach. According to The European League Against Rheumatism (EULAR) from 2016, treatment begins with patient education and involves the simultaneous application of pharmacological and nonpharmacological treatments. The application of only pharmacological or nonpharmacological treatment is most often not successful. Due to differences in pain threshold, psychological factors, and comorbidities, patients may respond differently to the same interventions. Although there is no universal treatment, this review brings up the fact that the timely recognition of symptoms and a tailored treatment with a patient-centered plan can significantly improve the quality of life of patients.
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Affiliation(s)
- Tamara Filipovic
- Institute for Rehabilitation, 11000 Belgrade, Serbia; (T.F.); (M.H.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.F.); (D.N.)
| | - Aleksandar Filipović
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.F.); (D.N.)
- Center for Radiology, Faculty of Medicine, University Clinical Centre of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Dejan Nikolic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.F.); (D.N.)
- Department of Physical Medicine and Rehabilitation, University Children’s Hospital, 11000 Belgrade, Serbia
| | - Francesca Gimigliano
- Department of Physical and Mental Health and Preventive Medicine, Luigi Vanvitelli University, 80138 Naples, Italy;
| | - Jelena Stevanov
- Clinic for Rehabilitation Dr M. Zotović, 11000 Belgrade, Serbia;
| | - Marija Hrkovic
- Institute for Rehabilitation, 11000 Belgrade, Serbia; (T.F.); (M.H.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.F.); (D.N.)
| | - Ivana Bosanac
- Institute for Rehabilitation, 11000 Belgrade, Serbia; (T.F.); (M.H.)
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Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics-Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2025; 26:1282. [PMID: 39941050 PMCID: PMC11818353 DOI: 10.3390/ijms26031282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort ("fatigue") that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
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Affiliation(s)
- James N Baraniuk
- Department of Medicine and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007, USA
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Saija C, Bertuccio MP, Scoglio A, Macaione V, Cacciola F, Micalizzi G, Caccamo D, Muscoli C, Currò M. Role of Vitamin D Status and Alterations in Gut Microbiota Metabolism in Fibromyalgia-Associated Chronic Inflammatory Pain. Biomedicines 2025; 13:139. [PMID: 39857723 PMCID: PMC11760899 DOI: 10.3390/biomedicines13010139] [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: 11/27/2024] [Revised: 12/26/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Several studies suggest gut microbiota metabolites as important immuno-modulators in inflammatory pain. We aimed to investigate the relationship between vitamin D status and gut dysbiosis markers in fibromyalgia (FM)-associated chronic inflammation. Methods: Blood samples were collected from sixty-eight female FM patients (49.9 ± 12.35 years). Pain intensity was assessed by FIQ-R. The serum levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-17, IFN-γ, as well as those of vitamin D (25(OH)D3) and the kynurenine/tryptophan ratio (Kyn/Trp) were determined by ELISA and HPLC, respectively. The plasma levels of the SCFAs acetate, butyrate, and propionate were detected by GC-MS. Results: A mean FIQ-R score indicated that the patients could be classified as having moderate FM. The mean levels of all cytokines, but IL-6 and IL-1β, were higher than the normal reference values. The highest concentrations of cytokines were observed in patients showing the highest FIQ-R scores and the lowest 25(OH)D3 levels. Deficient levels of acetate were found paralleled by an increase in Kyn/Trp. The highest acetate concentrations were detected in patients with the lowest FIQ-R scores and 25(OH)D3 levels. Significantly negative correlations were found between 25(OH)D3 concentrations and FIQ-R scores (p = 0.007) as well as IL-17 levels (p = 0.002) and between acetate and TNF-α (p = 0.040) as well as FIQ-R scores (p = 0.028), while significantly positive correlations were observed between Kyn/Trp and IL-17 (p = 0.027) as well as IFN-γ (p = 0.003). Conclusions: Our preliminary data suggest that the vitamin D status along with altered gut microbiota metabolism plays a major role in FM-related inflammatory pain. Replication of these findings in a larger cohort is required to provide additional insights.
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Affiliation(s)
- Caterina Saija
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy; (C.S.); (M.P.B.); (A.S.); (M.C.)
| | - Maria Paola Bertuccio
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy; (C.S.); (M.P.B.); (A.S.); (M.C.)
| | - Alberto Scoglio
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy; (C.S.); (M.P.B.); (A.S.); (M.C.)
| | - Vincenzo Macaione
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Francesco Cacciola
- Messina Institute of Technology, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Former Veterinary School, University of Messina, 98168 Messina, Italy; (F.C.); (G.M.)
| | - Giuseppe Micalizzi
- Messina Institute of Technology, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Former Veterinary School, University of Messina, 98168 Messina, Italy; (F.C.); (G.M.)
| | - Daniela Caccamo
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy; (C.S.); (M.P.B.); (A.S.); (M.C.)
| | - Carolina Muscoli
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Monica Currò
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy; (C.S.); (M.P.B.); (A.S.); (M.C.)
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Thomas DC, Khan J, Ananthan S, Kalladka M. Systemic Factors Affecting Pain Management in Dentistry. Dent Clin North Am 2024; 68:725-737. [PMID: 39244253 DOI: 10.1016/j.cden.2024.07.004] [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] [Indexed: 09/09/2024]
Abstract
There are several factors that affect a patient's experience of pain. These include both local and systemic factors. The systemic factors that affect patients' dental and orofacial pain experience include, but not limited to, hormonal, nutritional, systemic infections, neurodegenerative, and autoimmune, among others. Comprehensive medical history is essential to delineate any possible systemic factors affecting pain experience. A thorough review of systems should form the foundation, since multiple factors can affect the prognosis of pain management. This would facilitate early recognition and trigger prompt referrals to the appropriate medical professionals. This helps to reduce the health care burden.
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Affiliation(s)
- Davis C Thomas
- Center for Temporomandibular Disorders and Orofacial Pain, Rutgers School of Dental Medicine, 110 Bergen Street, Newark, NJ 07103, USA; Orofacial Pain and Temporomandibular Disorders, Eastman Institute of Oral Health, Rochester, NY 14620, USA
| | - Junad Khan
- Orofacial Pain and Temporomandibular Disorders, Eastman Institute of Oral Health, Rochester, NY 14620, USA
| | - Sowmya Ananthan
- Center for Temporomandibular Disorders and Orofacial Pain, Rutgers School of Dental Medicine, 110 Bergen Street, Newark, NJ 07103, USA
| | - Mythili Kalladka
- Orofacial Pain and Temporomandibular Disorders, Eastman Institute of Oral Health, Rochester, NY 14620, USA.
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Proietti E, Rapallo F, Molinari E, Mucci V, Marinelli L, Borgarelli C, Burlando B, Pisciotta L, Demori I. Online Questionnaire with Fibromyalgia Patients Shows Negative Correlations between Disease Severity and Adherence to Mediterranean Diet. Nutrients 2024; 16:1078. [PMID: 38613111 PMCID: PMC11013287 DOI: 10.3390/nu16071078] [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: 03/11/2024] [Revised: 04/03/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
Fibromyalgia (FM) is a multidimensional disorder in which intense chronic pain is accompanied by a variety of psychophysical symptoms that impose a burden on the patients' quality of life. Despite the efforts and the recent advancement in research, FM pathogenesis and effective treatment remain unknown. Recently, the possible role of dietary patterns and/or components has been gaining attention. The current study aimed to investigate a potential correlation between adherence to the Mediterranean diet (MedDiet) and FM severity in a sample of Italian FM patients. An online survey was designed, composed of customized questions and validated questionnaires with the aim of investigating the intensity and type of pain, the presence of other psychophysical symptoms, the overall impact of FM, general food and lifestyle habits, and adherence to the MedDiet. The collected responses were analyzed for descriptive statistics, linear regression, and propensity score analyses. The results show that, despite considerable use of pharmaceuticals and supplements, FM participants suffered from a high-severity grade disease. However, those with good adherence to the MedDiet experienced a lower pain intensity and overall FM impact. A propensity score analysis indicates a positive influence of the MedDiet against FM severity, thus unveiling the need for well-designed intervention studies to evaluate the therapeutic potential of different dietary patterns.
