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Bremner JD, Russo SJ, Gallagher R, Simon NM. Acute and long-term effects of COVID-19 on brain and mental health: A narrative review. Brain Behav Immun 2025; 123:928-945. [PMID: 39500417 PMCID: PMC11974614 DOI: 10.1016/j.bbi.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/16/2024] [Accepted: 11/02/2024] [Indexed: 11/09/2024] Open
Abstract
BACKGROUND COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome. METHODS This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression. RESULTS Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas. CONCLUSIONS Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.
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Affiliation(s)
- J Douglas Bremner
- Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta Georgia, and the Atlanta VA Medical Center, Decatur, GA, USA; Nash Family Department Neuroscience and Brain-Body Research Center, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Department of Child and Adolescent Psychiatry, New York University (NYU) Langone Health, New York, NY, USA.
| | - Scott J Russo
- Nash Family Department Neuroscience and Brain-Body Research Center, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - Richard Gallagher
- Department of Child and Adolescent Psychiatry, New York University (NYU) Langone Health, New York, NY, USA; Department of Psychiatry, New York University (NYU) Langone Health, New York, NY, USA
| | - Naomi M Simon
- Department of Psychiatry, New York University (NYU) Langone Health, New York, NY, USA
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Fallah A, Sedighian H, Kachuei R, Fooladi AAI. Human microbiome in post-acute COVID-19 syndrome (PACS). CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 8:100324. [PMID: 39717208 PMCID: PMC11665312 DOI: 10.1016/j.crmicr.2024.100324] [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] [Indexed: 12/25/2024] Open
Abstract
The global COVID-19 pandemic, which began in 2019, is still ongoing. SARS-CoV-2, also known as the severe acute respiratory syndrome coronavirus 2, is the causative agent. Diarrhea, nausea, and vomiting are common GI symptoms observed in a significant number of COVID-19 patients. Additionally, the respiratory and GI tracts express high level of transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme-2 (ACE2), making them primary sites for human microbiota and targets for SARS-CoV-2 infection. A growing body of research indicates that individuals with COVID-19 and post-acute COVID-19 syndrome (PACS) exhibit considerable alterations in their microbiome. In various human disorders, including diabetes, obesity, cancer, ulcerative colitis, Crohn's disease, and several viral infections, the microbiota play a significant immunomodulatory role. In this review, we investigate the potential therapeutic implications of the interactions between host microbiota and COVID-19. Microbiota-derived metabolites and components serve as primary mediators of microbiota-host interactions, influencing host immunity. We discuss the various mechanisms through which these metabolites or components produced by the microbiota impact the host's immune response to SARS-CoV-2 infection. Additionally, we address confounding factors in microbiome studies. Finally, we examine and discuss about a range of potential microbiota-based prophylactic measures and treatments for COVID-19 and PACS, as well as their effects on clinical outcomes and disease severity.
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Affiliation(s)
- Arezoo Fallah
- Department of Bacteriology and Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Sedighian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reza Kachuei
- Molecular Biology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Nascimento LS, Marson FAL, dos Santos RDC. Epidemiological profile of patients hospitalized with Crohn's disease due to severe acute respiratory infection during the COVID-19 pandemic: a 2-year report from Brazil. Front Med (Lausanne) 2024; 11:1440101. [PMID: 39507710 PMCID: PMC11537927 DOI: 10.3389/fmed.2024.1440101] [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: 05/29/2024] [Accepted: 09/16/2024] [Indexed: 11/08/2024] Open
Abstract
Background and aims The novel coronavirus-induced severe acute respiratory syndrome (COVID-19) led to one of the most significant global pandemics of the 21st century, causing substantial challenges for healthcare systems worldwide, including those in Brazil. This study aimed to investigate the demographic and clinical profiles of hospitalized patients in Brazil who had both COVID-19 and Crohn's disease (CD) over a 2-year period. Methods An epidemiological analysis was conducted using data from Open-Data-SUS. The study focused on describing the demographic characteristics, clinical manifestations, comorbidities, and hospitalization details of patients afflicted with severe acute respiratory syndrome due to COVID-19 and CD, with the aim of predicting mortality risk. Results The states of São Paulo, Paraná, and Minas Gerais accounted for 50% of the reported COVID-19 cases. The most affected racial group consisted of individuals who self-declared as mixed race. Common comorbidities included heart disease, diabetes mellitus, and obesity. The age group most affected was 25 to 60 years old, particularly among hospitalized patients with both CD and COVID-19 who ultimately succumbed to the illness. A multivariable analysis was conducted to identify the following significant risk factors for death: (a) the presence of neurological disorder (OR = 6.716; 95% CI = 1.954-23.078), (b) the need for intensive care (OR = 3.348; 95% CI = 1.770-6.335), and (c) the need for invasive mechanical ventilation (OR = 59.017; 95% CI = 19.796-175.944). Conclusion There was no discernible gender-based prevalence among hospitalized patients with CD and COVID-19; however, individuals of mixed race were disproportionately affected. The 25 to 60 age group emerged as the most vulnerable demographic group, with high risks of hospitalization and mortality. Moreover, the study highlights the potential for COVID-19 to induce systemic pathologies that may result in long-term degenerative effects and sequelae.
