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Hendi M, Zhang B, Lv JM, Cai XJ. Factors influencing anxiety and depression in advanced hepatocellular carcinoma patients and their impact on quality of life. World J Psychiatry 2025; 15:104995. [DOI: 10.5498/wjp.v15.i5.104995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/19/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Patients with middle and advanced hepatocellular carcinoma (HCC) frequently experience significant anxiety and depression, severely affecting their quality of life.
AIM To examine the anxiety and depression status of patients with middle and advanced HCC, the influencing factors, and the correlation between these psychological factors and quality of life.
METHODS We collected baseline data from 100 patients with HCC, assessing anxiety and depression levels using the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). Quality of life was evaluated with the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire. Multivariate logistic regression analyzed clinical and psychosocial factors affecting anxiety and depression, while Pearson correlation assessed relationships among HAMA, HAMD, and Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire scores.
RESULTS Results indicated that 64% of patients exhibited anxiety and 65% showed depression symptoms. Key influencing factors included Barcelona Clinic Liver Cancer C stage, multiple tumors, social support, prior treatments (such as liver resection and transcatheter arterial chemoembolization/hepatic artery infusion chemotherapy), as well as HAMA and HAMD scores. Anxiety and depression correlated negatively with quality of life, with coefficients of -0.671 and -0.575 for HAMA and HAMD, respectively.
CONCLUSION Anxiety and depression are prevalent among patients with middle and advanced HCC, impacting quality of life. This underscores the need for psychological health considerations in liver cancer treatment and establishing psychological interventions is essential.
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Affiliation(s)
- Maher Hendi
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
| | - Bin Zhang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
| | - Jie-Min Lv
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
| | - Xiu-Jun Cai
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
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Origüela V, Lopez-Zaplana A. Gut Microbiota: An Immersion in Dysbiosis, Associated Pathologies, and Probiotics. Microorganisms 2025; 13:1084. [PMID: 40431257 PMCID: PMC12113704 DOI: 10.3390/microorganisms13051084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025] Open
Abstract
The importance of the microbiome, particularly the gut microbiota and its implications for health, is well established. However, an increasing number of studies further strengthen the link between an imbalanced gut microbiota and a greater predisposition to different diseases. The gut microbiota constitutes a fundamental ecosystem for maintaining human health. Its alteration, known as dysbiosis, is associated with a wide range of conditions, including intestinal, metabolic, immunological, or neurological pathologies, among others. In recent years, there has been a substantial increase in knowledge about probiotics-bacterial species that enhance health or address various diseases-with numerous studies reporting their benefits in preventing or improving these conditions. This review aims to analyze the most common pathologies resulting from an imbalance in the gut microbiota, as well as detail the most important and known gut probiotics, their functions, and mechanisms of action in relation to these conditions.
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Affiliation(s)
- Valentina Origüela
- Department of Physiology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain;
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Pu L, Liu X, Fang C, Su Z, Sheng S, Yang H. Clinical Effect of Traditional Chinese Medicine (An Shen Jiao Tai Yi Zhi Decoction) on Sleep Disorders in Patients With Parkinson's Disease. ACTAS ESPANOLAS DE PSIQUIATRIA 2025; 53:535-545. [PMID: 40356006 PMCID: PMC12069914 DOI: 10.62641/aep.v53i3.1809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 05/15/2025]
Abstract
BACKGROUND Current research on An Shen Jiao Tai Yi Zhi decoction remains limited, highlighting the need for further investigation to validate its therapeutic efficacy and elucidate its underlying mechanisms of action. A study was conducted to evaluate the effects of An Shen Jiao Tai Yi Zhi decoction on sleep disorders in patients with Parkinson's disease. METHODS The study population comprised 85 patients diagnosed with Parkinson's disease and sleep disorders at the Department of Encephalopathy of Hebei Provincial Hospital of Traditional Chinese Medicine, between January 2021 and December 2023. In accordance with different treatment methods, they were divided into the Western medicine group (n = 45, conventional Western medicine treatment plus pramipexole hydrochloride) and the traditional Chinese medicine group (n = 40, An Shen Jiao Tai Yi Zhi decoction based on the Western medicine group). To minimize selection bias, propensity score matching (PSM) was employed with a 1:1 ratio, yielding 20 cases in the traditional Chinese medicine group and 20 cases in the Western medicine group. Clinical data, total effective rates, Epworth Sleepiness Scale (ESS) scores, sleep architecture parameters, homocysteine levels, interleukin-1β concentration, and adverse reactions were collected for all participants. Baseline characteristics were balanced between the two groups through PSM. The data were analyzed using t-test, chi-square test, and analysis of variance. RESULTS PSM matching was performed in a ratio of 1:1, and a total of 40 patients were divided into two groups. No significant differences in clinical characteristics were observed between the groups. The total effective rate of the traditional Chinese medicine group was higher than that of the Western medicine group (p < 0.05). Before the intervention, no differences in ESS score, sleep architecture, and related factors were found among the two groups (p > 0.05). After 14 days of intervention, the traditional Chinese medicine group exhibited significantly greater improvements across all measured indicators compared to the Western medicine group (p < 0.05). Notably, there were no significant differences in the incidence of adverse reactions between the two groups (p > 0.05). CONCLUSIONS An Shen Jiao Tai Yi Zhi decoction demonstrates significant therapeutic efficacy, exhibiting anti-inflammatory properties and promoting changes in sleep architecture, with minimal adverse effects.
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Affiliation(s)
- Lidan Pu
- Department of Encephalopathy II, Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
| | - Xuefei Liu
- Department of Encephalopathy II, Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
| | - Chaoyi Fang
- Traditional Chinese Medicine Diagnosis Teaching and Research Office, Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
| | - Zhiwei Su
- Department of Encephalopathy I, Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
| | - Shiyun Sheng
- Graduate School, Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
| | - Haolei Yang
- Phase I Clinical Trial Research Center of Hebei Provincial Hospital of Traditional Chinese Medicine, 050000 Shijiazhuang, Hebei, China
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van der Maden MM, Verbeek MM, Beckers M. Lactobacillaceae and Parkinson's disease: An apparent paradox. JOURNAL OF PARKINSON'S DISEASE 2025; 15:269-281. [PMID: 39973489 DOI: 10.1177/1877718x241312401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder predominantly known for its motor symptoms such as bradykinesia, rigidity and tremor, but the disorder is also increasingly recognized for its association with impaired gastrointestinal function. The composition of the gut microbiome is known to be different in PD compared with healthy individuals. One of the bacterial families with increased abundance in people with PD is Lactobacillaceae. Interestingly, opposite effects have been ascribed to Lactobacillaceae in PD. A number of studies have linked Lactobacillaceae spp. in the gut to worse motor function, and to premature degradation of levodopa. However, other studies have linked administration of Lactobacillaceae-containing probiotics to improved motor function and reduced gastrointestinal problems. In this narrative review, we investigate this apparent paradox. The key to its understanding appears to lie in the specific species of Lactobacillaceae. The species L. plantarum in particular seemed to show a correlation with improved motor symptoms, as well as a reduction in intestinal inflammation, whereas L. brevis, L. curvatus and L. fermentum have properties that might be detrimental to people with PD.
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Affiliation(s)
| | - Marcel M Verbeek
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboudumc Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Milan Beckers
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboudumc Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
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Li R, Fu R, Yang WM, Cui ZQ, Liang XJ, Yang JB, Liu L, Tan QR, Peng ZW. Acute treatment of bilateral rTMS combined with antidepressants on the plasma fatty acids for major depressive episodes. Brain Res 2024; 1843:149125. [PMID: 39025398 DOI: 10.1016/j.brainres.2024.149125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
Bilateral repetitive transcranial magnetic stimulation (B-rTMS) has been largely used in the treatment of major depressive disorder (MDD). Nonetheless, information on the acute treatment by B-rTMS combined with antidepressants (ADs) on the plasma fatty acids in MDD is limited. The present study focused on depressive symptoms; Plasma was obtained from 27 adult patients with MDD at baselinephase (MDD), after 2 weeks of treatment (MDD-2w), and 27 healthy controls (HC). Meanwhile, we evaluated the composition of short-chain fatty acids (SCFAs) and medium-and long-chain fatty acids (MLCFAs) in the plasma. Consequently, the levels of Isobutyric acid, Caproic acid, and Propionic acid were low both in the MDD and MDD-2w groups and negatively correlated with the scores of HAMD and HAMA. Besides, minimal changes were observed between the MDD and HC groups, whereas significant MLCFA levels were high in the MDD-2w group. Moreover, we developed combined panels that could effectively differentiate MDD from HCs (AUC=0.99), MDD-2w from HC (AUC=0.983), and MDD from MDD-2w (AUC=0.852). These findings may provide a reference for the use of B-rTMS combined with ADs against the acute phase of depressive episodes and shed light on the relationship between plasma FAs and MDD.