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Affiliation(s)
- Elisa Proietti
- Department of Internal Medicine (DIMI), University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy; (E.P.); (C.B.); (L.P.)
| | - Fabio Rapallo
- Department of Economics (DIEC), University of Genova, Via Vivaldi, 5, 16126 Genova, Italy;
| | - Elena Molinari
- Clincal Psychology Center, Division of Neurology, E.O. Ospedali Galliera, Via Mura delle Cappuccine 14, 16128 Genova, Italy;
| | - Viviana Mucci
- School of Science, Western Sydney University, Penrith, NSW 2750, Australia;
| | - Lucio Marinelli
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Largo P. Daneo 3, 16132 Genova, Italy;
- IRCCS Ospedale Policlinico San Martino, Department of Neuroscience, Division of Clinical Neurophysiology, Largo R. Benzi 10, 16132 Genova, Italy
| | - Consuelo Borgarelli
- Department of Internal Medicine (DIMI), University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy; (E.P.); (C.B.); (L.P.)
| | - Bruno Burlando
- Department of Pharmacy (DIFAR), University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy;
| | - Livia Pisciotta
- Department of Internal Medicine (DIMI), University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy; (E.P.); (C.B.); (L.P.)
- IRCCS Ospedale Policlinico San Martino, Department of Internal Medicine, Operative Unit of Dietetics and Clinical Nutrition, Largo R. Benzi 10, 16132 Genova, Italy
| | - Ilaria Demori
- Department of Pharmacy (DIFAR), University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy;
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Kerzhner O, Berla E, Har-Even M, Ratmansky M, Goor-Aryeh I. Consistency of inconsistency in long-COVID-19 pain symptoms persistency: A systematic review and meta-analysis. Pain Pract 2024; 24:120-159. [PMID: 37475709 DOI: 10.1111/papr.13277] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/29/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023]
Abstract
INTRODUCTION Individuals recovering from acute COVID-19 episodes may continue to suffer from various ongoing symptoms, collectively referred to as Long-COVID. Long-term pain symptoms are amongst the most common and clinically significant symptoms to be reported for this post-COVID-19 syndrome. OBJECTIVES This systematic review and meta-analysis aimed to evaluate the proportions of persisting pain symptoms experienced by individuals past the acute phase of COVID-19 and to identify their associated functional consequences and inflammatory correlates. METHODS Two online databases were systematically searched from their inception until 31 March 2022. We searched primary research articles in English, which evaluated individuals after laboratory-confirmed COVID-19 acute phase resolution and specifically reported on pain symptoms and their inflammatory and/or functional outcomes. RESULTS Of the 611 identified articles, 26 were included, used for data extraction, and assessed for their methodological quality and risk of bias by two independent reviewers. Pain symptoms were grouped under one of six major pain domains, serving as our primary co-outcomes. Proportional meta-analyses of pooled logit-transformed values of single proportions were performed using the random-effects-restricted maximum-likelihood model. An estimated 8%, 6%, 18%, 18%, 17%, and 12% of individuals continued to report the persistence of chest, gastrointestinal, musculoskeletal joint, musculoskeletal muscle, general body, and nervous system-related pain symptoms, respectively, for up to one year after acute phase resolution of COVID-19. Considerable levels of heterogeneity were demonstrated across all results. Functional and quality-of-life impairments and some inflammatory biomarker elevations were associated with the persistence of long-COVID pain symptoms. CONCLUSION This study's findings suggest that although not well characterized, long-COVID pain symptoms are being experienced by non-negligible proportions of those recovering from acute COVID-19 episodes, thus highlighting the importance of future research efforts to focus on this aspect.
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Affiliation(s)
- Oleg Kerzhner
- Loewenstein Rehabilitation Medical Center, Ra'anana, Israel
| | - Einat Berla
- Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Meirav Har-Even
- Department of Anatomy and Anthropology, School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Motti Ratmansky
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pain Clinic, Sheba Medical Center, Ramat Gan, Israel
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Murray KJ, Villalta PW, Griffin TJ, Balbo S. Discovery of Modified Metabolites, Secondary Metabolites, and Xenobiotics by Structure-Oriented LC-MS/MS. Chem Res Toxicol 2023; 36:1666-1682. [PMID: 37862059 DOI: 10.1021/acs.chemrestox.3c00209] [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] [Indexed: 10/21/2023]
Abstract
Exogenous compounds and metabolites derived from therapeutics, microbiota, or environmental exposures directly interact with endogenous metabolic pathways, influencing disease pathogenesis and modulating outcomes of clinical interventions. With few spectral library references, the identification of covalently modified biomolecules, secondary metabolites, and xenobiotics is a challenging task using global metabolomics profiling approaches. Numerous liquid chromatography-coupled mass spectrometry (LC-MS) small molecule analytical workflows have been developed to curate global profiling experiments for specific compound groups of interest. These workflows exploit shared structural moiety, functional groups, or elemental composition to discover novel and undescribed compounds through nontargeted small molecule discovery pipelines. This Review introduces the concept of structure-oriented LC-MS discovery methodology and aims to highlight common approaches employed for the detection and characterization of covalently modified biomolecules, secondary metabolites, and xenobiotics. These approaches represent a combination of instrument-dependent and computational techniques to rapidly curate global profiling experiments to detect putative ions of interest based on fragmentation patterns, predictable phase I or phase II metabolic transformations, or rare elemental composition. Application of these methods is explored for the detection and identification of novel and undescribed biomolecules relevant to the fields of toxicology, pharmacology, and drug discovery. Continued advances in these methods expand the capacity for selective compound discovery and characterization that promise remarkable insights into the molecular interactions of exogenous chemicals with host biochemical pathways.
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Affiliation(s)
- Kevin J Murray
- Department of Biochemistry, Molecular Biology, and Biophysics, College of Biological Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Peter W Villalta
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Timothy J Griffin
- Department of Biochemistry, Molecular Biology, and Biophysics, College of Biological Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Silvia Balbo
- Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, United States
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
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Martín F, Blanco-Suárez M, Zambrano P, Cáceres O, Almirall M, Alegre-Martín J, Lobo B, González-Castro AM, Santos J, Domingo JC, Jurek J, Castro-Marrero J. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery. Front Immunol 2023; 14:1253121. [PMID: 37744357 PMCID: PMC10512706 DOI: 10.3389/fimmu.2023.1253121] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/25/2023] [Indexed: 09/26/2023] Open
Abstract
Background There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions. Methods A pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-β-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis. Results FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-β-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1β negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001). Conclusion Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.
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Affiliation(s)
- Franz Martín
- Andalusian Centre of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, Seville, Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Blanco-Suárez
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Paola Zambrano
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Oscar Cáceres
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Miriam Almirall
- Division of Rheumatology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - José Alegre-Martín
- Division of Rheumatology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Maria González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Joan Carles Domingo
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Joanna Jurek
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jesús Castro-Marrero
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
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Rusch JA, Layden BT, Dugas LR. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2023; 14:1130689. [PMID: 37404311 PMCID: PMC10316519 DOI: 10.3389/fendo.2023.1130689] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/25/2023] [Indexed: 07/06/2023] Open
Abstract
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
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Affiliation(s)
- Jody A. Rusch
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa
- C17 Chemical Pathology Laboratory, Groote Schuur Hospital, National Health Laboratory Service, Cape Town, South Africa
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States
| | - Lara R. Dugas
- Division of Epidemiology and Biostatistics, School of Public Health, University of Cape Town, Cape Town, South Africa
- Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, United States
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10
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Garofalo C, Cristiani CM, Ilari S, Passacatini LC, Malafoglia V, Viglietto G, Maiuolo J, Oppedisano F, Palma E, Tomino C, Raffaeli W, Mollace V, Muscoli C. Fibromyalgia and Irritable Bowel Syndrome Interaction: A Possible Role for Gut Microbiota and Gut-Brain Axis. Biomedicines 2023; 11:1701. [PMID: 37371796 DOI: 10.3390/biomedicines11061701] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Fibromyalgia (FM) is a serious chronic pain syndrome, characterised by muscle and joint stiffness, insomnia, fatigue, mood disorders, cognitive dysfunction, anxiety, depression and intestinal irritability. Irritable Bowel Syndrome (IBS) shares many of these symptoms, and FM and IBS frequently co-exist, which suggests a common aetiology for the two diseases. The exact physiopathological mechanisms underlying both FM and IBS onset are unknown. Researchers have investigated many possible causes, including alterations in gut microbiota, which contain billions of microorganisms in the human digestive tract. The gut-brain axis has been proven to be the link between the gut microbiota and the central nervous system, which can then control the gut microbiota composition. In this review, we will discuss the similarities between FM and IBS. Particularly, we will focus our attention on symptomatology overlap between FM and IBS as well as the similarities in microbiota composition between FM and IBS patients. We will also briefly discuss the potential therapeutic approaches based on microbiota manipulations that are successfully used in IBS and could be employed also in FM patients to relieve pain, ameliorate the rehabilitation outcome, psychological distress and intestinal symptoms.