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Affiliation(s)
- Laís Silva Nascimento
- Laboratory of Natural Products, São Francisco University, Bragança Paulista, Brazil
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista, Brazil
| | - Fernando Augusto Lima Marson
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista, Brazil
- Laboratory of Clinical and Molecular Microbiology, São Francisco University, Bragança Paulista, Brazil
- LunGuardian Research Group-Epidemiology of Respiratory and Infectious Diseases, São Francisco University, Bragança Paulista, Brazil
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Menni AE, Tzikos G, Fyntanidou B, Ioannidis A, Loukipoudi L, Grosomanidis V, Chorti A, Shrewsbury A, Stavrou G, Kotzampassi K. The Effect of Probiotics on the Prognostication of the Neutrophil-to-Lymphocyte Ratio in Severe Multi-Trauma Patients. J Pers Med 2024; 14:419. [PMID: 38673046 PMCID: PMC11051514 DOI: 10.3390/jpm14040419] [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: 02/21/2024] [Revised: 04/04/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The ratio of neutrophils to lymphocytes [NLR] is one of the most accepted prognostic indices and demonstrates a positive correlation with the severity of a disease. Given that probiotics exerted immunomodulatory properties and thus positively affected lymphocytopenia induction in severely ill patients, we performed a post hoc analysis in the ProVAP protocol to investigate whether probiotics affected the prognostication of NLR in respect to ventilator-associated pneumonia in multi-trauma patients. This cohort mandatorily involved severe traumatic brain injury patients. METHODS The white blood cell data of all patients, after being retrieved for the days 0 and 7, were statistically assessed in respect to neutrophils, lymphocytes and NLR among the 4 sub-groups of the study: placebo/no-VAP, placebo/VAP, probiotics/no-VAP, and probiotics/VAP. RESULTS Lymphopenia was dominant in placebo sub-groups, while an increased level of lymphocytes was prominent in probiotics sub-groups. This resulted in an increase [p = 0.018] in the NLR value in the probiotics/VAP group in relation to the probiotics/no-VAP cohort; this was an increase of half the value of the placebo/VAP [p < 0.001], while the NLR value in placebo/no-VAP group increased almost four-fold in relation to probiotics/no-VAP [p < 0.001]. Additionally, the ROC curve for probiotic-treated patients revealed a NLR7 cut-off value of 7.20 as a prognostic factor of VAP (AUC: 78.6%, p = 0.015, 95% CI: 62.6-94.5%), having a high specificity of 90.2% and a sensitivity of 42.9%. CONCLUSIONS NLR may considered a credible prognostic biomarker in multi-trauma patients since it can evaluate the immunomodulatory benefits of probiotic treatment. However, the results of the present post hoc analysis should be interpreted meticulously until further evaluation, since they may be basically species- or strain-specific.