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Affiliation(s)
- Rui Li
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Rui Fu
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Wen-Mao Yang
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Zhi-Quan Cui
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Xue-Jun Liang
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China; Mental Diseases Prevention and Treatment Institute of Chinese PLA, No. 988 Hospital of Joint Logistic Support Force, Jiaozuo, Henan Province 454003, PR China.
| | - Jia-Bin Yang
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Ling Liu
- Military Medical Innovation Center, Air Force Medical University, Xi'an 710032, PR China.
| | - Qing-Rong Tan
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
| | - Zheng-Wu Peng
- Department of Psychiatry, Chang'an Hospital, Xi'an 710000, PR China.
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6
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Yao L, Yang Y, Yang X, Rezaei MJ. The Interaction Between Nutraceuticals and Gut Microbiota: a Novel Therapeutic Approach to Prevent and Treatment Parkinson's Disease. Mol Neurobiol 2024; 61:9078-9109. [PMID: 38587699 DOI: 10.1007/s12035-024-04151-2] [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: 12/12/2023] [Accepted: 03/25/2024] [Indexed: 04/09/2024]
Abstract
Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms. Emerging research has shed light on the role of gut microbiota in the pathogenesis and progression of PD. Nutraceuticals such as curcumin, berberine, phytoestrogens, polyphenols (e.g., resveratrol, EGCG, and fisetin), dietary fibers have been shown to influence gut microbiota composition and function, restoring microbial balance and enhancing the gut-brain axis. The mechanisms underlying these benefits involve microbial metabolite production, restoration of gut barrier integrity, and modulation of neuroinflammatory pathways. Additionally, probiotics and prebiotics have shown potential in promoting gut health, influencing the gut microbiome, and alleviating PD symptoms. They can enhance the gut's antioxidant capacity of the gut, reduce inflammation, and maintain immune homeostasis, contributing to a neuroprotective environment. This paper provides an overview of the current state of knowledge regarding the potential of nutraceuticals and gut microbiota modulation in the prevention and management of Parkinson's disease, emphasizing the need for further research and clinical trials to validate their effectiveness and safety. The findings suggest that a multifaceted approach involving nutraceuticals and gut microbiota may open new avenues for addressing the challenges of PD and improving the quality of life for affected individuals.
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Affiliation(s)
- Liyan Yao
- School of Public Health, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Yong Yang
- School of Public Health, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Xiaowei Yang
- School of Public Health, Mudanjiang Medical University, Mudanjiang, 157011, China.
| | - Mohammad J Rezaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Liao PH, Tung HY, Lim WS, Jang JSR, Li H, Shun CT, Chiu HM, Wu MS, Lin CH. Impaired gut barrier integrity and reduced colonic expression of free fatty acid receptors in patients with Parkinson's disease. Neurol Sci 2024; 45:5297-5307. [PMID: 38862654 DOI: 10.1007/s10072-024-07641-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD). OBJECTIVE We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity. METHODS In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria. RESULTS Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02). CONCLUSIONS Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD.
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Affiliation(s)
| | - Hsiao-Yen Tung
- College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Computer Science & Information Engineering, National Taiwan University, Taipei, Taiwan
| | - Wee Shin Lim
- Department of Computer Science & Information Engineering, National Taiwan University, Taipei, Taiwan
| | - Jyh-Shing Roger Jang
- Department of Computer Science & Information Engineering, National Taiwan University, Taipei, Taiwan
| | - Hsun Li
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Tung Shun
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Han-Mo Chiu
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chin-Hsien Lin
- College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Biomedical Engineering, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Andreozzi V, Cuoco S, Balestrieri M, Fierro F, Ferrara N, Erro R, Di Filippo M, Barbella G, Memoli MC, Silvestri A, Squillante M, Guglielmetti S, Barone P, Iovino P, Pellecchia MT. Synbiotic supplementation may globally improve non-motor symptoms in patients with stable Parkinson's disease: results from an open label single-arm study. Sci Rep 2024; 14:23095. [PMID: 39367119 PMCID: PMC11452401 DOI: 10.1038/s41598-024-74400-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/25/2024] [Indexed: 10/06/2024] Open
Abstract
Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson's Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms. We enrolled patients with stable PD who met diagnostic criteria for functional constipation and/or irritable bowel syndrome with constipation according to Rome IV Criteria. Patients received a synbiotic treatment (Enterolactis Duo, containing the probiotic strain Lacticaseibacillus paracasei DG and the prebiotic fiber inulin) for 12 weeks. A neurological and a gastroenterological evaluation were collected before and after the treatment. In addition, 16S rRNA gene profiling and short chain fatty acid quantification were performed to characterize the microbial ecosystem of fecal samples collected before (n = 22) and after (n = 9) the synbiotic administration. 30 patients were consecutively enrolled. After treatment, patients performed better in MDS-UPDRS part 1 (p = 0.000), SCOPA-AUT (p = 0.001), TAS-20 (p = 0.014), HAM-D (p = 0.026), DIFt (p = 0.003), PAS-A (p = 0.048). Gastroenterological evaluations showed improvements in PAC-SYM score (p < 0.001), number of complete bowel movement (p < 0.001) and BSFS (p < 0.001). After the synbiotic administration, we observed a significant increase in the abundance of the order Oscillospirales, as well as the Oscillospiraceae family and the species Faecalibacterium prausnitzii within this order in fecal samples. Synbiotic treatment demonstrates potential efficacy in ameliorating non-motor features in PD patients.
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Affiliation(s)
- V Andreozzi
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - S Cuoco
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - M Balestrieri
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Gastrointestinal Unit, University of Salerno, Salerno, Italy
| | - F Fierro
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Gastrointestinal Unit, University of Salerno, Salerno, Italy
| | - N Ferrara
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Gastrointestinal Unit, University of Salerno, Salerno, Italy
| | - R Erro
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - M Di Filippo
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - G Barbella
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - M C Memoli
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - A Silvestri
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - M Squillante
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - S Guglielmetti
- μbEat Lab, Department of Biotechnology and Biosciences (BtBs), University of Milano-Bicocca, Milan, Italy
| | - P Barone
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy
| | - P Iovino
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Gastrointestinal Unit, University of Salerno, Salerno, Italy
| | - M T Pellecchia
- Department of Medicine Surgery and Dentistry, Scuola Medica Salernitana, Neuroscience Section, University of Salerno, Salerno, Italy.
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Saadh MJ, Mustafa AN, Mustafa MA, S RJ, Dabis HK, Prasad GVS, Mohammad IJ, Adnan A, Idan AH. The role of gut-derived short-chain fatty acids in Parkinson's disease. Neurogenetics 2024; 25:307-336. [PMID: 39266892 DOI: 10.1007/s10048-024-00779-3] [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: 06/21/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024]
Abstract
The emerging function of short-chain fatty acids (SCFAs) in Parkinson's disease (PD) has been investigated in this article. SCFAs, which are generated via the fermentation of dietary fiber by gut microbiota, have been associated with dysfunction of the gut-brain axis and, neuroinflammation. These processes are integral to the development of PD. This article examines the potential therapeutic implications of SCFAs in the management of PD, encompassing their capacity to modulate gastrointestinal permeability, neuroinflammation, and neuronal survival, by conducting an extensive literature review. As a whole, this article emphasizes the potential therapeutic utility of SCFAs as targets for the management and treatment of PD.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | - Mohammed Ahmed Mustafa
- School of Pharmacy-Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Pharmacy, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Renuka Jyothi S
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | | | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra, Pradesh-531162, India
| | - Imad Jassim Mohammad
- College of Health and Medical Technology, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | - Ahmed Adnan
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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10
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Duru IC, Lecomte A, Shishido TK, Laine P, Suppula J, Paulin L, Scheperjans F, Pereira PAB, Auvinen P. Metagenome-assembled microbial genomes from Parkinson's disease fecal samples. Sci Rep 2024; 14:18906. [PMID: 39143178 PMCID: PMC11324757 DOI: 10.1038/s41598-024-69742-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/08/2024] [Indexed: 08/16/2024] Open
Abstract
The human gut microbiome composition has been linked to Parkinson's disease (PD). However, knowledge of the gut microbiota on the genome level is still limited. Here we performed deep metagenomic sequencing and binning to build metagenome-assembled genomes (MAGs) from 136 human fecal microbiomes (68 PD samples and 68 control samples). We constructed 952 non-redundant high-quality MAGs and compared them between PD and control groups. Among these MAGs, there were 22 different genomes of Collinsella and Prevotella, indicating high variability of those genera in the human gut environment. Microdiversity analysis indicated that Ruminococcus bromii was statistically significantly (p < 0.002) more diverse on the strain level in the control samples compared to the PD samples. In addition, by clustering all genes and performing presence-absence analysis between groups, we identified several control-specific (p < 0.05) related genes, such as speF and Fe-S oxidoreductase. We also report detailed annotation of MAGs, including Clusters of Orthologous Genes (COG), Cas operon type, antiviral gene, prophage, and secondary metabolites biosynthetic gene clusters, which can be useful for providing a reference for future studies.