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Affiliation(s)
- Cinzia Garofalo
- Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Costanza Maria Cristiani
- Department of Medical and Surgical Sciences, Neuroscience Research Center, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Sara Ilari
- Physiology and Pharmacology of Pain, IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - Lucia Carmela Passacatini
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | | | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Jessica Maiuolo
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Oppedisano
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Carlo Tomino
- Scientific Direction, IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - William Raffaeli
- Institute for Research on Pain, ISAL Foundation, Torre Pedrera, 47922 Rimini, Italy
| | - Vincenzo Mollace
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Carolina Muscoli
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
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11
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Alves MVS, Maciel LIL, Passos JOS, Morais CLM, Dos Santos MCD, Lima LAS, Vaz BG, Pegado R, Lima KMG. Spectrochemical approach combined with symptoms data to diagnose fibromyalgia through paper spray ionization mass spectrometry (PSI-MS) and multivariate classification. Sci Rep 2023; 13:4658. [PMID: 36949149 PMCID: PMC10033633 DOI: 10.1038/s41598-023-31565-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/14/2023] [Indexed: 03/24/2023] Open
Abstract
This study performs a chemical investigation of blood plasma samples from patients with and without fibromyalgia, combined with some of the symptoms and their levels of intensity used in the diagnosis of this disease. The symptoms evaluated were: visual analogue pain scale (VAS); fibromyalgia impact questionnaire (FIQ); Hamilton anxiety rating scale (HAM); Tampa Scale for Kinesiophobia (TAMPA); quality of life Questionnaire-physical and mental health (QL); and Pain Catastrophizing Scale (CAT). Plasma samples were analyzed by paper spray ionization mass spectrometry (PSI-MS). Spectral data were organized into datasets and related to each of the symptoms measured. The datasets were submitted to multivariate classification using supervised models such as principal component analysis with linear discriminant analysis (PCA-LDA), successive projections algorithm with linear discriminant analysis (SPA-LDA), genetic algorithm with linear discriminant analysis (GA-LDA) and their versions with quadratic discriminant analysis (PCA/SPA/GA-QDA) and support vector machines (PCA/SPA/GA-SVM). These algorithm combinations were performed aiming the best class separation. Good discrimination between the controls and fibromyalgia samples were observed using PCA-LDA, where the spectral data associated with the CAT symptom achieved 100% classification sensitivity, and associated with the VAS symptom achieved 100% classification specificity, with both symptoms at the moderate level of intensity. The spectral variable at 579 m/z was found to be substantially significant for classification according to the PCA loadings. According to the human metabolites database, this variable can be associated with a LysoPC compound, which comprises a class of metabolites already evidenced in other studies for fibromyalgia diagnosis. This study proposed an investigation of spectral data combined with clinical data to compare the classification ability of different datasets. The good classification results obtained confirm this technique is as a good analytical tool for the detection of fibromyalgia, and provides theoretical support for other studies about fibromyalgia diagnosis.
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Affiliation(s)
- Marcelo V S Alves
- Institute of Chemistry, Biological Chemistry and Chemometrics, Federal University of Rio Grande do Norte, Natal, 59072-970, Brazil
| | - Lanaia I L Maciel
- Institute of Chemistry, Federal University of Goiás, Samambaia St., Goiânia, GO, 74690-900, Brazil
| | - João O S Passos
- Health Sciences Center, Federal University of Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - Camilo L M Morais
- Institute of Chemistry, Biological Chemistry and Chemometrics, Federal University of Rio Grande do Norte, Natal, 59072-970, Brazil
| | - Marfran C D Dos Santos
- Federal Institute of Education, Science and Technology of Sertão Pernambucano, Floresta, Brazil
| | - Leomir A S Lima
- Estácio de Sá Goiás, North Regional, Goiânia, GO, 74063-010, Brazil
| | - Boniek G Vaz
- Institute of Chemistry, Federal University of Goiás, Samambaia St., Goiânia, GO, 74690-900, Brazil
| | - Rodrigo Pegado
- Health Sciences Center, Federal University of Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - Kássio M G Lima
- Institute of Chemistry, Biological Chemistry and Chemometrics, Federal University of Rio Grande do Norte, Natal, 59072-970, Brazil.
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12
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Moreau C, El Habnouni C, Lecron JC, Morel F, Delwail A, Le Gall-Ianotto C, Le Garrec R, Misery L, Piver E, Vaillant L, Lefevre A, Emond P, Blasco H, Samimi M. Salivary metabolome indicates a shift in tyrosine metabolism in patients with burning mouth syndrome: a prospective case-control study. Pain 2023; 164:e144-e156. [PMID: 35916738 DOI: 10.1097/j.pain.0000000000002733] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/31/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT The pathophysiology of primary burning mouth syndrome (BMS) remains controversial. Targeted analyses or "omics" approach of saliva provide diagnostic or pathophysiological biomarkers. This pilot study's primary objective was to explore the pathophysiology of BMS through a comparative analysis of the salivary metabolome among 26 BMS female cases and 25 age- and sex-matched control subjects. Secondary objectives included comparative analyses of inflammatory cytokines, neuroinflammatory markers, and steroid hormones among cases and control subjects, and among BMS patients according to their clinical characteristics. Salivary metabolome, neuroinflammatory markers, cytokines, and steroids were, respectively, analysed by liquid chromatography coupled with mass spectrometry, ELISA and protease activity assay, and multiparametric Luminex method. Among the 166 detected metabolites, univariate analysis did not find any discriminant metabolite between groups. Supervised multivariate analysis divided patients into 2 groups with an accuracy of 60% but did not allow significant discrimination (permutation test, P = 0.35). Among the metabolites contributing to the model, 3 belonging to the tyrosine pathway ( l -dopa, l -tyrosine, and tyramine) were involved in the discrimination between cases and control subjects, and among BMS patients according to their levels of pain. Among the detectable molecules, levels of cytokines, steroid hormones, and neuroinflammatory markers did not differ between cases and control subjects and were not associated with characteristics of BMS patients. These results do not support the involvement of steroid hormones, inflammatory cytokines, or inflammatory neurogenic mediators in the pathophysiology of pain in BMS, whereas the observed shift in tyrosine metabolism may indicate an adaptative response to chronic pain or an impaired dopaminergic transmission.