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Affiliation(s)
- Alexandra-Eleftheria Menni
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
| | - Georgios Tzikos
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
| | - Barbara Fyntanidou
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Aristeidis Ioannidis
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
| | - Lamprini Loukipoudi
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (L.L.); (V.G.)
| | - Vasilis Grosomanidis
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (L.L.); (V.G.)
| | - Angeliki Chorti
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
| | - Anne Shrewsbury
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
| | - George Stavrou
- Department of General Surgery, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK;
| | - Katerina Kotzampassi
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece (G.T.); (A.I.); (A.C.); (A.S.)
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Wang L, Koelink PJ, Garssen J, Folkerts G, Henricks PAJ, Braber S. Gut Microbiome and Transcriptomic Changes in Cigarette Smoke-Exposed Mice Compared to COPD and CD Patient Datasets. Int J Mol Sci 2024; 25:4058. [PMID: 38612871 PMCID: PMC11012690 DOI: 10.3390/ijms25074058] [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: 02/08/2024] [Revised: 03/12/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) patients and smokers have a higher incidence of intestinal disorders. The aim of this study was to gain insight into the transcriptomic changes in the lungs and intestines, and the fecal microbial composition after cigarette smoke exposure. Mice were exposed to cigarette smoke and their lung and ileum tissues were analyzed by RNA sequencing. The top 15 differentially expressed genes were investigated in publicly available gene expression datasets of COPD and Crohn's disease (CD) patients. The murine microbiota composition was determined by 16S rRNA sequencing. Increased expression of MMP12, GPNMB, CTSK, CD68, SPP1, CCL22, and ITGAX was found in the lungs of cigarette smoke-exposed mice and COPD patients. Changes in the intestinal expression of CD79B, PAX5, and FCRLA were observed in the ileum of cigarette smoke-exposed mice and CD patients. Furthermore, inflammatory cytokine profiles and adhesion molecules in both the lungs and intestines of cigarette smoke-exposed mice were profoundly changed. An altered intestinal microbiota composition and a reduction in bacterial diversity was observed in cigarette smoke-exposed mice. Altered gene expression in the murine lung was detected after cigarette smoke exposure, which might simulate COPD-like alterations. The transcriptomic changes in the intestine of cigarette smoke-exposed mice had some similarities with those of CD patients and were associated with changes in the intestinal microbiome. Future research could benefit from investigating the specific mechanisms underlying the observed gene expression changes due to cigarette smoke exposure, focusing on identifying potential therapeutic targets for COPD and CD.
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Affiliation(s)
- Lei Wang
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (L.W.); (J.G.); (G.F.); (P.A.J.H.)
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Pim J. Koelink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam Gastroenterology, Endocrinology, Metabolism (AGEM), 1105 BK Amsterdam, The Netherlands;
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (L.W.); (J.G.); (G.F.); (P.A.J.H.)
- Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Gert Folkerts
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (L.W.); (J.G.); (G.F.); (P.A.J.H.)
| | - Paul A. J. Henricks
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (L.W.); (J.G.); (G.F.); (P.A.J.H.)
| | - Saskia Braber
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (L.W.); (J.G.); (G.F.); (P.A.J.H.)
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Malik JR, Acharya A, Avedissian SN, Byrareddy SN, Fletcher CV, Podany AT, Dyavar SR. ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics. Int J Mol Sci 2023; 24:8622. [PMID: 37239978 PMCID: PMC10218482 DOI: 10.3390/ijms24108622] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Angiotensin Converting Enzyme 2 (ACE-2), Transmembrane Serine Protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells and are characterized at the molecular level. Some evidence on the expression of entry receptors at mRNA and protein levels in brain cells is available, but co-expression of these receptors and confirmatory evidence on brain cells is lacking. SARS-CoV-2 infects some brain cell types, but infection susceptibility, multiple entry receptor density, and infection kinetics are rarely reported in specific brain cell types. Highly sensitive Taqman ddPCR, flow-cytometry and immunocytochemistry assays were used to quantitate the expression of ACE-2, TMPRSS-2 and Neuropilin-1 at mRNA and protein levels on human brain-extracted pericytes and astrocytes, which are an integral part of the Blood-Brain-Barrier (BBB). Astrocytes showed moderate ACE-2 (15.9 ± 1.3%, Mean ± SD, n = 2) and TMPRSS-2 (17.6%) positive cells, and in contrast show high Neuropilin-1 (56.4 ± 39.8%, n = 4) protein expression. Whereas pericytes showed variable ACE-2 (23.1 ± 20.7%, n = 2), Neuropilin-1 (30.3 ± 7.5%, n = 4) protein expression and higher TMPRSS-2 mRNA (667.2 ± 232.3, n = 3) expression. Co-expression of multiple entry receptors on astrocytes and pericytes allows entry of SARS-CoV-2 and progression of infection. Astrocytes showed roughly four-fold more virus in culture supernatants than pericytes. SARS-CoV-2 cellular entry receptor expression and "in vitro" viral kinetics in astrocytes and pericytes may improve our understanding of viral infection "in vivo". In addition, this study may facilitate the development of novel strategies to counter the effects of SARS-CoV-2 and inhibit viral infection in brain tissues to prevent the spread and interference in neuronal functions.