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Affiliation(s)
- Ilhan Cem Duru
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
| | - Alexandre Lecomte
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | | | - Pia Laine
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Joni Suppula
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Lars Paulin
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Filip Scheperjans
- Department of Neurology, Helsinki University Hospital and Clinicum, University of Helsinki, Helsinki, Finland
| | - Pedro A B Pereira
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
- Department of Neurology, Helsinki University Hospital and Clinicum, University of Helsinki, Helsinki, Finland.
| | - Petri Auvinen
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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Bhardwaj K, Singh AA, Kumar H. Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration-Gut Connection in Parkinson's Disease. ACS Chem Neurosci 2024; 15:2454-2469. [PMID: 38896463 DOI: 10.1021/acschemneuro.4c00293] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024] Open
Abstract
Parkinson's disease, a classical motor disorder affecting the dopaminergic system of the brain, has been as a disease of the brain, but this classical notion has now been viewed differently as the pathology begins in the gut and then gradually moves up to the brain regions. The microorganisms in the gut play a critical role in maintaining the physiology of the gut from maintaining barrier integrity to secretion of microbial products that maintain a healthy gut state. The pathology subsequently alters the normal composition of gut microbes and causes deleterious effects that ultimately trigger strong neuroinflammation and nonmotor symptoms along with characteristic synucleopathy, a pathological hallmark of the disease. Understanding the complex pathomechanisms in distinct and established preclinical models is the primary goal of researchers to decipher how exactly gut pathology has a central effect; the quest has led to many answered and some open-ended questions for researchers. We summarize the popular opinions and some contrasting views, concise footsteps in the treatment strategies targeting the gastrointestinal system.
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Affiliation(s)
- Kritika Bhardwaj
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
| | - Aditya A Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
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12
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Kalyanaraman B, Cheng G, Hardy M. Gut microbiome, short-chain fatty acids, alpha-synuclein, neuroinflammation, and ROS/RNS: Relevance to Parkinson's disease and therapeutic implications. Redox Biol 2024; 71:103092. [PMID: 38377788 PMCID: PMC10891329 DOI: 10.1016/j.redox.2024.103092] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/22/2024] Open
Abstract
In this review, we explore how short-chain fatty acids (SCFAs) produced by the gut microbiome affect Parkinson's disease (PD) through their modulatory interactions with alpha-synuclein, neuroinflammation, and oxidative stress mediated by reactive oxygen and nitrogen species (ROS/RNS). In particular, SCFAs-such as acetate, propionate, and butyrate-are involved in gut-brain communication and can modulate alpha-synuclein aggregation, a hallmark of PD. The gut microbiome of patients with PD has lower levels of SCFAs than healthy individuals. Probiotics may be a potential strategy to restore SCFAs and alleviate PD symptoms, but the underlying mechanisms are not fully understood. Also in this review, we discuss how alpha-synuclein, present in the guts and brains of patients with PD, may induce neuroinflammation and oxidative stress via ROS/RNS. Alpha-synuclein is considered an early biomarker for PD and may link the gut-brain axis to the disease pathogenesis. Therefore, elucidating the role of SCFAs in the gut microbiome and their impact on alpha-synuclein-induced neuroinflammation in microglia and on ROS/RNS is crucial in PD pathogenesis and treatment.
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Affiliation(s)
- Balaraman Kalyanaraman
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, United States.
| | - Gang Cheng
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, United States
| | - Micael Hardy
- Aix-Marseille Univ, CNRS, ICR, UMR 7273, Marseille, 13013, France
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Dai HY, Zhang ZX, Tan C, Xian X, Ji D, Yang J, Sun J, Yao H. Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders. Heliyon 2024; 10:e28817. [PMID: 38699705 PMCID: PMC11063405 DOI: 10.1016/j.heliyon.2024.e28817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 05/05/2024] Open
Abstract
Background Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1β (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.
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Affiliation(s)
- Hong-yu Dai
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ze-xin Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Cheng Tan
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xian Xian
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dong Ji
- Department of Anesthesiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Yang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jie Sun
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hao Yao
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Siva Venkatesh IP, Majumdar A, Basu A. Prophylactic Administration of Gut Microbiome Metabolites Abrogated Microglial Activation and Subsequent Neuroinflammation in an Experimental Model of Japanese Encephalitis. ACS Chem Neurosci 2024; 15:1712-1727. [PMID: 38581382 DOI: 10.1021/acschemneuro.4c00028] [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: 04/08/2024] Open
Abstract
Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days (p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV group─42 ± 2.15 microglia/ROI; SCFA + JEV group─27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.
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MESH Headings
- Gastrointestinal Microbiome/physiology
- Neuroinflammatory Diseases/drug therapy
- Neuroinflammatory Diseases/immunology
- Neuroinflammatory Diseases/metabolism
- Neuroinflammatory Diseases/microbiology
- Microglia/drug effects
- Microglia/immunology
- Encephalitis, Japanese/drug therapy
- Encephalitis, Japanese/immunology
- Encephalitis, Japanese/microbiology
- Encephalitis, Japanese/prevention & control
- Encephalitis, Japanese/virology
- Fatty Acids, Volatile/pharmacology
- Fatty Acids, Volatile/therapeutic use
- Encephalitis Viruses, Japanese/drug effects
- Encephalitis Viruses, Japanese/immunology
- Encephalitis Viruses, Japanese/pathogenicity
- Survival Analysis
- Chemokines/immunology
- Chemokines/metabolism
- Inflammation Mediators/immunology
- Inflammation Mediators/metabolism
- Cytokine Release Syndrome/immunology
- Cytokine Release Syndrome/metabolism
- Cytokine Release Syndrome/prevention & control
- Humans
- Female
- Animals
- Mice
- Apoptosis/drug effects
- Brain/drug effects
- Brain/metabolism
- Brain/virology
- Viral Load/drug effects
- Time Factors
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Affiliation(s)
| | - Atreye Majumdar
- National Brain Research Centre, Manesar, Haryana 122052, India
| | - Anirban Basu
- National Brain Research Centre, Manesar, Haryana 122052, India
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15
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Elford JD, Becht N, Garssen J, Kraneveld AD, Perez-Pardo P. Buty and the beast: the complex role of butyrate in Parkinson's disease. Front Pharmacol 2024; 15:1388401. [PMID: 38694925 PMCID: PMC11061429 DOI: 10.3389/fphar.2024.1388401] [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: 02/19/2024] [Accepted: 04/02/2024] [Indexed: 05/04/2024] Open
Abstract
Parkinson's disease (PD) is a complex neurodegenerative disease which is often associated with gastrointestinal (GI) dysfunction. The GI tract is home to a wide range of microorganisms, among which bacteria, that can influence the host through various mechanisms. Products produced by these bacteria can act in the gut but can also exert effects in the brain via what is now well established to be the microbiota-gut-brain axis. In those with PD the gut-bacteria composition is often found to be different to that of non-PD individuals. In addition to compositional changes, the metabolic activity of the gut-microbiota is also changed in PD. Specifically, it is often reported that key producers of short chain fatty acids (SCFAs) as well as the concentration of SCFAs themselves are altered in the stool and blood of those with PD. These SCFAs, among which butyrate, are essential nutrients for the host and are a major energy source for epithelial cells of the GI tract. Additionally, butyrate plays a key role in regulating various host responses particularly in relation to inflammation. Studies have demonstrated that a reduction in butyrate levels can have a critical role in the onset and progression of PD. Furthermore, it has been shown that restoring butyrate levels in those with PD through methods such as probiotics, prebiotics, sodium butyrate supplementation, and fecal transplantation can have a beneficial effect on both motor and non-motor outcomes of the disease. This review presents an overview of evidence for the altered gut-bacteria composition and corresponding metabolite production in those with PD, with a particular focus on the SCFA butyrate. In addition to presenting current studies regarding SCFA in clinical and preclinical reports, evidence for the possibility to target butyrate production using microbiome based approaches in a therapeutic context is discussed.