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Affiliation(s)
- Charlotte Moreau
- University François Rabelais, Tours, France
- Department of Dermatology, University Hospital of Tours, Tours Cedex, France
| | - Chakib El Habnouni
- University François Rabelais, Tours, France
- Department of Dermatology, University Hospital of Tours, Tours Cedex, France
| | - Jean-Claude Lecron
- Laboratory Inflammation, Tissus Epithéliaux et Cytokines, Poitiers University and Immunology/inflammation Laboratory, Poitiers University Hospital, Poitiers, France
| | - Franck Morel
- Laboratory Inflammation, Tissus Epithéliaux et Cytokines, Poitiers University and Immunology/inflammation Laboratory, Poitiers University Hospital, Poitiers, France
| | - Adriana Delwail
- ImageUP, Plate-forme d'Imagerie and Laboratoire Signalisation et Transport Ioniques Membranaires ERL CNRS 7003/EA 7349, Poitiers University, Poitiers, France
| | | | - Raphaele Le Garrec
- Univ Brest, LIEN (Laboratoire Interactions Epithelium Neurones), Brest, France
| | - Laurent Misery
- Univ Brest, LIEN (Laboratoire Interactions Epithelium Neurones), Brest, France
| | - Eric Piver
- Department of Biochemistry and Molecular Biology, University Hospital of Tours, Tours Cedex, France
- Inserm UMR 1259-Morphogenèse et antigénicité du VIH et des virus des hépatites (MAVIVH)
| | - Loïc Vaillant
- University François Rabelais, Tours, France
- Department of Dermatology, University Hospital of Tours, Tours Cedex, France
| | | | - Patrick Emond
- UMR 1253 iBrain, Université de Tours, Inserm, Tours, France
- Department of In Vitro Nuclear Medicine, University Hospital of Tours, Tours Cedex, France
| | - Hélène Blasco
- Department of Biochemistry and Molecular Biology, University Hospital of Tours, Tours Cedex, France
- UMR 1253 iBrain, Université de Tours, Inserm, Tours, France
| | - Mahtab Samimi
- University François Rabelais, Tours, France
- Department of Dermatology, University Hospital of Tours, Tours Cedex, France
- BIP, 1282 INRA University of Tours, Tours, France
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13
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Kulshreshtha P, Deepak KK. Personality construct as a biomarker in fibromyalgia: A narrative review from an autonomic rehabilitation perspective. J Back Musculoskelet Rehabil 2023; 36:1251-1260. [PMID: 37482976 DOI: 10.3233/bmr-220353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
BACKGROUND The heterogeneity of symptoms and ineffective treatment raise questions about the current diagnostic criteria of fibromyalgia (FM). Misdiagnosis of FM often leads to less than efficacious treatment and poor quality of life. OBJECTIVE This article reviews relevant evidence-based literature on personality traits in FM patients with an autonomic dysfunction perspective based on a hierarchical model to explain the utility of considering the personality trait in FM diagnosis. METHODS A narrative review of articles concerning chronic pain, FM, and personality traits with respect to autonomic dysfunction in FM was conducted after extensive relevant literature searches. RESULTS Reports discussing the predisposing factors, including coping styles, anger, suicide risk, a lack of physical activity and social support, in maintaining persistent pain in FM exist. Relationships between pain duration and severity and personality traits like neuroticism and extraversion have been reported. Coexisting clinical manifestations of FM like sleep disorders, anxiety, and intestinal irritability indicate autonomic dysfunction. CONCLUSIONS This article lays out a constructive framework for individualized and personalized medicine for the effective rehabilitation of FM patients. The quest to find a definitive diagnosis of FM should include personality biomarkers that might translate into personalized medicine. An individualistic approach may bank upon artificial intelligence algorithms for both diagnostic as well as prognostic purposes in FM.
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14
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Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain. Int J Mol Sci 2022; 23:ijms23158274. [PMID: 35955410 PMCID: PMC9368269 DOI: 10.3390/ijms23158274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 12/26/2022] Open
Abstract
The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.
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15
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Baldi S, Pagliai G, Dinu M, Di Gloria L, Nannini G, Curini L, Pallecchi M, Russo E, Niccolai E, Danza G, Benedettelli S, Ballerini G, Colombini B, Bartolucci G, Ramazzotti M, Sofi F, Amedei A. Effect of ancient Khorasan wheat on gut microbiota, inflammation, and short-chain fatty acid production in patients with fibromyalgia. World J Gastroenterol 2022; 28:1965-1980. [PMID: 35664958 PMCID: PMC9150053 DOI: 10.3748/wjg.v28.i18.1965] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/19/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) syndrome is mainly characterized by widespread pain, sleeping disorders, fatigue, and cognitive dysfunction. In many cases, gastrointestinal distress is also reported, suggesting the potential pathogenic role of the gut microbiota (GM). The GM is deeply influenced by several environmental factors, especially the diet, and recent findings highlighted significant symptom improvement in FM patients following various nutritional interventions such as vegetarian diet, low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols based diets, gluten-free diet, and especially an ancient grain supplementation. In particular, a recent study reported that a replacement diet with ancient Khorasan wheat led to an overall improvement in symptom severity of FM patients.
AIM To examine the effects of ancient Khorasan wheat on the GM, inflammation, and short-chain fatty acid production in FM patients.
METHODS After a 2-wk run-in period, 20 FM patients were enrolled in this randomized, double-blind crossover trial. In detail, they were assigned to consume either Khorasan or control wheat products for 8 wk and then, following an 8-wk washout period, crossed. Before and after treatments, GM characterization was performed by 16S rRNA sequencing while the fecal molecular inflammatory response and the short-chain fatty acids (SCFAs) were respectively determined with the Luminex MAGPIX detection system and a mass chromatography-mass spectrometry method.
RESULTS The Khorasan wheat replacement diet, in comparison with the control wheat diet, had more positive effects on intestinal microbiota composition and on both the fecal immune and SCFAs profiles such as the significant increase of butyric acid levels (P = 0.054), candidatus Saccharibacteria (P = 9.95e-06) and Actinobacteria, and the reduction of Enterococcaceae (P = 4.97e-04). Moreover, the improvement of various FM symptoms along with the variation of some gut bacteria after the Khorasan wheat diet have been documented; in fact we reported positive correlations between Actinobacteria and both Tiredness Symptoms Scale (P < 0.001) and Functional Outcome of Sleep Questionnaire (P < 0.05) scores, between Verrucomicrobiae and both Widespread Pain Index (WPI) + Symptom Severity scale (SS) (P < 0.05) and WPI (P < 0.05) scores, between candidatus Saccharibacteria and SS score (P < 0.05), and between Bacteroidales and Sleep-Related and Safety Behaviour Questionnaire score (P < 0.05).
CONCLUSION The replacement diet based on ancient Khorasan wheat results in beneficial GM compositional and functional modifications that positively correlate with an improvement of FM symptomatology.
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Affiliation(s)
- Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giuditta Pagliai
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Monica Dinu
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Leandro Di Gloria
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Lavinia Curini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Marco Pallecchi
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino 50019, Italy
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giovanna Danza
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Stefano Benedettelli
- Department of Agriculture, Food, Environment and Forestry, University of Florence, Florence 50144, Italy
| | - Giovanna Ballerini
- Multidisciplinary Center for Pain Therapy, Reference Center for Fibromyalgia, Piero Palagi Hospital, USL Toscana Centro, Florence 50122, Italy
| | - Barbara Colombini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gianluca Bartolucci
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino 50019, Italy
| | - Matteo Ramazzotti
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Francesco Sofi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Careggi University Hospital, Florence 50134, Italy
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16
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Piras C, Pintus BM, Noto A, Evangelista M, Fanos V, Musu M, Mussap M, Atzori L, Sardo S, Finco G. Metabolomics and Microbiomics: New Potential Strategies in Chronic Pain Syndrome. J Pain Res 2022; 15:723-731. [PMID: 35310896 PMCID: PMC8923834 DOI: 10.2147/jpr.s354516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/02/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
| | - Bruno Maria Pintus
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Antonio Noto
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
- Correspondence: Antonio Noto, Email
| | - Maurizio Evangelista
- Department of Anesthesiology and Pain Medicine, Cattolica University, Rome, 00168, Italy
| | - Vassilios Fanos
- Department of Surgical Science, University of Cagliari, Monserrato, 09042, Italy
| | - Mario Musu
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Michele Mussap
- Department of Surgical Science, University of Cagliari, Monserrato, 09042, Italy
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
| | - Salvatore Sardo
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Gabriele Finco
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
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17
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Alves MVS, Maciel LIL, Ramalho RRF, Lima LAS, Vaz BG, Morais CLM, Passos JOS, Pegado R, Lima KMG. Multivariate classification techniques and mass spectrometry as a tool in the screening of patients with fibromyalgia. Sci Rep 2021; 11:22625. [PMID: 34799667 PMCID: PMC8604931 DOI: 10.1038/s41598-021-02141-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/29/2021] [Indexed: 11/09/2022] Open
Abstract
Fibromyalgia is a rheumatological disorder that causes chronic pain and other symptomatic conditions such as depression and anxiety. Despite its relevance, the disease still presents a complex diagnosis where the doctor needs to have a correct clinical interpretation of the symptoms. In this context, it is valid to study tools that assist in the screening of this disease, using chemical work techniques such as mass spectroscopy. In this study, an analytical method is proposed to detect individuals with fibromyalgia (n = 20, 10 control samples and 10 samples with fibromyalgia) from blood plasma samples analyzed by mass spectrometry with paper spray ionization and subsequent multivariate classification of the spectral data (unsupervised and supervised), in addition to the treatment of selected variables with possible associations with metabolomics. Exploratory analysis with principal component analysis (PCA) and supervised analysis with successive projections algorithm with linear discriminant analysis (SPA-LDA) showed satisfactory results with 100% accuracy for sample prediction in both groups. This demonstrates that this combination of techniques can be used as a simple, reliable and fast tool in the development of clinical diagnosis of Fibromyalgia.
