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Pathak A, Agrawal DK. Role of Gut Microbiota in Long COVID: Impact on Immune Function and Organ System Health. ARCHIVES OF MICROBIOLOGY & IMMUNOLOGY 2025; 9:38-53. [PMID: 40051430 PMCID: PMC11883900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/09/2025]
Abstract
SARS-CoV-2 infection has led to a range of long-lasting symptoms, collectively referred to as long COVID. Current research highlights the critical role of angiotensin-converting enzyme 2 (ACE2) in regulating gut microbiota diversity, vascular function, and homeostasis within the renin-angiotensin system (RAS). ACE2 is utilized by the SARS-CoV-2 virus to enter host cells, but its downregulation following infection contributes to gut microbiota dysbiosis and RAS disruption. These imbalances have been linked to a range of long COVID symptoms, including joint pain, chest pain, chronic cough, fatigue, brain fog, anxiety, depression, myalgia, peripheral neuropathy, memory difficulties, and impaired attention. This review investigates the dysregulation caused by SARS-CoV-2 infection and the long-term effects it has on various organ systems, including the musculoskeletal, neurological, renal, respiratory, and cardiovascular systems. We explored the bidirectional interactions between the gut microbiota, immune function, and these organ systems, focusing on how microbiota dysregulation contributes to the chronic inflammation and dysfunction observed in long COVID symptoms. Understanding these interactions is key for identifying effective therapeutic strategies and interventional targets aimed at mitigating the impact of long COVID on organ health and improving patient outcomes.
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Affiliation(s)
- Angelie Pathak
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA
| | - Devendra K Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA
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Labandeira-Garcia JL, Labandeira CM, Guerra MJ, Rodriguez-Perez AI. The role of the brain renin-angiotensin system in Parkinson´s disease. Transl Neurodegener 2024; 13:22. [PMID: 38622720 PMCID: PMC11017622 DOI: 10.1186/s40035-024-00410-3] [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: 12/13/2023] [Accepted: 03/22/2024] [Indexed: 04/17/2024] Open
Abstract
The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
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Affiliation(s)
- Jose Luis Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | | | - Maria J Guerra
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana I Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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Marangi M, Boughattas S, Valzano F, La Bella G, De Nittis R, Margaglione M, Arena F. Prevalence of Blastocystis sp. and other gastrointestinal pathogens among diarrheic COVID-19 patients in Italy. New Microbes New Infect 2024; 58:101228. [PMID: 38406386 PMCID: PMC10884970 DOI: 10.1016/j.nmni.2024.101228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/27/2024] Open
Abstract
Background Gastrointestinal pathogens (GPs) contribute significantly to the burden of illness worldwide with diarrhoea being the most common among gastrointestinal symptoms (GSs). In the COVID-19 disease, diarrhoea, could be one of the initial presenting symptoms. However, no data on the potential correlation between diarrhoea-causing pathogens and SARS-CoV-2 infection are available. Therefore, we carried out a 2-years retrospective study aimed to evaluate the prevalence of "classic" GPs among SARS-CoV-2 infected and non-infected patients with diarrhoea in Italy. Methods Results of SARS-CoV-2 research from nasopharyngeal and detection of GPs from stool swab samples by Allplex™ SARS-CoV-2 and GI Virus, Bacteria and Parasite Assay were analysed for all patients with diarrhoea referring to Policlinico Ospedaliero Universitario, Foggia, (Italy) from February 2022 to October 2023. Results Out of the 833 involved patients, 81 (3.9%) were COVID-19 positive, while 752 (90.3%) were COVID-19 negative. Among COVID-19-positive patients, 37% (n = 30/81) were found positive for one or more GPs with a higher prevalence of protozoan parasites (18.5%) (Blastocystis ST1-ST4 subtypes, Dientamoeba fragilis genotype I), followed by bacteria (7.4%) (Campylobacter sp., Salmonella sp.). Viral pathogens were more frequent among COVID-19 negative patients (Adenovirus, Norovirus). Among GPs, Blastocystis ST3 subtype was the most prevalent registered in the 16% of patients (p = 0.0001). Conclusions Based on obtained results, a likely interaction between the classic GPs and SARS-CoV-2 infection can be speculated, driven by protozoan parasites. Moreover, these results also provide baseline data to understand more deeply Blastocystis sp. role in this scenario of dysbiosis, particularly in those cases of SARS-CoV-2 co-infection.