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Affiliation(s)
- Joshua D. Elford
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Nanette Becht
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Danone Nutricia Research, Utrecht, Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Department of Neuroscience, Faculty of Science, Vrije Universiteit, Amsterdam, Netherlands
| | - Paula Perez-Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
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16
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Duan WX, Wang F, Liu JY, Liu CF. Relationship Between Short-chain Fatty Acids and Parkinson's Disease: A Review from Pathology to Clinic. Neurosci Bull 2024; 40:500-516. [PMID: 37755674 PMCID: PMC11003953 DOI: 10.1007/s12264-023-01123-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/15/2023] [Indexed: 09/28/2023] Open
Abstract
Parkinson's disease (PD) is a complicated neurodegenerative disease, characterized by the accumulation of α-synuclein (α-syn) in Lewy bodies and neurites, and massive loss of midbrain dopamine neurons. Increasing evidence suggests that gut microbiota and microbial metabolites are involved in the development of PD. Among these, short-chain fatty acids (SCFAs), the most abundant microbial metabolites, have been proven to play a key role in brain-gut communication. In this review, we analyze the role of SCFAs in the pathology of PD from multiple dimensions and summarize the alterations of SCFAs in PD patients as well as their correlation with motor and non-motor symptoms. Future research should focus on further elucidating the role of SCFAs in neuroinflammation, as well as developing novel strategies employing SCFAs and their derivatives to treat PD.
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Affiliation(s)
- Wen-Xiang Duan
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Fen Wang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Jun-Yi Liu
- Department of Neurology, Dushu Lake Hospital affiliated to Soochow University, Suzhou, 215125, China.
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
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17
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Panda SS, Behera B, Ghosh R, Bagh B, Aich P. Antibiotic induced adipose tissue browning in C57BL/6 mice: An association with the metabolic profile and the gut microbiota. Life Sci 2024; 340:122473. [PMID: 38290571 DOI: 10.1016/j.lfs.2024.122473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/01/2024]
Abstract
AIMS The use of antibiotics affects health. The gut microbial dysbiosis by antibiotics is thought to be an essential pathway to influence health. It is important to have optimized energy utilization, in which adipose tissues (AT) play crucial roles in maintaining health. Adipocytes regulate the balance between energy expenditure and storage. While it is known that white adipose tissue (WAT) stores energy and brown adipose tissue (BAT) produces energy by thermogenesis, the role of an intermediate AT plays an important role in balancing host internal energy. In the current study, we tried to understand how treating an antibiotic cocktail transforms WAT into BAT or, more precisely, into beige adipose tissue (BeAT). METHODS Since antibiotic treatment perturbs the host microbiota, we wanted to understand the role of gut microbial dysbiosis in transforming WAT into BeAT in C57BL/6 mice. We further correlated the metabolic profile at the systemic level with this BeAT transformation and gut microbiota profile. KEY FINDINGS In the present study, we have reported that the antibiotic cocktail treatment increases the Proteobacteria and Actinobacteria while reducing the Bacteroidetes phylum. We observed that prolonged antibiotic treatment could induce the formation of BeAT in the inguinal and perigonadal AT. The correlation analysis showed an association between the gut microbiota phyla, beige adipose tissue markers, and serum metabolites. SIGNIFICANCE Our study revealed that the gut microbiota has a significant role in regulating the metabolic health of the host via microbiota-adipose axis communication.
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Affiliation(s)
- Swati Sagarika Panda
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. - Bhimpur-Padanpur, Jatni - 752050, Dist. -Khurda, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, Maharashtra, India
| | - Biplab Behera
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. - Bhimpur-Padanpur, Jatni - 752050, Dist. -Khurda, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, Maharashtra, India
| | - Rahul Ghosh
- School of Chemical Sciences, National Institute of Science Education and Research (NISER), P.O. - Bhimpur-Padanpur, Jatni - 752050, Dist. -Khurda, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, Maharashtra, India
| | - Bidraha Bagh
- School of Chemical Sciences, National Institute of Science Education and Research (NISER), P.O. - Bhimpur-Padanpur, Jatni - 752050, Dist. -Khurda, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, Maharashtra, India
| | - Palok Aich
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. - Bhimpur-Padanpur, Jatni - 752050, Dist. -Khurda, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, Maharashtra, India.
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18
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Lan Z, Tang X, Lu M, Hu Z, Tang Z. The role of short-chain fatty acids in central nervous system diseases: A bibliometric and visualized analysis with future directions. Heliyon 2024; 10:e26377. [PMID: 38434086 PMCID: PMC10906301 DOI: 10.1016/j.heliyon.2024.e26377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/11/2024] [Accepted: 02/12/2024] [Indexed: 03/05/2024] Open
Abstract
Background Short-chain fatty acids (SCFAs) are thought to play a key role in the microbe-gut-brain axis and involve in the pathogenesis of a variety of neurological diseases. This study aimed to identify research hotspots and evolution trends in SCFAs in central nervous diseases (CNS) and examine current research trends. Methods The bibliometric analysis was performed using CiteSpace, and the results were visualized via network maps. Results From 2002 to 2022, 480 publications in the database met the criteria. On the country level, China produced the highest number of publications, while the United States had the highest centrality. On the institutional level, University College Cork contributed to the most publications, and John F. Cryan from this university was the key researcher with considerable academic influence. The article, the role of short-chain fatty acids in microbiota-gut-brain, written by Boushra Dalile et al., in 2019 was the most cited article. Furthermore, the journal Nutrients had the maximum number of publications, while Plos One was the most cited journal. "Gut microbiome", "SCFAs", and "central nervous system" were the three most frequent keywords. Among them, SCFAs had the highest centrality. "Animal model" was the keyword with the highest burst strength, with the latest burst keywords being "social behavior", "pathogenesis", and "insulin sensitive". In addition, the research topics on SCFAs in CNS diseases from 2002 to 2022 mainly focused on following aspects: SCFAs plays a key role in microbe-gut-brain crosstalk; The classification and definition of SCFAs in the field of CNS; Several CNS diseases that are closely related to SCFAs research; Mechanism and translational studies of SCFAs in the CNS diseases. And the hotspots over the past 5 years have gradually increased the attention to the therapeutic potential of SCFAs in the CNS diseases. Conclusion The research of SCFAs in CNS diseases is attracting growing attention. However, there is a lack of cooperation between countries and institutions, and additional measures are required to promote cooperation. The current evidence for an association between SCFAs and CNS diseases is preliminary and more work is needed to pinpoint the precise mechanism. Moreover, large-scale clinical trials are needed in the future to define the therapeutic potential of SCFAs in CNS diseases.
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Affiliation(s)
- Ziwei Lan
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Xiangqi Tang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Ming Lu
- Hunan Provincial Key Laboratory of Neurorestoratology, The Second Affiliated Hospital, Hunan Normal University, Changsha, 410003, Hunan, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Zhenchu Tang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
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19
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Candeias E, Pereira-Santos AR, Empadinhas N, Cardoso SM, Esteves ARF. The Gut-Brain Axis in Alzheimer's and Parkinson's Diseases: The Catalytic Role of Mitochondria. J Alzheimers Dis 2024; 100:413-429. [PMID: 38875045 DOI: 10.3233/jad-240524] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2024]
Abstract
Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer's and Parkinson's diseases. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer's and Parkinson's disease strengthen by cellular, animal and clinical studies.
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Affiliation(s)
- Emanuel Candeias
- CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Ana Raquel Pereira-Santos
- CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Nuno Empadinhas
- CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Sandra Morais Cardoso
- CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Ana Raquel Fernandes Esteves
- CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
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20
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Nápoles-Medina AY, Aguilar-Uscanga BR, Solís-Pacheco JR, Tejeda-Martínez AR, Ramírez-Jirano LJ, Urmeneta-Ortiz MF, Chaparro-Huerta V, Flores-Soto ME. Oral Administration of Lactobacillus Inhibits the Permeability of Blood-Brain and Gut Barriers in a Parkinsonism Model. Behav Neurol 2023; 2023:6686037. [PMID: 38025189 PMCID: PMC10653970 DOI: 10.1155/2023/6686037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/26/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
It has recently been shown that the administration of probiotics can modulate the microbiota-gut-brain axis and may have favorable effects in models of Parkinson's disease. In this study, we used a hemiparkinsonism model induced by the neurotoxin 6-OHDA to evaluate the efficacy of the administration of a four-week administration of a mixture containing the microorganisms Lactobacillus fermentum LH01, Lactobacillus reuteri LH03, and Lactobacillus plantarum LH05. The hemiparkinsonism model induced an increase in rotations in the apomorphine test, along with a decrease in the latency time to fall in the rotarod test on days 14 and 21 after surgery, respectively. The administration of probiotics was sufficient to improve this condition. The model also showed a decrease in tyrosine hydroxylase immunoreactivity in the striatum and the number of labeled cells in the substantia nigra, both of which were counteracted by the administration of probiotics. The permeability of the blood-brain barrier was increased in the model, but this effect was reversed by the probiotics for both brain regions. The gut barrier was permeated with the model, and this effect was reversed and dropped to lower levels than the control group after the administration of probiotics. Finally, lipid peroxidation showed a pattern of differences similar to that of permeabilities. The inhibition of the permeability of the blood-brain and gut barriers mediated by the administration of probiotics will likely provide protection by downregulating oxidative stress, thus affecting the rotarod test performance.