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Affiliation(s)
- Marcelo V S Alves
- Institute of Chemistry, Biological Chemistry and Chemometrics, Federal University of Rio Grande do Norte, Natal, 59072-970, Brazil
| | - Lanaia I L Maciel
- Institute of Chemistry, Federal University of Goiás, Samambaia St., Goiânia, GO, 74690-900, Brazil
| | - Ruver R F Ramalho
- Institute of Chemistry, Federal University of Goiás, Samambaia St., Goiânia, GO, 74690-900, Brazil
| | - Leomir A S Lima
- Estácio de Sá Goiás, North Regional, Goiânia, GO, 74063-010, Brazil
| | - Boniek G Vaz
- Institute of Chemistry, Federal University of Goiás, Samambaia St., Goiânia, GO, 74690-900, Brazil
| | - Camilo L M Morais
- School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, UK
| | - João O S Passos
- Postgraduation Program in Rehabilitation Sciences, Faculty of Health Science of Trairí, Federal University of Rio Grande do Norte, Trairí St., Santa Cruz, RN, 59200-000, Brazil
| | - Rodrigo Pegado
- Postgraduation Program in Rehabilitation Sciences, Faculty of Health Science of Trairí, Federal University of Rio Grande do Norte, Trairí St., Santa Cruz, RN, 59200-000, Brazil
| | - Kássio M G Lima
- Institute of Chemistry, Biological Chemistry and Chemometrics, Federal University of Rio Grande do Norte, Natal, 59072-970, Brazil.
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18
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Hsu WH, Han DS, Ku WC, Chao YM, Chen CC, Lin YL. Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia. Eur J Pain 2021; 26:445-462. [PMID: 34608709 PMCID: PMC9298249 DOI: 10.1002/ejp.1871] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/16/2021] [Accepted: 10/03/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fibromyalgia (FM) is characterized by chronic widespread pain. Its pathophysiological mechanisms remain poorly understood, and effective diagnosis and treatments are lacking. This study aimed to identify significantly changed biosignatures in FM and propose a novel classification for FM based on pain and soreness (sng) symptoms. METHODS Urine and serum samples from 30 FM patients and 25 controls underwent metabolomic and proteomic profiling. RESULTS Compared with controls, FM patients showed significant differential expression of three metabolites in urine and five metabolites and eight proteins in serum. Of them, DETP, 4-guanidinobutanoic acid, SM(d18:1/18:0), PC(20:1(11Z)/18:0), S100A7, SERPINB3, galectin-7 and LYVE1 were first reported as potential biomarkers for FM. Furthermore, lactate, 2-methylmaleate and cotinine in urine and lactate, SM(d18:1/25:1), SM(d18:1/26:1) and prostaglandin D2 (PGD2) and PCYOX1, ITIH4, PFN1, LRG1, C8G, C8A, CP, CDH5 and DBH in serum could differentiate pain- (PG) and sng-dominant groups (SG). Lactate, 2-methylmaleate, cotinine, PCYOX1, ITIH4, PFN1 and DBH have a higher level in SG. SM(d18:1/25:1), SM(d18:1/26:1), PGD2, LRG1, C8G, C8A, CP and CDH5 in SG are lower than PG. The omics results indicated disordered free radical scavenging, and lipid and amino acid metabolism networks and resulting NF-κB-dependent cytokine generation in FM. Lactate level was altered simultaneously in urine and serum and significantly higher in sng-dominant patients than others. CONCLUSIONS In this study, we identified potential biomarkers from FM patients. The selected biomarkers could discriminate sng and pain phenotypes in FM patients. These results could help elucidate the underlying pathological mechanisms for more effective diagnosis and therapy for FM.
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Affiliation(s)
- Wei-Hsiang Hsu
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
| | - Der-Sheng Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan.,Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan.,Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan.,Health Science and Wellness Center, National Taiwan University, Taipei, Taiwan
| | - Wei-Chi Ku
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Yen-Ming Chao
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.,Taiwan Mouse Clinic, Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
| | - Yun-Lian Lin
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.,Department of Pharmacy, National Taiwan University, Taipei, Taiwan
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19
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Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. World J Stem Cells 2021; 13:1134-1150. [PMID: 34567431 PMCID: PMC8422931 DOI: 10.4252/wjsc.v13.i8.1134] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/19/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these “plasma factors”, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.
AIM To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.
METHODS A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms “metabolomic” or “metabolites” in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.
RESULTS Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.
CONCLUSION This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.
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Affiliation(s)
- María B Monzón-Nomdedeu
- School of Biotechnology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
| | - Karl J Morten
- Nuffield Department of Women's and Reproductive Health, The Women Centre, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Elisa Oltra
- Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
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20
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Brenner D, Cherry P, Switzer T, Butt I, Stanton C, Murphy K, McNamara B, Iohom G, O'Mahony SM, Shorten G. Pain after upper limb surgery under peripheral nerve block is associated with gut microbiome composition and diversity. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2021; 10:100072. [PMID: 34485761 PMCID: PMC8404729 DOI: 10.1016/j.ynpai.2021.100072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 07/30/2021] [Accepted: 08/12/2021] [Indexed: 01/17/2023]
Abstract
Gut microbiota play a role in certain pain states. Hence, these microbiota also influence somatic pain. We aimed to determine if there was an association between gut microbiota (composition and diversity) and postoperative pain. Patients (n = 20) undergoing surgical fixation of distal radius fracture under axillary brachial plexus block were studied. Gut microbiota diversity and abundance were analysed for association with: (i) a verbal pain rating scale of < 4/10 throughout the first 24 h after surgery (ii) a level of pain deemed "acceptable" by the patient during the first 24 h following surgery (iii) a maximum self-reported pain score during the first 24 h postoperatively and (iv) analgesic consumption during the first postoperative week. Analgesic consumption was inversely correlated with the Shannon index of alpha diversity. There were also significant differences, at the genus level (including Lachnospira), with respect to pain being "not acceptable" at 24 h postoperatively. Porphyromonas was more abundant in the group reporting an acceptable pain level at 24 h. An inverse correlation was noted between abundance of Collinsella and maximum self-reported pain score with movement. We have demonstrated for the first time that postoperative pain is associated with gut microbiota composition and diversity. Further work on the relationship between the gut microbiome and somatic pain may offer new therapeutic targets.