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Affiliation(s)
- Marianna Marangi
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | | | - Felice Valzano
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Gianfranco La Bella
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
- Istituto Zooprofilattico Sperimentale della Puglia e della Basilicata, Via Manfredonia 20, 71121, Foggia, Italy
| | - Rosella De Nittis
- Microbiology and Virology Unit, Ospedali Riuniti, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Maurizio Margaglione
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Fabio Arena
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
- Microbiology and Virology Unit, Ospedali Riuniti, Viale Luigi Pinto, 71122, Foggia, Italy
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Marzano V, Mortera SL, Marangelo C, Piazzesi A, Rapisarda F, Pane S, Del Chierico F, Vernocchi P, Romani L, Campana A, Palma P, Putignani L, the CACTUS Study Team. The metaproteome of the gut microbiota in pediatric patients affected by COVID-19. Front Cell Infect Microbiol 2023; 13:1327889. [PMID: 38188629 PMCID: PMC10766818 DOI: 10.3389/fcimb.2023.1327889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
Introduction The gut microbiota (GM) play a significant role in the infectivity and severity of COVID-19 infection. However, the available literature primarily focuses on adult patients and it is known that the microbiota undergoes changes throughout the lifespan, with significant alterations occurring during infancy and subsequently stabilizing during adulthood. Moreover, children have exhibited milder symptoms of COVID-19 disease, which has been associated with the abundance of certain protective bacteria. Here, we examine the metaproteome of pediatric patients to uncover the biological mechanisms that underlie this protective effect of the GM. Methods We performed nanoliquid chromatography coupled with tandem mass spectrometry on a high resolution analytical platform, resulting in label free quantification of bacterial protein groups (PGs), along with functional annotations via COG and KEGG databases by MetaLab-MAG. Additionally, taxonomic assignment was possible through the use of the lowest common ancestor algorithm provided by Unipept software. Results A COVID-19 GM functional dissimilarity respect to healthy subjects was identified by univariate analysis. The alteration in COVID-19 GM function is primarily based on bacterial pathways that predominantly involve metabolic processes, such as those related to tryptophan, butanoate, fatty acid, and bile acid biosynthesis, as well as antibiotic resistance and virulence. Discussion These findings highlight the mechanisms by which the pediatric GM could contribute to protection against the more severe manifestations of the disease in children. Uncovering these mechanisms can, therefore, have important implications in the discovery of novel adjuvant therapies for severe COVID-19.
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Affiliation(s)
- Valeria Marzano
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Stefano Levi Mortera
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Chiara Marangelo
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Antonia Piazzesi
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Federica Rapisarda
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Stefania Pane
- Unit of Microbiomics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Federica Del Chierico
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Pamela Vernocchi
- Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Lorenza Romani
- Unit of Infectious Disease, Bambino Gesu’ Children’s Hospital, IRCCS, Rome, Italy
| | - Andrea Campana
- Department of Pediatrics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Paolo Palma
- Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Lorenza Putignani
- Unit of Microbiomics and Research Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Guo C, Yi B, Wu J, Lu J. The microbiome in post-acute infection syndrome (PAIS). Comput Struct Biotechnol J 2023; 21:3904-3911. [PMID: 37602232 PMCID: PMC10432703 DOI: 10.1016/j.csbj.2023.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/22/2023] Open
Abstract
Post-Acute Infection Syndrome (PAIS) is a relatively new medical terminology that represents prolonged sequelae symptoms after acute infection by numerous pathogenic agents. Imposing a substantial public health burden worldwide, PASC (post-acute sequelae of COVID-19 infection) and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) are two of the most recognized and prevalent PAIS conditions. The presences of prior infections and similar symptom profiles in PAIS reflect a plausible common etiopathogenesis. The human microbiome is known to play an essential role in health and disease. In this review, we reviewed and summarized available research on oral and gut microbiota alterations in patients with different infections or PAIS conditions. We discussed key theories about the associations between microbiome dysbiosis and PAIS disease development, aiming to explore the mechanistic roles and potential functions the microbiome may have in the process. Additionally, we discuss the areas of knowledge gaps and propose the potential clinical applications of the microbiome for prevention and treatment of PAIS conditions.