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Affiliation(s)
- Angélica Y. Nápoles-Medina
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Blanca R. Aguilar-Uscanga
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Josué R. Solís-Pacheco
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Aldo R. Tejeda-Martínez
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Luis J. Ramírez-Jirano
- División de Neurociencias, Centro de Investigación Biomédica Occidente (IMSS), Guadalajara, Mexico
| | - María F. Urmeneta-Ortiz
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Veronica Chaparro-Huerta
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Mario E. Flores-Soto
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
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21
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De Marchi F, Munitic I, Vidatic L, Papić E, Rački V, Nimac J, Jurak I, Novotni G, Rogelj B, Vuletic V, Liscic RM, Cannon JR, Buratti E, Mazzini L, Hecimovic S. Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders. Biomedicines 2023; 11:2793. [PMID: 37893165 PMCID: PMC10604382 DOI: 10.3390/biomedicines11102793] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.
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Affiliation(s)
- Fabiola De Marchi
- Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore Della Carità Hospital, Corso Mazzini 18, 28100 Novara, Italy;
| | - Ivana Munitic
- Laboratory for Molecular Immunology, Department of Biotechnology, University of Rijeka, R. Matejcic 2, 51000 Rijeka, Croatia;
| | - Lea Vidatic
- Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia;
| | - Eliša Papić
- Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (E.P.); (V.R.); (V.V.)
- Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Valentino Rački
- Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (E.P.); (V.R.); (V.V.)
- Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Jerneja Nimac
- Department of Biotechnology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia; (J.N.); (B.R.)
- Graduate School of Biomedicine, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Igor Jurak
- Molecular Virology Laboratory, Department of Biotechnology, University of Rijeka, R. Matejcic 2, 51000 Rijeka, Croatia;
| | - Gabriela Novotni
- Department of Cognitive Neurology and Neurodegenerative Diseases, University Clinic of Neurology, Medical Faculty, University Ss. Cyril and Methodius, 91701 Skoplje, North Macedonia;
| | - Boris Rogelj
- Department of Biotechnology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia; (J.N.); (B.R.)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Vladimira Vuletic
- Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (E.P.); (V.R.); (V.V.)
- Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Rajka M. Liscic
- Department of Neurology, Sachsenklinik GmbH, Muldentalweg 1, 04828 Bennewitz, Germany;
| | - Jason R. Cannon
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA;
- Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA
| | - Emanuele Buratti
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149 Trieste, Italy;
| | - Letizia Mazzini
- Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore Della Carità Hospital, Corso Mazzini 18, 28100 Novara, Italy;
| | - Silva Hecimovic
- Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia;
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22
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Schmitt V, Masanetz RK, Weidenfeller M, Ebbinghaus LS, Süß P, Rosshart SP, von Hörsten S, Zunke F, Winkler J, Xiang W. Gut-to-brain spreading of pathology in synucleinopathies: A focus on molecular signalling mediators. Behav Brain Res 2023; 452:114574. [PMID: 37423320 DOI: 10.1016/j.bbr.2023.114574] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/11/2023]
Abstract
Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.
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Affiliation(s)
- Verena Schmitt
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Rebecca Katharina Masanetz
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Martin Weidenfeller
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Lara Savannah Ebbinghaus
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Patrick Süß
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Stephan P Rosshart
- Department of Microbiome Research, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Stephan von Hörsten
- Department for Experimental Therapy, University Hospital Erlangen, Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Jürgen Winkler
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Wei Xiang
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany.
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23
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Huh E, Choi JG, Lee MY, Kim JH, Choi Y, Ju IG, Eo H, Park MG, Kim DH, Park HJ, Lee CH, Oh MS. Peripheral metabolic alterations associated with pathological manifestations of Parkinson's disease in gut-brain axis-based mouse model. Front Mol Neurosci 2023; 16:1201073. [PMID: 37635904 PMCID: PMC10447900 DOI: 10.3389/fnmol.2023.1201073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction Parkinson's disease (PD) is a representative neurodegenerative disease, and its diagnosis relies on the evaluation of clinical manifestations or brain neuroimaging in the absence of a crucial noninvasive biomarker. Here, we used non-targeted metabolomics profiling to identify metabolic alterations in the colon and plasma samples of Proteus mirabilis (P. mirabilis)-treated mice, which is a possible animal model for investigating the microbiota-gut-brain axis. Methods We performed gas chromatography-mass spectrometry to analyze the samples and detected metabolites that could reflect P. mirabilis-induced disease progression and pathology. Results and discussion Pattern, correlation and pathway enrichment analyses showed significant alterations in sugar metabolism such as galactose metabolism and fructose and mannose metabolism, which are closely associated with energy metabolism and lipid metabolism. This study indicates possible metabolic factors for P. mirabilis-induced pathological progression and provides evidence of metabolic alterations associated with P. mirabilis-mediated pathology of brain neurodegeneration.
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Affiliation(s)
- Eugene Huh
- Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Jin Gyu Choi
- Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Mee Youn Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Jin Hee Kim
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Yujin Choi
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - In Gyoung Ju
- Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Hyeyoon Eo
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Myoung Gyu Park
- MetaCen Therapeutics Inc. R&D Center, Suwon, Republic of Korea
| | - Dong-Hyun Kim
- Neurobiota Research Center, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Hi-Joon Park
- Acupuncture and Meridian Science Research Center (AMSRC), College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Myung Sook Oh
- Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul, Republic of Korea
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Macpherson AJ, Pachnis V, Prinz M. Boundaries and integration between microbiota, the nervous system, and immunity. Immunity 2023; 56:1712-1726. [PMID: 37557080 DOI: 10.1016/j.immuni.2023.07.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023]
Abstract
The enteric nervous system is largely autonomous, and the central nervous system is compartmentalized behind the blood-brain barrier. Yet the intestinal microbiota shapes gut function, local and systemic immune responses, and central nervous system functions including cognition and mood. In this review, we address how the gut microbiota can profoundly influence neural and immune networks. Although many of the interactions between these three systems originate in the intestinal mucosa, intestinal function and immunity are modulated by neural pathways that connect the gut and brain. Furthermore, a subset of microbe-derived penetrant molecules enters the brain and regulates central nervous system function. Understanding how these seemingly isolated entities communicate has the potential to open up new avenues for therapies and interventions.
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Affiliation(s)
- Andrew J Macpherson
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| | - Vassilis Pachnis
- Nervous System Development and Homeostasis Laboratory, The Francis Crick Institute, London, UK
| | - Marco Prinz
- Institute of Neuropathology, University of Freiburg, Faculty of Medicine, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
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25
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Gong Y, Chen A, Zhang G, Shen Q, Zou L, Li J, Miao YB, Liu W. Cracking Brain Diseases from Gut Microbes-Mediated Metabolites for Precise Treatment. Int J Biol Sci 2023; 19:2974-2998. [PMID: 37416776 PMCID: PMC10321288 DOI: 10.7150/ijbs.85259] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/24/2023] [Indexed: 07/08/2023] Open
Abstract
The gut-brain axis has been a subject of significant interest in recent years. Understanding the link between the gut and brain axis is crucial for the treatment of disorders. Here, the intricate components and unique relationship between gut microbiota-derived metabolites and the brain are explained in detail. Additionally, the association between gut microbiota-derived metabolites and the integrity of the blood-brain barrier and brain health is emphasized. Meanwhile, gut microbiota-derived metabolites with their recent applications, challenges and opportunities their pathways on different disease treatment are focus discussed. The prospective strategy of gut microbiota-derived metabolites potential applies to the brain disease treatments, such as Parkinson's disease and Alzheimer's disease, is proposed. This review provides a broad perspective on gut microbiota-derived metabolites characteristics facilitate understand the connection between gut and brain and pave the way for the development of a new medication delivery system for gut microbiota-derived metabolites.