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Affiliation(s)
- David Brenner
- Department of Anesthesia and Intensive Care Medicine, Cork University
Hospital and University College Cork, Ireland
| | - Paul Cherry
- Teagasc Food Research Centre, Moorepark, Fermoy, County Cork,
Ireland
- APC Microbiome Ireland, University College Cork, Ireland
| | - Tim Switzer
- Department of Anesthesia and Intensive Care Medicine, Cork University
Hospital and University College Cork, Ireland
| | - Ihsan Butt
- Department of Anesthesia and Intensive Care Medicine, Cork University
Hospital and University College Cork, Ireland
| | - Catherine Stanton
- Teagasc Food Research Centre, Moorepark, Fermoy, County Cork,
Ireland
- APC Microbiome Ireland, University College Cork, Ireland
| | - Kiera Murphy
- Teagasc Food Research Centre, Moorepark, Fermoy, County Cork,
Ireland
| | - Brian McNamara
- Department of Clinical Neurophysiology Cork University Hospital,
Ireland
| | - Gabriella Iohom
- Department of Anesthesia and Intensive Care Medicine, Cork University
Hospital and University College Cork, Ireland
| | - Siobhain M. O'Mahony
- APC Microbiome Ireland, University College Cork, Ireland
- Department of Anatomy and Neuroscience University College Cork,
Ireland
| | - George Shorten
- Department of Anesthesia and Intensive Care Medicine, Cork University
Hospital and University College Cork, Ireland
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21
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Marino C, Grimaldi M, Sabatini P, Amato P, Pallavicino A, Ricciardelli C, D’Ursi AM. Fibromyalgia and Depression in Women: An 1H-NMR Metabolomic Study. Metabolites 2021; 11:429. [PMID: 34209136 PMCID: PMC8304744 DOI: 10.3390/metabo11070429] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/15/2021] [Accepted: 06/23/2021] [Indexed: 12/18/2022] Open
Abstract
Fibromyalgia is a chronic and systemic syndrome characterized by muscle, bone, and joint pain. It is a gender-specific condition with a 9:1 incidence ratio between women and men. Fibromyalgia is frequently associated with psychic disorders affecting the cognitive and emotional spheres. In the reported work, we compared 31 female fibromyalgia patients to 31 female healthy controls. They were analyzed for biochemical clinical parameters, for autoimmune markers, and were subjected to 1H-NMR metabolomics analysis. To identify a correlation between the metabolomic profile and the psychic condition, a subset of 19 fibromyalgia patients was subjected to HAM-A and HAM-D Hamilton depression tests. Multivariate statistical analysis showed the dysmetabolism of several metabolites involved in energy balance that are associated with systemic inflammatory conditions. The severity of depression worsens dysmetabolic conditions; conversely, glycine and glutamate, known for their critical role as neuromodulators, appear to be potential biomarkers of fibromyalgia and are associated with different severity depression conditions.
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Affiliation(s)
- Carmen Marino
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Manuela Grimaldi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Paola Sabatini
- U.O.C. Clinical Pathology D.E.A. III Umberto I, Viale S. Francesco D’Assisi, 84014 Nocera Inferiore, Italy;
| | - Patrizia Amato
- ASL Ser. T Cava de’ Tirreni, Piazza Matteo Galdi 1/3, 84013 Pregiato, Italy;
| | - Arianna Pallavicino
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Carmen Ricciardelli
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Anna Maria D’Ursi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
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22
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Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int J Mol Sci 2021; 22:ijms22083891. [PMID: 33918736 PMCID: PMC8068842 DOI: 10.3390/ijms22083891] [Citation(s) in RCA: 239] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Fibromyalgia is a syndrome characterized by chronic and widespread musculoskeletal pain, often accompanied by other symptoms, such as fatigue, intestinal disorders and alterations in sleep and mood. It is estimated that two to eight percent of the world population is affected by fibromyalgia. From a medical point of view, this pathology still presents inexplicable aspects. It is known that fibromyalgia is caused by a central sensitization phenomenon characterized by the dysfunction of neuro-circuits, which involves the perception, transmission and processing of afferent nociceptive stimuli, with the prevalent manifestation of pain at the level of the locomotor system. In recent years, the pathogenesis of fibromyalgia has also been linked to other factors, such as inflammatory, immune, endocrine, genetic and psychosocial factors. A rheumatologist typically makes a diagnosis of fibromyalgia when the patient describes a history of pain spreading in all quadrants of the body for at least three months and when pain is caused by digital pressure in at least 11 out of 18 allogenic points, called tender points. Fibromyalgia does not involve organic damage, and several diagnostic approaches have been developed in recent years, including the analysis of genetic, epigenetic and serological biomarkers. Symptoms often begin after physical or emotional trauma, but in many cases, there appears to be no obvious trigger. Women are more prone to developing the disease than men. Unfortunately, the conventional medical therapies that target this pathology produce limited benefits. They remain largely pharmacological in nature and tend to treat the symptomatic aspects of various disorders reported by the patient. The statistics, however, highlight the fact that 90% of people with fibromyalgia also turn to complementary medicine to manage their symptoms.
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23
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Livshits G, Kalinkovich A. Specialized, pro-resolving mediators as potential therapeutic agents for alleviating fibromyalgia symptomatology. PAIN MEDICINE 2021; 23:977-990. [PMID: 33565588 DOI: 10.1093/pm/pnab060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To present a hypothesis on a novel strategy in the treatment of fibromyalgia (FM). DESIGN A narrative review. SETTING FM as a disease remains a challenging concept for numerous reasons, including undefined etiopathogenesis, unclear triggers and unsuccessful treatment modalities. We hypothesize that the inflammatome, the entire set of molecules involved in inflammation, acting as a common pathophysiological instrument of gut dysbiosis, sarcopenia, and neuroinflammation, is one of the major mechanisms underlying FM pathogenesis. In this setup, dysbiosis is proposed as the primary trigger of the inflammatome, sarcopenia as the peripheral nociceptive source, and neuroinflammation as the central mechanism of pain sensitization, transmission and symptomatology of FM. Whereas neuroinflammation is highly-considered as a critical deleterious element in FM pathogenesis, the presumed pathogenic roles of sarcopenia and systemic inflammation remain controversial. Nevertheless, sarcopenia-associated processes and dysbiosis have been recently detected in FM individuals. The prevalence of pro-inflammatory factors in the cerebrospinal fluid and blood has been repeatedly observed in FM individuals, supporting an idea on the role of inflammatome in FM pathogenesis. As such, failed inflammation resolution might be one of the underlying pathogenic mechanisms. In accordance, the application of specialized, inflammation pro-resolving mediators (SPMs) seems most suitable for this goal. CONCLUSIONS The capability of various SPMs to prevent and attenuate pain has been repeatedly demonstrated in laboratory animal experiments. Since SPMs suppress inflammation in a manner that does not compromise host defense, they could be attractive and safe candidates for the alleviation of FM symptomatology, probably in combination with anti-dysbiotic medicine.
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Affiliation(s)
- Gregory Livshits
- Adelson School of Medicine, Ariel University, Ariel, Israel.,Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Alexander Kalinkovich
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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24
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Erdrich S, Hawrelak JA, Myers SP, Harnett JE. A systematic review of the association between fibromyalgia and functional gastrointestinal disorders. Therap Adv Gastroenterol 2020; 13:1756284820977402. [PMID: 33343707 PMCID: PMC7727037 DOI: 10.1177/1756284820977402] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/09/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Fibromyalgia and functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS) are common conditions presenting in clinical settings and are more prevalent in women. While the relationship between IBS and fibromyalgia has been demonstrated, a review of the prevalence of the broader group of FGID in adults with fibromyalgia has not been undertaken. The aim of this review was to systematically review the published literature, identifying the comorbidity of FGID in people with fibromyalgia, and to discuss the clinical implications, limitations of current research and areas of interest for future research. METHODS Medline, Embase, CINAHL and Web of Science were searched during June 2019. Results were screened for original research articles meeting established criteria for identification of FGID in adults diagnosed with fibromyalgia. RESULTS A total of 14 studies involving 1340 adults with fibromyalgia, 363 healthy controls and 441 adults with other pathologies were included in this review. Only 1 of the 14 studies included surveyed the full range of FGID . Functional gut disorders were matched to Rome II criteria for reporting and comparison. In addition to increased abdominal pain and functional bloating or gas, IBS of mixed-pattern and constipation-types appear to be more prevalent than diarrhoea-predominant IBS in adults with fibromyalgia. CONCLUSION This review confirms previous reports that IBS is common in people living with fibromyalgia and suggests that IBS-mixed and constipation types predominate. An association with a range of FGID other than IBS is suggested, but data are limited. Research exploring the association between fibromyalgia and functional gastrointestinal dysfunction beyond IBS are warranted.