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Affiliation(s)
- Johid Reza Malik
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.R.M.); (S.N.A.); (C.V.F.)
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (A.A.); (S.N.B.)
| | - Sean N. Avedissian
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.R.M.); (S.N.A.); (C.V.F.)
| | - Siddappa N. Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (A.A.); (S.N.B.)
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, 17177 Stockholm, Sweden
| | - Courtney V. Fletcher
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.R.M.); (S.N.A.); (C.V.F.)
| | - Anthony T. Podany
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.R.M.); (S.N.A.); (C.V.F.)
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.R.M.); (S.N.A.); (C.V.F.)
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Schmidt J, Cruz M, Tolentino J, Carmo A, Paes M, de Lacerda G, Gjorup A, Schmidt S. COVID-19 Patients with Early Gastrointestinal Symptoms Show Persistent Deficits in Specific Attention Subdomains. J Clin Med 2023; 12:jcm12051931. [PMID: 36902717 PMCID: PMC10003448 DOI: 10.3390/jcm12051931] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/17/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Previous studies have shown that COVID-19 inpatients exhibited significant attentional deficits on the day of discharge. However, the presence of gastrointestinal symptoms (GIS) has not been evaluated. Here, we aimed to verify: (1) whether COVID-19 patients with GIS exhibited specific attention deficits; (2) which attention subdomain deficits discriminated patients with GIS and without gastrointestinal symptoms (NGIS) from healthy controls. On admission, the presence of GIS was recorded. Seventy-four physically functional COVID-19 inpatients at discharge and sixty-eight controls underwent a Go/No-go computerized visual attentional test (CVAT). A Multivariate Analysis of Covariance (MANCOVA) was performed to examine group differences in attentional performance. To discriminate which attention subdomain deficits discriminated GIS and NGIS COVID-19 patients from healthy controls, a discriminant analysis was applied using the CVAT variables. The MANCOVA showed a significant overall effect of COVID-19 with GIS on attention performance. The discriminant analysis indicated that the GIS group could be differentiated from the controls by variability of reaction time and omissions errors. The NGIS group could be differentiated from controls by reaction time. Late attention deficits in COVID-19 patients with GIS may reflect a primary problem in the sustained and focused attention subsystems, whereas in NGIS patients the attention problems are related to the intrinsic-alertness subsystem.
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Affiliation(s)
- Juliana Schmidt
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Maria Cruz
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Julio Tolentino
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Aureo Carmo
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Maria Paes
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Glenda de Lacerda
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Ana Gjorup
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Sergio Schmidt
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
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Enichen E, Harvey C, Demmig-Adams B. COVID-19 Spotlights Connections between Disease and Multiple Lifestyle Factors. Am J Lifestyle Med 2023; 17:231-257. [PMID: 36883129 PMCID: PMC9445631 DOI: 10.1177/15598276221123005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2), and the disease it causes (COVID-19), have had a profound impact on global human society and threaten to continue to have such an impact with newly emerging variants. Because of the widespread effects of SARS-CoV-2, understanding how lifestyle choices impact the severity of disease is imperative. This review summarizes evidence for an involvement of chronic, non-resolving inflammation, gut microbiome disruption (dysbiosis with loss of beneficial microorganisms), and impaired viral defenses, all of which are associated with an imbalanced lifestyle, in severe disease manifestations and post-acute sequelae of SARS-CoV-2 (PASC). Humans' physiological propensity for uncontrolled inflammation and severe COVID-19 are briefly contrasted with bats' low propensity for inflammation and their resistance to viral disease. This insight is used to identify positive lifestyle factors with the potential to act in synergy for restoring balance to the immune response and gut microbiome, and thereby protect individuals against severe COVID-19 and PASC. It is proposed that clinicians should consider recommending lifestyle factors, such as stress management, balanced nutrition and physical activity, as preventative measures against severe viral disease and PASC.