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Affiliation(s)
- Ying Gong
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610041, China
| | - Anmei Chen
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China
| | - Guohui Zhang
- Key Laboratory of reproductive medicine, Sichuan Provincial maternity and Child Health Care Hospital, Chengdu 610000, China
| | - Qing Shen
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610041, China
| | - Liang Zou
- School of Food and Biological Engineering, Chengdu University, Chengdu 610106, Sichuan, China
| | - Jiahong Li
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610041, China
| | - Yang-Bao Miao
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China
| | - Weixin Liu
- Key Laboratory of reproductive medicine, Sichuan Provincial maternity and Child Health Care Hospital, Chengdu 610000, China
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26
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Swer NM, Venkidesh BS, Murali TS, Mumbrekar KD. Gut microbiota-derived metabolites and their importance in neurological disorders. Mol Biol Rep 2023; 50:1663-1675. [PMID: 36399245 PMCID: PMC9889412 DOI: 10.1007/s11033-022-08038-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 10/18/2022] [Indexed: 11/19/2022]
Abstract
Microbial-derived metabolites are the intermediate or end products of bacterial digestion. They are one of the most important molecules for the gut to connect with the brain. Depending on the levels of specific metabolites produced in the host, it can exert beneficial or detrimental effects on the brain and have been linked to several neurodegenerative and neuropsychiatric disorders. However, the underlying mechanisms remain largely unexplored. Insight into these mechanisms could reveal new pathways or targets, resulting in novel treatment approaches targeting neurodegenerative diseases. We have reviewed selected metabolites, including short-chain fatty acids, aromatic amino acids, trimethylamine-N-oxide, urolithin A, anthocyanins, equols, imidazole, and propionate to highlight their mechanism of action, underlying role in maintaining intestinal homeostasis and regulating neuro-immunoendocrine function. Further discussed on how altered metabolite levels can influence the gut-brain axis could lead to new prevention strategies or novel treatment approaches to neural disorders.
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Affiliation(s)
- Nicole Mary Swer
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - B S Venkidesh
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Thokur Sreepathy Murali
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Kamalesh Dattaram Mumbrekar
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
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Papić E, Rački V, Hero M, Tomić Z, Starčević-Čižmarević N, Kovanda A, Kapović M, Hauser G, Peterlin B, Vuletić V. The effects of microbiota abundance on symptom severity in Parkinson's disease: A systematic review. Front Aging Neurosci 2022; 14:1020172. [PMID: 36570528 PMCID: PMC9772822 DOI: 10.3389/fnagi.2022.1020172] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/22/2022] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Parkinson's disease (PD) is neurodegenerative disease with a multifactorial etiopathogenesis with accumulating evidence identifying microbiota as a potential factor in the earliest, prodromal phases of the disease. Previous research has already shown a significant difference between gut microbiota composition in PD patients as opposed to healthy controls, with a growing number of studies correlating gut microbiota changes with the clinical presentation of the disease in later stages, through various motor and non-motor symptoms. Our aim in this systematic review is to compose and assess current knowledge in the field and determine if the findings could influence future clinical practice as well as therapy in PD. METHODS We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria. RESULTS 20 studies were included in this systematic review according to the selected inclusion and exclusion criteria. The search yielded 18 case control studies, 1 case study, and 1 prospective case study with no controls. The total number of PD patients encompassed in the studies cited in this review is 1,511. CONCLUSION The link between gut microbiota and neurodegeneration is a complex one and it depends on various factors. The relative abundance of various microbiota taxa in the gut has been consistently shown to have a correlation with motor and non-motor symptom severity. The answer could lie in the products of gut microbiota metabolism which have also been linked to PD. Further research is thus warranted in the field, with a focus on the metabolic function of gut microbiota in relation to motor and non-motor symptoms.
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Affiliation(s)
- Eliša Papić
- Department of Neurology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Clinic of Neurology, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Valentino Rački
- Department of Neurology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Clinic of Neurology, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Mario Hero
- Department of Neurology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Clinic of Neurology, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Zoran Tomić
- Clinic of Neurology, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Nada Starčević-Čižmarević
- Department of Medical Genetics and Biology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Anja Kovanda
- Clinical Institute of Genomic Medicine, Ljubljana University Medical Center, Ljubljana, Slovenia
| | - Miljenko Kapović
- Department of Medical Genetics and Biology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Borut Peterlin
- Clinical Institute of Genomic Medicine, Ljubljana University Medical Center, Ljubljana, Slovenia
| | - Vladimira Vuletić
- Department of Neurology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Clinic of Neurology, Clinical Hospital Center Rijeka, Rijeka, Croatia
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Wang K, Zhang C, Zhang B, Li G, Shi G, Cai Q, Huang M. Gut dysfunction may be the source of pathological aggregation of alpha-synuclein in the central nervous system through Paraquat exposure in mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 246:114152. [PMID: 36201918 DOI: 10.1016/j.ecoenv.2022.114152] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND One of the most common types of neurodegenerative diseases (NDDs) is Lewy body disease (LBD), which is characterized by excessive accumulation of α-synuclein (α-syn) in the neurons and affects around 6 million individuals globally. In recent years, due to the environmental factors that can affect the development of this condition, such as exposure to herbicides and pesticides, so it has become a younger disease. Currently, the vast majority of studies on the neurotoxic effects of paraquat (PQ) focus on the late mechanisms of neuronal-glial network regulation, and little is known about the early origins of this environmental factor leading to LBD. OBJECTIVE To observe the effect of PQ exposure on intestinal function and to explore the key components of communicating the gut-brain axis by establishing a mouse model. METHODS AND RESULTS In this study, C57BL/6J mice were treated by intraperitoneal injection of 15 mg/kg PQ to construct an LBD time-series model, and confirmed by neurobehavioral testing and pathological examination. After PQ exposure, on the one hand, we found that fecal particle counts and moisture content were abnormal. on the other hand, we found that the expression levels of colonic tight junction proteins decreased, the expression levels of inflammatory markers increased, and the diversity and abundance of gut microbiota altered. In addition, pathological aggregation of α-syn was consistent in the colon and midbrain, and the metabolism and utilization of short-chain fatty acids (SCFAs) were also markedly altered. This suggests that pathological α-syn and SCFAs form the gut may be key components of the communicating gut-brain axis. CONCLUSION In this PQ-induced mouse model, gut microbiota disruption, intestinal epithelial barrier damage, and inflammatory responses may be the main causes of gut dysfunction, and pathological α-syn and SCFAs in the gut may be key components of the communicating gut-brain axis.
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Affiliation(s)
- Kaidong Wang
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China
| | - Chunhui Zhang
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China
| | - Baofu Zhang
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China
| | - Guoliang Li
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China
| | - Ge Shi
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China
| | - Qian Cai
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.
| | - Min Huang
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.
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29
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Kazemi D, Hajishah H, Chadeganipour AS. Association of Total Bilirubin with Motor Signs in Early Parkinson's Disease in LRRK2 Variant Carriers. J Mol Neurosci 2022; 72:2338-2344. [PMID: 36125733 DOI: 10.1007/s12031-022-02067-x] [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: 07/31/2022] [Accepted: 09/13/2022] [Indexed: 12/13/2022]
Abstract
Oxidative stress is considered a possible mechanism in Parkinson's disease (PD) progression. Bilirubin has been recognized as a powerful antioxidant that increases due to heme-oxygenase activity. We aimed to investigate the association of total bilirubin (TB) with motor signs and asymmetry in different stages of early PD. A case-control study was performed to investigate the differences in TB levels in PD patients and healthy controls (HC) both carrying LRRK2 variants. We compared TB levels in HC and Hoehn and Yahr (HY) I and II cohorts separately, followed by multiple linear regression analysis to evaluate the association between TB and motor dysfunction in each stage. We used Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (UPDRS) part III scores and asymmetry scores to address motor disability. Asymmetry scores were calculated from the corresponding UPDRS III tasks. TB was significantly increased in HY II compared to HC (P < 0.001). Positive correlations with TB were found for UPDRS III total score (ρ = 0.303, P = 0.034) and asymmetry score (ρ = 0.418, P = 0.003) in HY I. Multiple linear regression found a significant relationship between TB and asymmetry scores in HY I (R2 = 0.261, P = 0.037), but no relationship was achieved with UPDRS III total scores. Increased TB serves as an important diagnostic marker in earlier stages of PD. A significant relationship was found between TB and motor asymmetry in HY I patients. According to our findings, bilirubin mainly exhibits its protective effects in HY I population.