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Affiliation(s)
- Cheng Guo
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, USA
| | - Boyang Yi
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Jianyong Wu
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Jiahai Lu
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
- Hainan Key Novel Thinktank “Hainan Medical University ‘One Health’ Research Center”, Haikou, China
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Tan L, Zhong MM, Liu Q, Chen Y, Zhao YQ, Zhao J, Dusenge MA, Feng Y, Ye Q, Hu J, Ou-Yang ZY, Zhou YH, Guo Y, Feng YZ. Potential interaction between the oral microbiota and COVID-19: a meta-analysis and bioinformatics prediction. Front Cell Infect Microbiol 2023; 13:1193340. [PMID: 37351182 PMCID: PMC10282655 DOI: 10.3389/fcimb.2023.1193340] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/16/2023] [Indexed: 06/24/2023] Open
Abstract
Objectives The purpose of this study was to evaluate available evidence on the association between the human oral microbiota and coronavirus disease 2019 (COVID-19) and summarize relevant data obtained during the pandemic. Methods We searched EMBASE, PubMed, and the Cochrane Library for human studies published up to October 2022. The main outcomes of the study were the differences in the diversity (α and β) and composition of the oral microbiota at the phylum and genus levels between patients with laboratory-confirmed SARS-CoV-2 infection (CPs) and healthy controls (HCs). We used the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA) database, Protein-protein interaction (PPI) network (STRING) and Gene enrichment analysis (Metascape) to evaluate the expression of dipeptidyl peptidase 4 (DPP4) (which is the cell receptor of SARS CoV-2) in oral tissues and evaluate its correlation with viral genes or changes in the oral microbiota. Results Out of 706 studies, a meta-analysis of 9 studies revealed a significantly lower alpha diversity (Shannon index) in CPs than in HCs (standardized mean difference (SMD): -0.53, 95% confidence intervals (95% CI): -0.97 to -0.09). Subgroup meta-analysis revealed a significantly lower alpha diversity (Shannon index) in older than younger individuals (SMD: -0.54, 95% CI: -0.86 to -0.23/SMD: -0.52, 95% CI: -1.18 to 0.14). At the genus level, the most significant changes were in Streptococcus and Neisseria, which had abundances that were significantly higher and lower in CPs than in HCs based on data obtained from six out of eleven and five out of eleven studies, respectively. DPP4 mRNA expression in the oral salivary gland was significantly lower in elderly individuals than in young individuals. Spearman correlation analysis showed that DPP4 expression was negatively correlated with the expression of viral genes. Gene enrichment analysis showed that DPP4-associated proteins were mainly enriched in biological processes, such as regulation of receptor-mediated endocytosis of viruses by host cells and bacterial invasion of epithelial cells. Conclusion The oral microbial composition in COVID-19 patients was significantly different from that in healthy individuals, especially among elderly individuals. DPP4 may be related to viral infection and dysbiosis of the oral microbiome in elderly individuals.