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Affiliation(s)
- Elizabeth Enichen
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, USA (EE, CH, BDA)
| | - Caitlyn Harvey
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, USA (EE, CH, BDA)
| | - Barbara Demmig-Adams
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, USA (EE, CH, BDA)
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Zhang L, Zhang Y, Jiang X, Mao L, Xia Y, Fan Y, Li N, Jiang Z, Qin X, Jiang Y, Liu G, Qiu F, Zhang J, Zou Z, Chen C. Disruption of the lung-gut-brain axis is responsible for cortex damage induced by pulmonary exposure to zinc oxide nanoparticles. Toxicology 2023; 485:153390. [PMID: 36535435 DOI: 10.1016/j.tox.2022.153390] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/23/2022]
Abstract
Increasing evidence shows that gut microbiota is important for host health in response to metal nanomaterials exposure. However, the effect of gut microbiota on the cortex damage caused by pulmonary exposure to zinc oxide nanoparticles (ZnONPs) remains mainly unknown. In this study, a total of 48 adult C57BL/6J mice were intratracheally instilled with 0.6 mg/kg ZnONPs in the presence or absence of antibiotics (ABX) treatment. Besides, 24 mice were treated with or without fecal microbiota transplantation (FMT) after the intraperitoneal administration of ABX. Our results demonstrated for the first time that dysbiosis induced by ABX treatment significantly aggravated cortex damage induced by pulmonary exposure to ZnONPs. Such damage might highly occur through the induction of oxidative stress, manifested by the enhancement of antioxidative enzymes and products of lipid peroxidation. However, ferroptosis was not involved in this process. Interestingly, our data revealed that ABX treatment exacerbated the alterations of gut-brain peptides (including Sst, Sstr2, and Htr4) induced by ZnONPs in both gut and cortex tissues. Moreover, fecal microbiota transplantation (FMT) was able to alleviate cerebral cortex damage, oxidative stress, and alterations of gut-brain peptides induced by pulmonary exposure to ZnONPs. The results together indicate that pulmonary exposure to ZnONPs causes cerebral cortex damage possibly via the disruption of the lung-gut-brain axis. These findings not only propose valuable insights into the mechanism of ZnONPs neurotoxicity but also provide a potential therapeutic method against brain disorders induced by pulmonary exposure to ZnONPs. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the The corresponding author on reasonable request.
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Affiliation(s)
- Lingbing Zhang
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Yandan Zhang
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China
| | - Xuejun Jiang
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, PR China; Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, PR China
| | - Lejiao Mao
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China; Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yinyin Xia
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, PR China
| | - Yinzhen Fan
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China
| | - Na Li
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China
| | - Ziqi Jiang
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China
| | - Xia Qin
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Yu Jiang
- Department of Respiratory Medicine, The University‑Town Affiliated Hospital of Chongqing Medical University, Chongqing 401331, PR China
| | - Gang Liu
- Department of Emergency, The University‑Town Affiliated Hospital of Chongqing Medical University, Chongqing 401331, PR China
| | - Feng Qiu
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Jun Zhang
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China; Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Zhen Zou
- Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China; Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Chengzhi Chen
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, PR China; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, PR China.
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10
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Vakili K, Fathi M, Yaghoobpoor S, Sayehmiri F, Nazerian Y, Nazerian A, Mohamadkhani A, Khodabakhsh P, Réus GZ, Hajibeygi R, Rezaei-Tavirani M. The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature. Front Cell Infect Microbiol 2022; 12:983089. [PMID: 36619768 PMCID: PMC9815719 DOI: 10.3389/fcimb.2022.983089] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2022] Open
Abstract
The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.