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Affiliation(s)
- Danial Kazemi
- Faculty of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan, Iran.
| | - Hamed Hajishah
- Student Research Committee, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
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The Interplay between Gut Microbiota and Parkinson's Disease: Implications on Diagnosis and Treatment. Int J Mol Sci 2022; 23:ijms232012289. [PMID: 36293176 PMCID: PMC9603886 DOI: 10.3390/ijms232012289] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
The bidirectional interaction between the gut microbiota (GM) and the Central Nervous System, the so-called gut microbiota brain axis (GMBA), deeply affects brain function and has an important impact on the development of neurodegenerative diseases. In Parkinson’s disease (PD), gastrointestinal symptoms often precede the onset of motor and non-motor manifestations, and alterations in the GM composition accompany disease pathogenesis. Several studies have been conducted to unravel the role of dysbiosis and intestinal permeability in PD onset and progression, but the therapeutic and diagnostic applications of GM modifying approaches remain to be fully elucidated. After a brief introduction on the involvement of GMBA in the disease, we present evidence for GM alterations and leaky gut in PD patients. According to these data, we then review the potential of GM-based signatures to serve as disease biomarkers and we highlight the emerging role of probiotics, prebiotics, antibiotics, dietary interventions, and fecal microbiota transplantation as supportive therapeutic approaches in PD. Finally, we analyze the mutual influence between commonly prescribed PD medications and gut-microbiota, and we offer insights on the involvement also of nasal and oral microbiota in PD pathology, thus providing a comprehensive and up-to-date overview on the role of microbial features in disease diagnosis and treatment.
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31
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Abstract
The mammalian gut contains a large, complex community of microorganisms collectively termed the microbiota. It is increasingly appreciated that gut microbes are closely integrated into mammalian physiology, participating in metabolic symbiosis, promoting immune function and signaling to a wide variety of distant cells, including the brain, via circulating metabolites. Recent advances indicate that microglia, the brain's resident immune cells, are influenced by microbial metabolites at all stages of life, under both physiological and pathological conditions. The pathways by which microbiota regulate microglial function are therefore of interest for investigating links between neurological disorders and gut microbiome changes. In this review, we discuss the effects and mechanisms of microbiota-microglia signaling in steady state, as well as evidence for the involvement of this signaling axis in CNS pathologies.
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Affiliation(s)
- James Cook
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany,CONTACT James Cook
| | - Marco Prinz
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany,Centre for NeuroModulation (Neuromodbasics), University of Freiburg, Freiburg, Germany,Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany,Marco Prinz Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
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López de Frutos L, Almeida F, Murillo-Saich J, Conceição VA, Guma M, Queheberger O, Giraldo P, Miltenberger-Miltenyi G. Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson's Disease. Int J Mol Sci 2022; 23:ijms231810387. [PMID: 36142296 PMCID: PMC9499334 DOI: 10.3390/ijms231810387] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson's disease, suggesting a potential role of these lipids as biomarkers. This project's objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson's patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson's patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography-mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson's groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson's and GBA1-mutation-carrier Parkinson's patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson's. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson's groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson's patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.
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Affiliation(s)
- Laura López de Frutos
- Fundación para el Estudio y la Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain
- GIIS-012, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Francisco Almeida
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649004 Lisbon, Portugal
| | | | - Vasco A. Conceição
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649004 Lisbon, Portugal
| | - Monica Guma
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- VA Medical Center, San Diego, CA 92093, USA
- Department of Medicine, Autonomous University of Barcelona, 08193 Bellaterra, Spain
| | - Oswald Queheberger
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Pilar Giraldo
- Fundación para el Estudio y la Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain
- Correspondence: (P.G.); (G.M.-M.); Tel.: +34-670-285-339 (P.G.); +351-21-799-9435 (G.M.-M.)
| | - Gabriel Miltenberger-Miltenyi
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649004 Lisbon, Portugal
- Laboratório de Genética, Faculdade de Medicina, Universidade de Lisboa, 1649004 Lisbon, Portugal
- Department of Neurology, Ludwig-Maximilians-Universität München, 80539 Munich, Germany
- Genetics Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, 4835-044 Guimarães, Portugal
- Correspondence: (P.G.); (G.M.-M.); Tel.: +34-670-285-339 (P.G.); +351-21-799-9435 (G.M.-M.)
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Bailey MJ, Holzhausen EA, Morgan ZEM, Naik N, Shaffer JP, Liang D, Chang HH, Sarnat J, Sun S, Berger PK, Schmidt KA, Lurmann F, Goran MI, Alderete TL. Postnatal exposure to ambient air pollutants is associated with the composition of the infant gut microbiota at 6-months of age. Gut Microbes 2022; 14:2105096. [PMID: 35968805 PMCID: PMC9466616 DOI: 10.1080/19490976.2022.2105096] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Epidemiological studies in adults have shown that exposure to ambient air pollution (AAP) is associated with the composition of the adult gut microbiome, but these relationships have not been examined in infancy. We aimed to determine if 6-month postnatal AAP exposure was associated with the infant gut microbiota at 6 months of age in a cohort of Latino mother-infant dyads from the Southern California Mother's Milk Study (n = 103). We estimated particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) exposure from birth to 6-months based on residential address histories. We characterized the infant gut microbiota using 16S rRNA amplicon sequencing at 6-months of age. At 6-months, the gut microbiota was dominated by the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Our results show that, after adjusting for important confounders, postnatal AAP exposure was associated with the composition of the gut microbiota. As an example, PM10 exposure was positively associated with Dialister, Dorea, Acinetobacter, and Campylobacter while PM2.5 was positively associated with Actinomyces. Further, exposure to PM10 and PM2.5 was inversely associated with Alistipes and NO2 exposure was positively associated with Actinomyces, Enterococcus, Clostridium, and Eubacterium. Several of these taxa have previously been linked with systemic inflammation, including the genera Dialister and Dorea. This study provides the first evidence of significant associations between exposure to AAP and the composition of the infant gut microbiota, which may have important implications for future infant health and development.
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Affiliation(s)
- Maximilian J. Bailey
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | | | | | - Noopur Naik
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Justin P. Shaffer
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Donghai Liang
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Howard H. Chang
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Jeremy Sarnat
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Shan Sun
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Paige K. Berger
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA
| | - Kelsey A. Schmidt
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA
| | | | - Michael I. Goran
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA
| | - Tanya L. Alderete
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA,CONTACT Tanya L. Alderete Department of Integrative Physiology, University of Colorado, Boulder, CO80309, USA
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34
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Zeng J, Wang X, Pan F, Mao Z. The relationship between Parkinson's disease and gastrointestinal diseases. Front Aging Neurosci 2022; 14:955919. [PMID: 36034146 PMCID: PMC9399652 DOI: 10.3389/fnagi.2022.955919] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/25/2022] [Indexed: 01/03/2023] Open
Abstract
An increasing number of studies have provided evidence for the hypothesis that the pathogenesis of Parkinson's disease (PD) may derive from the gut. Firstly, Lewy pathology can be induced in the enteric nervous system (ENS) and be transported to the central nervous system (CNS) via the vagal nerve. Secondly, the altered composition of gut microbiota causes an imbalance between beneficial and deleterious microbial metabolites which interacts with the increased gut permeability and the gut inflammation as well as the systemic inflammation. The activated inflammatory status then affects the CNS and promotes the pathology of PD. Given the above-mentioned findings, researchers start to pay attention to the connection between PD and gastrointestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), microscopic colitis (MC), gastrointestinal infections, gastrointestinal neoplasms, and colonic diverticular disease (CDD). This review focuses on the association between PD and gastrointestinal diseases as well as the pathogenesis of PD from the gut.
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Affiliation(s)
- Jiaqi Zeng
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xinchan Wang
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Nankai University, Tianjin, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhiqi Mao
- Department of Neurosurgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
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35
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Chen SJ, Lin CH. Gut microenvironmental changes as a potential trigger in Parkinson's disease through the gut-brain axis. J Biomed Sci 2022; 29:54. [PMID: 35897024 PMCID: PMC9327249 DOI: 10.1186/s12929-022-00839-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/22/2022] [Indexed: 11/10/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.
