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1.
J Genet Genomics ; 48(9): 803-814, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1720312

ABSTRACT

Children are less susceptible to coronavirus disease 2019 (COVID-19), and they have manifested lower morbidity and mortality after infection, for which a multitude of mechanisms may be considered. Whether the normal development of the gut-airway microbiome in children is affected by COVID-19 has not been evaluated. Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the upper respiratory tract and the gut microbiomes in nine children. The alteration of the microbiome is dominated by the genus Pseudomonas, and it sustains for up to 25-58 days in different individuals. Moreover, the patterns of alternation are different between the upper respiratory tract and the gut. Longitudinal investigation shows that the upper respiratory tract and the gut microbiomes are extremely variable among children during the course of COVID-19. The dysbiosis of microbiome persists in 7 of 8 children for at least 19-24 days after discharge from the hospital. Disturbed development of both the gut and the upper respiratory microbiomes and prolonged dysbiosis in these nine children imply possible long-term complications after clinical recovery from COVID-19, such as predisposition to the increased health risk in the post-COVID-19 era.


Subject(s)
COVID-19/pathology , Computational Biology/methods , Respiratory Tract Infections/microbiology , Dysbiosis/microbiology , Dysbiosis/pathology , Gastrointestinal Microbiome/physiology , Humans
2.
J Genet Genomics ; 48(9): 792-802, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1720311

ABSTRACT

Gut microbial dysbiosis has been linked to many noncommunicable diseases. However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection. Here, we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers, which have recently been identified as molecular signatures predicting the progression of the COVID-19. We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals. We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals. Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation. Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals. These results may provide novel insights into the cross-talk between gut microbiota and host immune system.


Subject(s)
Gastrointestinal Microbiome/physiology , Inflammation/metabolism , COVID-19/microbiology , Dysbiosis/microbiology , Gastrointestinal Microbiome/genetics , Humans , Inflammation/genetics , Proteomics/methods
3.
Gut Microbes ; 14(1): 2031840, 2022.
Article in English | MEDLINE | ID: covidwho-1692369

ABSTRACT

There is a growing debate about the involvement of the gut microbiome in COVID-19, although it is not conclusively understood whether the microbiome has an impact on COVID-19, or vice versa, especially as analysis of amplicon data in hospitalized patients requires sophisticated cohort recruitment and integration of clinical parameters. Here, we analyzed fecal and saliva samples from SARS-CoV-2 infected and post COVID-19 patients and controls considering multiple influencing factors during hospitalization. 16S rRNA gene sequencing was performed on fecal and saliva samples from 108 COVID-19 and 22 post COVID-19 patients, 20 pneumonia controls and 26 asymptomatic controls. Patients were recruited over the first and second corona wave in Germany and detailed clinical parameters were considered. Serial samples per individual allowed intra-individual analysis. We found the gut and oral microbiota to be altered depending on number and type of COVID-19-associated complications and disease severity. The occurrence of individual complications was correlated with low-risk (e.g., Faecalibacterium prausznitzii) and high-risk bacteria (e.g., Parabacteroides ssp.). We demonstrated that a stable gut bacterial composition was associated with a favorable disease progression. Based on gut microbial profiles, we identified a model to estimate mortality in COVID-19. Gut microbiota are associated with the occurrence of complications in COVID-19 and may thereby influencing disease severity. A stable gut microbial composition may contribute to a favorable disease progression and using bacterial signatures to estimate mortality could contribute to diagnostic approaches. Importantly, we highlight challenges in the analysis of microbial data in the context of hospitalization.


Subject(s)
COVID-19/microbiology , Dysbiosis/microbiology , Gastrointestinal Microbiome , Aged , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , COVID-19/complications , COVID-19/mortality , Disease Progression , Dysbiosis/etiology , Feces/microbiology , Female , Humans , Male , Microbiota , Middle Aged , SARS-CoV-2 , Saliva/microbiology , Severity of Illness Index
4.
J Affect Disord ; 303: 187-195, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1676788