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Affiliation(s)
- Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sayehmiri
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ashraf Mohamadkhani
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gislaine Z. Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Ramtin Hajibeygi
- Department of Cardiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Wais T, Hasan M, Rai V, Agrawal DK. Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics. Expert Rev Clin Immunol 2022; 18:947-960. [PMID: 35868344 PMCID: PMC9388545 DOI: 10.1080/1744666x.2022.2105697] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Infection with COVID-19 results in acute respiratory symptoms followed by long COVID multi-organ effects presenting with neurological, cardiovascular, musculoskeletal, and gastrointestinal (GI) manifestations. Temporal relationship between gastrointestinal and neurological symptoms is unclear but warranted for exploring better clinical care for COVID-19 patients. AREAS COVERED We critically reviewed the temporal relationship between gut-brain axis after SARS-CoV-2 infection and the molecular mechanisms involved in neuroinvasion following GI infection. Mediators are identified that could serve as biomarkers and therapeutic targets in SARS-CoV-2. We discussed the potential therapeutic approaches to mitigate the effects of GI infection with SARS-CoV-2. EXPERT OPINION Altered gut microbiota cause increased expression of various mediators, including zonulin causing disruption of tight junction. This stimulates enteric nervous system and signals to CNS precipitating neurological sequalae. Published reports suggest potential role of cytokines, immune cells, B(0)AT1 (SLC6A19), ACE2, TMRSS2, TMPRSS4, IFN-γ, IL-17A, zonulin, and altered gut microbiome in gut-brain axis and associated neurological sequalae. Targeting these mediators and gut microbiome to improve immunity will be of therapeutic significance. In-depth research and well-designed large-scale population-based clinical trials with multidisciplinary and collaborative approaches are warranted. Investigating the temporal relationship between organs involved in long-term sequalae is critical due to evolving variants of SARS-CoV-2.
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Affiliation(s)
- Tameena Wais
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Mehde Hasan
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Vikrant Rai
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
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12
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Pandrea I, Brooks K, Desai RP, Tare M, Brenchley JM, Apetrei C. I've looked at gut from both sides now: Gastrointestinal tract involvement in the pathogenesis of SARS-CoV-2 and HIV/SIV infections. Front Immunol 2022; 13:899559. [PMID: 36032119 PMCID: PMC9411647 DOI: 10.3389/fimmu.2022.899559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/25/2022] [Indexed: 01/08/2023] Open
Abstract
The lumen of the gastrointestinal (GI) tract contains an incredibly diverse and extensive collection of microorganisms that can directly stimulate the immune system. There are significant data to demonstrate that the spatial localization of the microbiome can impact viral disease pathogenesis. Here we discuss recent studies that have investigated causes and consequences of GI tract pathologies in HIV, SIV, and SARS-CoV-2 infections with HIV and SIV initiating GI pathology from the basal side and SARS-CoV-2 from the luminal side. Both these infections result in alterations of the intestinal barrier, leading to microbial translocation, persistent inflammation, and T-cell immune activation. GI tract damage is one of the major contributors to multisystem inflammatory syndrome in SARS-CoV-2-infected individuals and to the incomplete immune restoration in HIV-infected subjects, even in those with robust viral control with antiretroviral therapy. While the causes of GI tract pathologies differ between these virus families, therapeutic interventions to reduce microbial translocation-induced inflammation and improve the integrity of the GI tract may improve the prognoses of infected individuals.