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Affiliation(s)
- Li Tan
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Meng-Mei Zhong
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiong Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yun Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ya-Qiong Zhao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jie Zhao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Marie Aimee Dusenge
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yao Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qin Ye
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Hu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ze-Yue Ou-Yang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying-Hui Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yue Guo
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yun-Zhi Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Ray M, Manjunath A, Halami PM. Effect of probiotics as an immune modulator for the management of COVID-19. Arch Microbiol 2023; 205:182. [PMID: 37031431 PMCID: PMC10098245 DOI: 10.1007/s00203-023-03504-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 04/10/2023]
Abstract
COVID-19, an acute respiratory viral infection conveyed by pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of individuals globally, and is a public health emergency of international concern. Till now, there are no highly effective therapies for this infection without vaccination. As they can evolve quickly and cross the strain level easily, these viruses are causing epidemics or pandemics that are allied with more severe clinical diseases. A new approach is needed to improve immunity to confirm the protection against emerging viral infections. Probiotics can modify gut microbial dysbiosis, improve the host immune system, and stimulate immune signaling, increasing systemic immunity. Several probiotic bacterial therapies have been proven to decrease the period of bacterial or viral infections. Superinduction of inflammation, termed cytokine storm, has been directly linked with pneumonia and severe complications of viral respiratory infections. In this case, probiotics as potential immunomodulatory agents can be an appropriate candidate to improve the host's response to respiratory viral infections. During this COVID-19 pandemic, any approach that can induce mucosal and systemic immunity could be helpful. Here, we summarize contexts regarding the effectiveness of various probiotics for preventing virus-induced respiratory infectious diseases, especially those that could be employed for COVID-19 patients. In addition, the effects of probiotics, their mechanisms on different aspects of immune responses against respiratory viral infection, and their antiviral properties in clinical findings have been described in detail.
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Affiliation(s)
- Mousumi Ray
- Department of Microbiology and Fermentation Technology, CSIR-Central Food Technological Research Institute, Mysuru, 570020, India
| | - Ashwini Manjunath
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, 560012, India
| | - Prakash M Halami
- Department of Microbiology and Fermentation Technology, CSIR-Central Food Technological Research Institute, Mysuru, 570020, India.
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Ahsan K, Anwar MA, Munawar N. Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients. World J Gastroenterol 2023; 29:1708-1720. [PMID: 37077515 PMCID: PMC10107217 DOI: 10.3748/wjg.v29.i11.1708] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/06/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) infection caused by the severe acute respiratory syndrome coronavirus 2 virus, its symptoms, treatment, and post-COVID-19 effects have been a major focus of research since 2020. In addition to respiratory symptoms, different clinical variants of the virus have been associated with dynamic symptoms and multiorgan diseases, including liver abnormalities. The release of cytokines by the activation of innate immune cells during viral infection and the high doses of drugs used for COVID-19 treatment are considered major drivers of liver injury in COVID-19 patients. The degree of hepatic inflammation in patients suffering from chronic liver disease and having COVID-19 could be severe and can be estimated through different liver chemistry abnormality markers. Gut microbiota influences liver chemistry through its metabolites. Gut dysbiosis during COVID-19 treatment can promote liver inflammation. Here, we highlighted the bidirectional association of liver physiology and gut microbiota (gut-liver axis) and its potential to manipulate drug-induced chemical abnormalities in the livers of COVID-19 patients.
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Affiliation(s)
- Khansa Ahsan
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Munir Ahmad Anwar
- Industrial Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Pakistan
| | - Nayla Munawar
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
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Mańkowska-Wierzbicka D, Zuraszek J, Wierzbicka A, Gabryel M, Mahadea D, Baturo A, Zakerska-Banaszak O, Slomski R, Skrzypczak-Zielinska M, Dobrowolska A. Alterations in Gut Microbiota Composition in Patients with COVID-19: A Pilot Study of Whole Hypervariable 16S rRNA Gene Sequencing. Biomedicines 2023; 11:biomedicines11020367. [PMID: 36830905 PMCID: PMC9953267 DOI: 10.3390/biomedicines11020367] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/13/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
It is crucial to consider the importance of the microbiome and the gut-lung axis in the context of SARS-CoV-2 infection. This pilot study examined the fecal microbial composition of patients with COVID-19 following a 3-month recovery. Using for the first time metagenomic analysis based on all hypervariable regions (V1-V9) of the 16S rRNA gene, we have identified 561 microbial species; however, 17 were specific only for the COVID-19 group (n = 8). The patients' cohorts revealed significantly greater alpha diversity of the gut microbiota compared to healthy controls (n = 14). This finding has been demonstrated by operational taxonomic units (OTUs) richness (p < 0.001) and Chao1 index (p < 0.01). The abundance of the phylum Verrucomicrobia was 30 times higher in COVID-19 patients compared to healthy subjects. Accordingly, this disproportion was also noted at other taxonomic levels: in the class Verrucomicrobiae, the family Verrucomicrobiaceae, and the genus Akkermansia. Elevated pathobionts such as Escherichia coli, Bilophila wadsworthia, and Parabacteroides distasonis were found in COVID-19 patients. Considering the gut microbiota's ability to disturb the immune response, our findings suggest the importance of the enteric microbiota in the course of SARS-CoV-2 infection. This pilot study shows that the composition of the microbial community may not be fully restored in individuals with SARS-CoV-2 following a 3-month recovery.