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Affiliation(s)
- Szu-Ju Chen
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.,Department of Neurology, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. .,Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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36
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Du Y, Li X, An Y, Song Y, Lu Y. Association of gut microbiota with sort-chain fatty acids and inflammatory cytokines in diabetic patients with cognitive impairment: A cross-sectional, non-controlled study. Front Nutr 2022; 9:930626. [PMID: 35938126 PMCID: PMC9355148 DOI: 10.3389/fnut.2022.930626] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/30/2022] [Indexed: 12/12/2022] Open
Abstract
Emerging evidence suggests that gut microbiota, short-chain fatty acids (SCFAs), and inflammatory cytokines play important roles in the pathogenesis of diabetic cognitive impairment (DCI). However, little is known about alterations of gut microbiota and SCFA levels as well as the relationships between inflammatory cytokines and cognitive function in Chinese DCI patients. Herein, the differences in the gut microbiota, plasma SCFAs, and inflammatory cytokines in DCI patients and type 2 diabetes mellitus (T2DM) patients were explored. A cross-sectional study of 30 DCI patients and 30 T2DM patients without mild cognitive impairment (MCI) was conducted in Tianjin city, China. The gut microbiota, plasma SCFAs, and inflammatory cytokines were determined using 16S ribosomal RNA (rRNA) gene sequencing, gas chromatography-mass spectrometry (GC-MS), and Luminex immunofluorescence assays, respectively. In addition, the correlation between gut microbiota and DCI clinical characteristics, SCFAs, and inflammatory cytokines was investigated. According to the results, at the genus level, DCI patients presented a greater abundance of Gemmiger, Bacteroides, Roseburia, Prevotella, and Bifidobacterium and a poorer abundance of Escherichia and Akkermansia than T2DM patients. The plasma concentrations of acetic acid, propionic acid, isobutyric acid, and butyric acid plummeted in DCI patients compared to those in T2DM patients. TNF-α and IL-8 concentrations in plasma were significantly higher in DCI patients than in T2DM patients. Moreover, the concentrations of acetic acid, propionic acid, butyric acid, and isovaleric acid in plasma were negatively correlated with TNF-α, while those of acetic acid and butyric acid were negatively correlated with IL-8. Furthermore, the abundance of the genus Alloprevotella was negatively correlated with butyric acid, while that of Holdemanella was negatively correlated with propanoic acid and isobutyric acid. Fusobacterium abundance was negatively correlated with propanoic acid. Clostridium XlVb abundance was negatively correlated with TNF-α, while Shuttleworthia abundance was positively correlated with TNF-α. It was demonstrated that the gut microbiota alterations were accompanied by a change in SCFAs and inflammatory cytokines in DCI in Chinese patients, potentially causing DCI development. These findings might help to identify more effective microbiota-based therapies for DCI in the future.
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Affiliation(s)
- Yage Du
- School of Nursing, Peking University, Beijing, China
| | - Xiaoying Li
- Geriatrics Department, Beijing Jishuitan Hospital, Beijing, China
| | - Yu An
- Endocrinology Department, Beijing Chaoyang Hospital, Beijing, China
| | - Ying Song
- School of Nursing, Peking University, Beijing, China
| | - Yanhui Lu
- School of Nursing, Peking University, Beijing, China
- *Correspondence: Yanhui Lu
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37
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Guo X, Tang P, Hou C, Chong L, Zhang X, Liu P, Chen L, Liu Y, Zhang L, Li R. Integrated Microbiome and Host Transcriptome Profiles Link Parkinson’s Disease to Blautia Genus: Evidence From Feces, Blood, and Brain. Front Microbiol 2022; 13:875101. [PMID: 35722294 PMCID: PMC9204254 DOI: 10.3389/fmicb.2022.875101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/20/2022] [Indexed: 01/01/2023] Open
Abstract
A link between the gut microbiome and Parkinson’s disease (PD) has been intensively studied, and more than 100 differential genera were identified across the studies. However, the predominant genera contributing to PD remain poorly understood. Inspired by recent advances showing microbiota distribution in the blood and brain, we, here, comprehensively investigated currently available fecal microbiome data (1,914 samples) to identify significantly altered genera, which were further validated by comparison to the results from microbiome analysis of blood (85 samples) and brain (268 samples). Our data showed that the composition of fecal microbiota was different from that of blood and brain. We found that Blautia was the unique genus consistently depleted across feces, blood, and brain samples of PD patients (P < 0.05), despite using rigorous criteria to remove contaminants. Moreover, enrichment analyses revealed that host genes correlated with Blautia genus abundance were mainly involved in mitochondrial function and energy metabolism, and mapped to neurodegenerative diseases (NDDs) and metabolic diseases. A random forest classifier constructed with fecal microbiota data demonstrated that Blautia genus was an important feature contributing to discriminating PD patients from controls [receiver operating characteristic (ROC)-area under curve (AUC) = 0.704, precision-recall curve (PRC)-AUC = 0.787]. Through the integration of microbiome and transcriptome, our study depicted microbial profiles in the feces, blood, and brain of PD patients, and identified Blautia genus as a potential genus linked to PD. Further studies are greatly encouraged to determine the role of Blautia genus in the pathogenesis of PD.
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Affiliation(s)
- Xingzhi Guo
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an, China
| | - Peng Tang
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Chen Hou
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Li Chong
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Xin Zhang
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Peng Liu
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Li Chen
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Yue Liu
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Lina Zhang
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
| | - Rui Li
- Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, China
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an, China
- *Correspondence: Rui Li,
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Walker AC, Bhargava R, Dove AS, Brust AS, Owji AA, Czyż DM. Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis. Int J Mol Sci 2022; 23:4807. [PMID: 35563197 PMCID: PMC9103901 DOI: 10.3390/ijms23094807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/14/2022] [Accepted: 04/24/2022] [Indexed: 12/10/2022] Open
Abstract
Neurodegenerative protein conformational diseases are characterized by the misfolding and aggregation of metastable proteins encoded within the host genome. The host is also home to thousands of proteins encoded within exogenous genomes harbored by bacteria, fungi, and viruses. Yet, their contributions to host protein-folding homeostasis, or proteostasis, remain elusive. Recent studies, including our previous work, suggest that bacterial products contribute to the toxic aggregation of endogenous host proteins. We refer to these products as bacteria-derived protein aggregates (BDPAs). Furthermore, antibiotics were recently associated with an increased risk for neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis-possibly by virtue of altering the composition of the human gut microbiota. Other studies have shown a negative correlation between disease progression and antibiotic administration, supporting their protective effect against neurodegenerative diseases. These contradicting studies emphasize the complexity of the human gut microbiota, the gut-brain axis, and the effect of antibiotics. Here, we further our understanding of bacteria's effect on host protein folding using the model Caenorhabditis elegans. We employed genetic and chemical methods to demonstrate that the proteotoxic effect of bacteria on host protein folding correlates with the presence of BDPAs. Furthermore, the abundance and proteotoxicity of BDPAs are influenced by gentamicin, an aminoglycoside antibiotic that induces protein misfolding, and by butyrate, a short-chain fatty acid that we previously found to affect host protein aggregation and the associated toxicity. Collectively, these results increase our understanding of host-bacteria interactions in the context of protein conformational diseases.
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Affiliation(s)
| | | | | | | | | | - Daniel M. Czyż
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA; (A.C.W.); (R.B.); (A.S.D.); (A.S.B.); (A.A.O.)
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39
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Gawlik-Kotelnicka O, Margulska A, Gabryelska A, Sochal M, Białasiewicz P, Strzelecki D. “Leaky Gut” as a Keystone of the Connection between Depression and Obstructive Sleep Apnea Syndrome? A Rationale and Study Design. Metabolites 2022; 12:metabo12020152. [PMID: 35208226 PMCID: PMC8878827 DOI: 10.3390/metabo12020152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 11/16/2022] Open
Abstract
Obstructive sleep apnea (OSA) and depression are highly comorbid. Immune alterations, oxidative stress or microbiota dysfunction have been proposed as some mechanisms underlying this association. The aim of the proposed study is to assess the severity and profile of OSA and depressive symptoms in the context of serum microbiota metabolites, biomarkers of intestinal permeability, inflammation and oxidative stress in adult patients diagnosed with OSA syndrome. The study population consists of 200 subjects. An apnoea-hypopnoea index ≥ 5/hour is used for the diagnosis. Depressive symptoms are assessed with Beck Depression Inventory. Measured serum markers are: tumour necrosis factor–alpha and interleukin-6 for inflammation, total antioxidant capacity and malondialdehyde concentration for oxidative stress, zonulin, calprotectin, lipopolisaccharide-binding protein and intestinal fatty acids-binding protein for intestinal permeability. All of the above will be measured by enzyme-linked immunosorbent assay (ELISA). Associations between clinical symptoms profile and severity and the above markers levels will be tested. It would be valuable to seek for overlap indicators of depression and OSA to create this endophenotype possible biomarkers and form new prophylactic or therapeutic methods. The results may be useful to establish a subpopulation of patients sensitive to microbiota therapeutic interventions (probiotics, prebiotics, and microbiota transplantation).
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Affiliation(s)
- Oliwia Gawlik-Kotelnicka
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 90-419 Lodz, Poland;
- Correspondence: ; Tel.: +48-603819776
| | | | - Agata Gabryelska
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (A.G.); (M.S.); (P.B.)
| | - Marcin Sochal
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (A.G.); (M.S.); (P.B.)
| | - Piotr Białasiewicz
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (A.G.); (M.S.); (P.B.)
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 90-419 Lodz, Poland;
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