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Affiliation(s)
- Sharon Erdrich
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Science Road, Camperdown, Sydney, New South Wales 2006, Australia
| | - Jason A. Hawrelak
- College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Stephen P. Myers
- NatMed Research Unit, Office of the Deputy Vice Chancellor (Research), Southern Cross University, Lismore, New South Wales, Australia
| | - Joanna E. Harnett
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia
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25
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Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance. J Clin Med 2020; 9:jcm9113527. [PMID: 33142767 PMCID: PMC7693920 DOI: 10.3390/jcm9113527] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/14/2022] Open
Abstract
In fibromyalgia (FM) muscle metabolism, studies are sparse and conflicting associations have been found between muscle metabolism and pain aspects. This study compared alterations in metabolic substances and blood flow in erector spinae and trapezius of FM patients and healthy controls. FM patients (n = 33) and healthy controls (n = 31) underwent a clinical examination that included pressure pain thresholds and physical tests, completion of a health questionnaire, participation in microdialysis investigations of the etrapezius and erector spinae muscles, and also underwent phosphorus-31 magnetic resonance spectroscopy of the erector spinae muscle. At the baseline, FM had significantly higher levels of pyruvate in both muscles. Significantly lower concentrations of phosphocreatine (PCr) and nucleotide triphosphate (mainly adenosine triphosphate) in erector spinae were found in FM. Blood flow in erector spinae was significantly lower in FM. Significant associations between metabolic variables and pain aspects (pain intensity and pressure pain threshold PPT) were found in FM. Our results suggest that FM has mitochondrial dysfunction, although it is unclear whether inactivity, obesity, aging, and pain are causes of, the results of, or coincidental to the mitochondrial dysfunction. The significant regressions of pain intensity and PPT in FM agree with other studies reporting associations between peripheral biological factors and pain aspects.
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26
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Teckchandani S, Nagana Gowda GA, Raftery D, Curatolo M. Metabolomics in chronic pain research. Eur J Pain 2020; 25:313-326. [PMID: 33065770 DOI: 10.1002/ejp.1677] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/22/2020] [Accepted: 10/11/2020] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND OBJECTIVE Metabolomics deals with the identification and quantification of small molecules (metabolites) in biological samples. As metabolite levels can reflect normal or altered metabolic pathways, their measurement provides information to improve the understanding, diagnosis and management of diseases. Despite its immense potential, metabolomics applications to pain research have been sparse. This paper describes current metabolomics techniques, reviews published human metabolomics pain research and compares successful metabolomics research in other areas of medicine with the goal of highlighting opportunities offered by metabolomics to advance pain medicine. DATABASES AND DATA TREATMENT Non-systematic review. RESULTS Our search identified 19 studies that adopted a metabolomics approach in: fibromyalgia (7), chronic widespread pain (4), other musculoskeletal pain conditions (5), neuropathic pain (1), complex regional pain syndrome (1) and pelvic pain (1). The studies used either mass spectrometry or nuclear magnetic resonance. Most are characterized by small sample sizes. Some consistency has been found for alterations in glutamate and testosterone metabolism, and metabolic imbalances caused by the gut microbiome. CONCLUSIONS Metabolomics research in chronic pain is in its infancy. Most studies are at the pilot stage. Metabolomics research has been successful in other areas of medicine. These achievements should motivate investigators to expand metabolomics research to improve the understanding of the basic mechanisms of human pain, as well as provide tools to diagnose, predict and monitor chronic pain conditions. Metabolomics research can lead to the identification of biomarkers to support the development and testing of treatments, thereby facilitating personalized pain medicine.
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Affiliation(s)
- Shweta Teckchandani
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA
| | - G A Nagana Gowda
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Daniel Raftery
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Michele Curatolo
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA.,CLEAR Research Center for Musculoskeletal Disorders, University of Washington, Seattle, WA, USA
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27
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Wåhlén K, Ernberg M, Kosek E, Mannerkorpi K, Gerdle B, Ghafouri B. Significant correlation between plasma proteome profile and pain intensity, sensitivity, and psychological distress in women with fibromyalgia. Sci Rep 2020; 10:12508. [PMID: 32719459 PMCID: PMC7385654 DOI: 10.1038/s41598-020-69422-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/10/2020] [Indexed: 12/29/2022] Open
Abstract
Fibromyalgia (FM) is a complex pain condition where the pathophysiological and molecular mechanisms are not fully elucidated. The primary aim of this study was to investigate the plasma proteome profile in women with FM compared to controls. The secondary aim was to investigate if plasma protein patterns correlate with the clinical variables pain intensity, sensitivity, and psychological distress. Clinical variables/background data were retrieved through questionnaires. Pressure pain thresholds (PPT) were assessed using an algometer. The plasma proteome profile of FM (n = 30) and controls (n = 32) was analyzed using two-dimensional gel electrophoresis and mass spectrometry. Quantified proteins were analyzed regarding group differences, and correlations to clinical parameters in FM, using multivariate statistics. Clear significant differences between FM and controls were found in proteins involved in inflammatory, metabolic, and immunity processes. Pain intensity, PPT, and psychological distress in FM had associations with specific plasma proteins involved in blood coagulation, metabolic, inflammation and immunity processes. This study further confirms that systemic differences in protein expression exist in women with FM compared to controls and that altered levels of specific plasma proteins are associated with different clinical parameters.
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Affiliation(s)
- Karin Wåhlén
- Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Malin Ernberg
- Department of Dental Medicine, Karolinska Institutet and Scandinavian Center for Orofacial Neurosciences (SCON), 141 04, Huddinge, Sweden
| | - Eva Kosek
- Department of Clinical Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Kaisa Mannerkorpi
- Department of Health and Rehabilitation/Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
| | - Björn Gerdle
- Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Bijar Ghafouri
- Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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28
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Aroke EN, Powell-Roach KL. The Metabolomics of Chronic Pain Conditions: A Systematic Review. Biol Res Nurs 2020; 22:458-471. [PMID: 32666804 DOI: 10.1177/1099800420941105] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Chronic pain is a significant public health problem in the United States, affecting approximately 100 million people. Yet there is a lack of robust biomarkers for clinical use in chronic pain conditions. Downstream effects of environmental, genomic, and proteomic variations in individuals with chronic pain conditions can be identified and quantified using a metabolomic approach. AIM/DESIGN The purpose of this systematic review was to examine the literature for reports of potential metabolomic signatures associated with chronic pain conditions. METHODS We searched relevant electronic databases for published studies that used various metabolomic approaches to investigate chronic pain conditions among subjects of all ages. RESULTS Our search identified a total of 586 articles, 18 of which are included in this review. The reviewed studies used metabolomics to investigate fibromyalgia (n = 5), osteoarthritis (n = 4), migraine (n = 3), musculoskeletal pain (n = 2), and other chronic pain conditions (n = 1/condition). Results show that several known and newly identified metabolites differ in individuals with chronic pain conditions compared to those without these conditions. These include amino acids (e.g., glutamine, serine, and phenylalanine) and intermediate products (e.g., succinate, citrate, acetylcarnitine, and N-acetylornithine) of pathways that metabolize various macromolecules. CONCLUSION Though more high-quality research is needed, this review provides insights into potential biomarkers for future metabolomics studies in people with chronic pain conditions.
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Affiliation(s)
- Edwin N Aroke
- School of Nursing, University of Alabama at Birmingham, AL, USA
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29
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Miller JS, Rodriguez-Saona L, Hackshaw KV. Metabolomics in Central Sensitivity Syndromes. Metabolites 2020; 10:E164. [PMID: 32344505 PMCID: PMC7240948 DOI: 10.3390/metabo10040164] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/11/2020] [Accepted: 04/19/2020] [Indexed: 01/09/2023] Open
Abstract
Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse. Although these disorders cause significant morbidity, they frequently lack reliable diagnostic tests. As such, technologies that can identify key moieties in central sensitization disorders may contribute to the identification of novel therapeutic targets and more precise treatment options. The analysis of small molecules in biological samples through metabolomics has improved greatly and may be the technology needed to identify key moieties in difficult to diagnose diseases. In this review, we discuss the current state of metabolomics as it relates to central sensitization disorders. From initial literature review until Feb 2020, PubMed, Embase, and Scopus were searched for applicable studies. We included cohort studies, case series, and interventional studies of both adults and children affected by central sensitivity syndromes. The majority of metabolomic studies addressing a CSS found significantly altered metabolites that allowed for differentiation of CSS patients from healthy controls. Therefore, the published literature overwhelmingly supports the use of metabolomics in CSS. Further research into these altered metabolites and their respective metabolic pathways may provide more reliable and effective therapeutics for these syndromes.