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Affiliation(s)
- Dorota Mańkowska-Wierzbicka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
- Correspondence: (D.M.-W.); (M.S.-Z.)
| | - Joanna Zuraszek
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
| | - Adrianna Wierzbicka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Marcin Gabryel
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Dagmara Mahadea
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Alina Baturo
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | | | - Ryszard Slomski
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
| | - Marzena Skrzypczak-Zielinska
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
- Correspondence: (D.M.-W.); (M.S.-Z.)
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland
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Tovani-Palone MR, Pedersini P. Potential role of the microbiome in liver injury during COVID-19: Further research is needed. World J Gastroenterol 2023; 29:503-507. [PMID: 36688015 PMCID: PMC9850931 DOI: 10.3748/wjg.v29.i3.503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/30/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Although different studies have associated coronavirus disease 2019 (COVID-19) with the occurrence of liver injury, the hepatic injury route during the COVID-19 course is not yet fully understood. In order to better understand the mechanisms of the disease, the human gut microbiota has been the subject of extensive discussion in the context of COVID-19 pathophysiology. However, many questions remain, including the risks of liver injury due to COVID-19 specific populations. Further research in this field could allow the discovery of new personalized treatment strategies aimed at improving the microbiota composition, thereby reducing COVID-19 severity and its complications in different populations. In this article, we discussed basic mechanisms of severe acute respiratory syndrome coronavirus 2 infection and recent evidence on the relationship between COVID-19, the gut microbiome and liver injury as well as proposed recommendations for further research.
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Affiliation(s)
- Marcos Roberto Tovani-Palone
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600077, India
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Gupta P, Rani V. The Surging Mechanistic Role of Angiotensin Converting Enzyme 2 in Human Pathologies: A Potential Approach for Herbal Therapeutics. Curr Drug Targets 2023; 24:1046-1054. [PMID: 37861036 DOI: 10.2174/0113894501247616231009065415] [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: 02/13/2023] [Revised: 07/27/2023] [Accepted: 09/15/2023] [Indexed: 10/21/2023]
Abstract
Advancements in biological sciences revealed the significant role of angiotensin-converting enzyme 2 (ACE2), a key cell surface receptor in various human pathologies. ACE2 is a metalloproteinase that not only functions in the regulation of Angiotensin II but also possesses some non-catalytic roles in the human body. There is considerable uncertainty regarding its protein expression, despite its presence in virtually all organs. The level of ACE2 expression and its subcellular localisation in humans may be a key determinant of susceptibility to various infections, symptoms, and outcomes of numerous diseases. Therefore, we summarize the distribution and expression pattern of ACE2 in different cell types related to all major human tissues and organs. Moreover, this review constitutes accumulated evidences of the important resources for further studies on ACE2 Inhibitory capacity via different natural compounds in order to understand its mechanism as the potential drug target in disease pathophysiology and to aid in the development of an effective therapeutic approach towards the various diseases.
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Affiliation(s)
- Priyadarshini Gupta
- Transcriptome laboratory, Centre of Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida, Uttar Pradesh, India
| | - Vibha Rani
- Transcriptome laboratory, Centre of Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida, Uttar Pradesh, India
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Wang T, Cao Y, Zhang H, Wang Z, Man CH, Yang Y, Chen L, Xu S, Yan X, Zheng Q, Wang Y. COVID-19 metabolism: Mechanisms and therapeutic targets. MedComm (Beijing) 2022; 3:e157. [PMID: 35958432 PMCID: PMC9363584 DOI: 10.1002/mco2.157] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 01/18/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS-CoV-2-induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID-19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS-CoV-2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID-19 metabolism. SARS-CoV-2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS-CoV-2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID-19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS-CoV-2-induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID-19 pandemic.