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Affiliation(s)
- Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Kelsie Brooks
- Barrier Immunity Section, Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Rahul P. Desai
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Minali Tare
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jason M. Brenchley
- Barrier Immunity Section, Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Cristian Apetrei
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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13
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Chakraborty C, Sharma AR, Bhattacharya M, Dhama K, Lee SS. Altered gut microbiota patterns in COVID-19: Markers for inflammation and disease severity. World J Gastroenterol 2022; 28:2802-2822. [PMID: 35978881 PMCID: PMC9280735 DOI: 10.3748/wjg.v28.i25.2802] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/19/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a severe respiratory illness and alters the gut microbiota, which dynamically interacts with the human immune system. Microbiota alterations include decreased levels of beneficial bacteria and augmentation of opportunistic pathogens. Here, we describe critical factors affecting the microbiota in coronavirus disease 2019 (COVID-19) patients. These include, such as gut microbiota imbalance and gastrointestinal symptoms, the pattern of altered gut microbiota composition in COVID-19 patients, and crosstalk between the microbiome and the gut-lung axis/gut-brain-lung axis. Moreover, we have illustrated the hypoxia state in COVID-19 associated gut microbiota alteration. The role of ACE2 in the digestive system, and control of its expression using the gut microbiota is discussed, highlighting the interactions between the lungs, the gut, and the brain during COVID-19 infection. Similarly, we address the gut microbiota in elderly or co-morbid patients as well as gut microbiota dysbiosis of in severe COVID-19. Several clinical trials to understand the role of probiotics in COVID-19 patients are listed in this review. Augmented inflammation is one of the major driving forces for COVID-19 symptoms and gut microbiome disruption and is associated with disease severity. However, understanding the role of the gut microbiota in immune modulation during SARS-CoV-2 infection may help improve therapeutic strategies for COVID-19 treatment.
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Affiliation(s)
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopaedic Surgery, Hallym University, Chuncheon-si 24252, South Korea
| | | | - Kuldeep Dhama
- Division of Pathology, Indian Council of Agricultural Research (ICAR)-Indian Veterinary Research Institute (IVRI), Bareilly 243122, Uttar Pradesh, India
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University, Chuncheon-si 24252, South Korea
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14
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Jing Y, Wang J, Zhang H, Yang K, Li J, Zhao T, Liu J, Wu J, Chen Y. Alterations of Urinary Microbial Metabolites and Immune Indexes Linked With COVID-19 Infection and Prognosis. Front Immunol 2022; 13:841739. [PMID: 35422810 PMCID: PMC9001849 DOI: 10.3389/fimmu.2022.841739] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) has evolved into an established global pandemic. Metabolomic studies in COVID-19 patients is worth exploring for further available screening methods. In our study, we recruited a study cohort of 350 subjects comprising 248 COVID-19 patients (161 non-severe cases, 60 asymptomatic cases, and 27 severe cases) and 102 healthy controls (HCs), and herein present data with respect to their demographic features, urinary metabolome, immunological indices, and follow-up health status. We found that COVID-19 resulted in alterations of 39 urinary, mainly microbial, metabolites. Using random forest analysis, a simplified marker panel including three microbial metabolites (oxoglutaric acid, indoxyl, and phenylacetamide) was constructed (AUC=0.963, 95% CI, 0.930-0.983), which exhibited higher diagnostic performance than immune feature-based panels between COVID-19 and HC groups (P<0.0001). Meanwhile, we observed that urine metabolic markers enabled discriminating asymptomatic patients (ASY) from HCs (AUC = 0.981, 95% CI, 0.946-0.996), and predicting the incidence of high-risk sequalae in COVID-19 individuals (AUC=0.931, 95% CI, 0.877-0.966). Co-expression network analysis showed that 13 urinary microbial metabolites (e.g., oxoglutaric acid) were significantly correlated with alterations of CD4+, CD3+, and CD8+ T-cells, as well as IFN-γ, IL-2 and IL-4 levels, suggesting close interactions between microbial metabolites and host immune dysregulation in COVID-19. Taken together, our findings indicate that urinary metabolites may have promising potential for screening of COVID-19 in different application scenarios, and provide a new entry point to understand the microbial metabolites and related immune dysfunction in COVID-19.
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Affiliation(s)
- Yixian Jing
- Division of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Wang
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, China
| | - Haiyan Zhang
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, China
| | - Kun Yang
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, China
| | - Jungang Li
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, China
| | - Ting Zhao
- Division of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiaxiu Liu
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Wu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,National Health Commission of the People's Republic of China (NHC) Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yaokai Chen
- Division of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
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