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Affiliation(s)
- Joseph S. Miller
- Department of Medicine, Ohio University Heritage College of Osteopathic Medicine, Dublin, OH 43016, USA;
| | - Luis Rodriguez-Saona
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA;
| | - Kevin V. Hackshaw
- Department of Internal Medicine, Division of Rheumatology, Dell Medical School, The University of Texas, 1701 Trinity St, Austin, TX 78712, USA
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30
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Isaiah S, Loots DT, Solomons R, van der Kuip M, Tutu Van Furth AM, Mason S. Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis. Front Neurosci 2020; 14:296. [PMID: 32372900 PMCID: PMC7186443 DOI: 10.3389/fnins.2020.00296] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
A new paradigm in neuroscience has recently emerged - the brain-gut axis (BGA). The contemporary focus in this paradigm has been gut → brain ("bottom-up"), in which the gut-microbiome, and its perturbations, affects one's psychological state-of-mind and behavior, and is pivotal in neurodegenerative disorders. The emerging brain → gut ("top-down") concept, the subject of this review, proposes that dysfunctional brain health can alter the gut-microbiome. Feedback of this alternative bidirectional highway subsequently aggravates the neurological pathology. This paradigm shift, however, focuses upon non-communicable neurological diseases (progressive neuroinflammation). What of infectious diseases, in which pathogenic bacteria penetrate the blood-brain barrier and interact with the brain, and what is this effect on the BGA in bacterial infection(s) that cause chronic neuroinflammation? Persistent immune activity in the CNS due to chronic neuroinflammation can lead to irreversible neurodegeneration and neuronal death. The properties of cerebrospinal fluid (CSF), such as immunological markers, are used to diagnose brain disorders. But what of metabolic markers for such purposes? If a BGA exists, then chronic CNS bacterial infection(s) should theoretically be reflected in the urine. The premise here is that chronic CNS bacterial infection(s) will affect the gut-microbiome and that perturbed metabolism in both the CNS and gut will release metabolites into the blood that are filtered (kidneys) and excreted in the urine. Here we assess the literature on the effects of chronic neuroinflammatory diseases on the gut-microbiome caused by bacterial infection(s) of the CNS, in the context of information attained via metabolomics-based studies of urine. Furthermore, we take a severe chronic neuroinflammatory infectious disease - tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, and examine three previously validated CSF immunological biomarkers - vascular endothelial growth factor, interferon-gamma and myeloperoxidase - in terms of the expected changes in normal brain metabolism. We then model the downstream metabolic effects expected, predicting pivotal altered metabolic pathways that would be reflected in the urinary profiles of TBM subjects. Our cascading metabolic model should be adjustable to account for other types of CNS bacterial infection(s) associated with chronic neuroinflammation, typically prevalent, and difficult to distinguish from TBM, in the resource-constrained settings of poor communities.
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Affiliation(s)
- Simon Isaiah
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Du Toit Loots
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Regan Solomons
- Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Martijn van der Kuip
- Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Academic Medical Center, Emma Children’s Hospital, Amsterdam, Netherlands
| | - A. Marceline Tutu Van Furth
- Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Academic Medical Center, Emma Children’s Hospital, Amsterdam, Netherlands
| | - Shayne Mason
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
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Erdrich S, Hawrelak JA, Myers SP, Harnett JE. Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review. BMC Musculoskelet Disord 2020; 21:181. [PMID: 32192466 PMCID: PMC7083062 DOI: 10.1186/s12891-020-03201-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The association between fibromyalgia and irritable bowel syndrome is well-established. Alterations in the composition and diversity of the gut microbiome in irritable bowel syndrome have been reported, however, this association is poorly understood in fibromyalgia. Our aim was to summarise the research reporting on the gastrointestinal microbiome and its biomarkers in people with fibromyalgia. METHODS A systematic review of published original research reporting on the gastrointestinal microbiota and its biomarkers in adults with a diagnosis of fibromyalgia was undertaken. RESULTS From 4771 studies, 11 met our inclusion criteria and were separated into four main groups: papers reporting Helicobacter pylori; other gut bacterial markers; metabolomics and other biomarkers, which included intestinal permeability and small intestinal bacterial overgrowth. CONCLUSION The results suggest there is a paucity of quality research in this area, with indications that the gut microbiota may play a role in fibromyalgia within the emerging field of the gut-musculoskeletal axis. Further investigations into the relationship between the gut microbiota, gut dysfunction and fibromyalgia are warranted.
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Affiliation(s)
- Sharon Erdrich
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
| | - Jason A Hawrelak
- College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Stephen P Myers
- NatMed Research Unit, Division of Research, Southern Cross University, Lismore, New South Wales, Australia
| | - Joanna E Harnett
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia
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Abstract
Fibromyalgia is characterized by generalized pain, specific sites of musculoskeletal tenderness, fatigue, sleep disturbance, headaches, and many other visceral and cognitive maladies. The epidemiology is not well-elucidated and the diagnoses and management can be difficult. Surgery may not be the most appropriate management of some of these pain conditions like fibromyalgia. It may even be more difficult to discern some surgical conditions from points of heightened sensitivity in the fibromyalgia patient. Close attention to the current and past medical history in such patients should aid the surgeon in his attempt to rid the patient of painful conditions through surgery.
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Affiliation(s)
- Michael W Neumeister
- Department of Surgery, Institute for Plastic Surgery, Southern Illinois University School of Medicine, 747 North Rutledge Suite 357, Baylis Building, Springfield, IL 62702, USA.
| | - Evyn L Neumeister
- Institute for Plastic Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA
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Zhou X, Li Y, Li H, Yang Z, Zuo C. Responses in the crucian carp (Carassius auratus) exposed to environmentally relevant concentration of 17α-Ethinylestradiol based on metabolomics. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 183:109501. [PMID: 31401330 DOI: 10.1016/j.ecoenv.2019.109501] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/27/2019] [Accepted: 07/30/2019] [Indexed: 06/10/2023]
Abstract
17α-ethynylestradiol (EE2), a ubiquitous synthetic endocrine disrupting chemical, was the principal component of contraceptive drugs and one of common hormone medications. The detrimental impact of EE2 on the reproduction of organisms was widely recognized. However, the underlying mechanisms of physiological and metabolome effects of EE2 on freshwater fish are still unclear. This study investigated the toxic effects and related mechanisms of EE2 on freshwater fish crucian carp (Carassius auratus) based on metabolomics. Crucian carp were exposed to EE2 at environmentally relevant concentration for 9 days, 18 days, and 27 days, and the biological responses were explored through analysis of the physiological endpoints, steroid hormones, and metabolome. The physiological endpoints of crucian carp had no distinct change after EE2 exposure. However, metabolomics analysis probed significant deviation based on chemometrics, indicating that the metabolomics approach was more sensitive to the effects of EE2 at environmentally relevant concentration to freshwater fish than the traditional endpoints. The alterations of 24 metabolites in gonad and 16 metabolites in kidney were induced by treatment with EE2, respectively, which suggesting the perturbations in amino acid metabolism, lipid metabolism, energy metabolism, and oxidative stress. Moreover, EE2 exposure could induce the disruption of lipid metabolism and then broke the homeostasis of endogenous steroid hormones. Metabolomics provided a new strategy for the studies on contaminant exposure at a low dose in the short term and gave important information for the toxicology and mechanism of EE2.
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Affiliation(s)
- Xinyi Zhou
- Center for Environment and Water Resources, College of Chemistry and Chemical Engineering, Central South University, Changsha, China; Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, China.
| | - Yue Li
- Center for Environment and Water Resources, College of Chemistry and Chemical Engineering, Central South University, Changsha, China; Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, China.
| | - Haipu Li
- Center for Environment and Water Resources, College of Chemistry and Chemical Engineering, Central South University, Changsha, China; Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, China.
| | - Zhaoguang Yang
- Center for Environment and Water Resources, College of Chemistry and Chemical Engineering, Central South University, Changsha, China; Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, China.
| | - Chenchen Zuo
- Center for Environment and Water Resources, College of Chemistry and Chemical Engineering, Central South University, Changsha, China; Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, China.
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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: 2560] [Impact Index Per Article: 426.7] [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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