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Affiliation(s)
- Tianshi Wang
- Shanghai Key Laboratory for Tumor Microenvironment and InflammationDepartment of Biochemistry and Molecular Cell BiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ying Cao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haiyan Zhang
- Bai Jia Obstetrics and Gynecology HospitalShanghaiChina
| | - Zihao Wang
- Fudan University Shanghai Cancer CenterKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyCancer Instituteand The Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- The International Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghaiChina
| | - Cheuk Him Man
- Division of HematologyDepartment of MedicineUniversity of Hong KongPokfulamHong Kong, China
| | - Yunfan Yang
- Department of Cell BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanChina
| | - Lingchao Chen
- Department of NeurosurgeryHuashan HospitalShanghai Medical CollegeFudan UniversityNational Center for Neurological DisordersShanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationNeurosurgical Institute of Fudan UniversityShanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Shuangnian Xu
- Department of HematologySouthwest HospitalArmy Medical UniversityChongqingChina
| | - Xiaojing Yan
- Department of HematologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
| | - Quan Zheng
- Center for Single‐Cell OmicsSchool of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi‐Ping Wang
- Fudan University Shanghai Cancer CenterKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyCancer Instituteand The Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- The International Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghaiChina
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Abstract
COVID-19, which is caused by SARS-CoV-2, is a major public health concern around the world. The beta coronavirus family includes SARS-CoV2, which enters cells via the ACE2 receptor. Patients in Wuhan, China, who suffered from the first sickness had no symptoms concerning the digestive system. Only 2.6% developed diarrhea, and only 2% had chronic liver illness. As the situation becomes more complicated, more people are reporting gastric issues. The disorder is characterized by diarrhea, anorexia, nausea, vomiting, abdominal discomfort and gastrointestinal bleeding, with diarrhea being the most common symptom. Several theories have been proposed for the genesis of gastrointestinal issues. Virus-induced cytopathic effects via ACE2, immune-mediated inflammatory cytokine storm, gut–lung axis function and drug-related damage are among them, not only in cases of COVID-19, but also in gastrointestinal illnesses.
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Affiliation(s)
- Carmine Finelli
- Department of Internal Medicine, ASL Napoli 3 Sud, Via di Marconi, 66, Torre del Greco, 80035 Naples, Italy
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The Concept of Intrauterine Programming and the Development of the Neonatal Microbiome in the Prevention of SARS-CoV-2 Infection. Nutrients 2022; 14:nu14091702. [PMID: 35565670 PMCID: PMC9104449 DOI: 10.3390/nu14091702] [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: 03/13/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
The process of intrauterine programming is related to the quality of the microbiome formed in the fetus and the newborn. The implementation of probiotics, prebiotics, and psychobiotics shows immunomodulatory potential towards the organism, especially the microbiome of the pregnant woman and her child. Nutrigenomics, based on the observation of pregnant women and the developing fetus, makes it possible to estimate the biological effects of active dietary components on gene expression or silencing. Nutritional intervention for pregnant women should consider the nutritional status of the patient, biological markers, and the potential impact of dietary intervention on fetal physiology. The use of a holistic model of nutrition allows for appropriately targeted and effective dietary prophylaxis that can impact the physical and mental health of both the mother and the newborn. This model targets the regulation of the immune response of the pregnant woman and the newborn, considering the clinical state of the microbiota and the pathomechanism of the nervous system. Current scientific reports indicate the protective properties of immunobiotics (probiotics) about the reduction of the frequency of infections and the severity of the course of COVID-19 disease. The aim of this study was to test the hypothesis that intrauterine programming influences the development of the microbiome for the prevention of SARS-CoV-2 infection based on a review of research studies.
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GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation. Cells 2022; 11:cells11071187. [PMID: 35406751 PMCID: PMC8998127 DOI: 10.3390/cells11071187] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.
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