ABSTRACT

OBJECTIVE: The microbiota-gut-brain axis is a key pathway perturbed by prolonged stressors to produce brain and behavioral disorders. Frontline healthcare workers (FHWs) fighting against COVID-19 typically experience stressful event sequences and manifest some mental symptoms; however, the role of gut microbiota in such stress-induced mental problems remains unclear. We investigated the association between the psychological stress of FHW and gut microbiota. METHODS: We used full-length 16S rRNA gene sequencing to characterize the longitudinal changes in gut microbiota and investigated the impact of microbial changes on FHWs' mental status. RESULTS: Stressful events induced significant depression, anxiety, and stress in FHWs and disrupted the gut microbiome; gut dysbiosis persisted for at least half a year. Different microbes followed discrete trajectories during the half-year of follow-up. Microbes associated with mental health were mainly Faecalibacterium spp. and [Eubacterium] eligens group spp. with anti-inflammatory effects. Of note, the prediction model indicated that low abundance of [Eubacterium] hallii group uncultured bacterium and high abundance of Bacteroides eggerthii at Day 0 (immediately after the two-month frontline work) were significant determinants of the reappearance of post-traumatic stress symptoms in FHWs. LIMITATIONS: The lack of metabolomic evidence and animal experiments result in the unclear mechanism of gut dysbiosis-related stress symptoms. CONCLUSION: The stressful event sequences of fighting against COVID-19 induce characteristic longitudinal changes in gut microbiota, which underlies dynamic mental state changes.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Stress Disorders, Post-Traumatic , Animals , Dysbiosis/epidemiology , Dysbiosis/microbiology , Feces/microbiology , Health Personnel , Humans , RNA, Ribosomal, 16S/genetics , SARS-CoV-2
5.
J Clin Gastroenterol ; 56(4): 285-298, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1672371

ABSTRACT

BACKGROUND: Gastrointestinal symptoms are common in Coronavirus Disease 2019 (COVID-19), related to infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) of intestinal cells through the angiotensin converting enzyme 2 (ACE2) receptor in the brush border. Also, patients are treated with multiple antibiotics. Therefore, an increase in gut dysbiosis and in the prevalence of Clostridium difficile infection (CDI) is expected in patients with COVID-19. METHODS: A PubMed search was conducted using the terms "gut microbiota," "gut mycobiota," "dysbiosis" AND "COVID-19"; "Clostridium difficile," "Clostridioides difficile" AND "COVID-19"; "probiotics," "bacteriotherapy AND COVID-19." Only case series, observational and experimental studies were included. RESULTS: A total of 384 papers were retrieved and 21 fulfilled selection criteria. Later, a new paper was identified, thus 22 papers were reviewed. Main findings: (1) gut bacterial dysbiosis has been found in fecal samples of COVID-19 patients, with enrichment of opportunistic organisms and decrease of beneficial commensals such as Faecalibacterium prausnitizii. Dysbiosis is related to inflammatory markers and illness severity. (2) There is evidence for abnormal gut barrier and bacterial translocation with a negative impact in the lungs. (3) Fungal dysbiosis correlating with pulmonary mycobiota, has also been found. (4) There is controversy in the CDI rates among COVID-19 patients versus controls and pandemic versus prepandemic era. (5) There is no available evidence yet to support bacteriotherapy in COVID-19. (6) Fecal microbiota transplantation (FMT) has been proposed for COVID-19, although there is no evidence to support it. Also, FMT can be safely used during the pandemic for CDI if strict screening protocols for donors and fecal product are implemented. CONCLUSIONS: In COVID-19 there is bacterial and fungal dysbiosis that correlates with systemic and pulmonary inflammation, and illness severity. Further investigations are warranted to determine the efficacy of bacteriotherapy and FMT for modulating gut dysbiosis in COVID-19.


Subject(s)
COVID-19 , Clostridioides difficile , Clostridium Infections , COVID-19/therapy , Clostridium Infections/therapy , Dysbiosis/microbiology , Dysbiosis/therapy , Fecal Microbiota Transplantation/methods , Humans , SARS-CoV-2
6.
Int J Infect Dis ; 117: 233-240, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1670583

ABSTRACT

BACKGROUND: The COVID-19 pandemic has intensified interest in how the infection affects the lung microbiome of critically ill patients and how it contributes to acute respiratory distress syndrome (ARDS). We aimed to characterize the lower respiratory tract mycobiome of critically ill patients with COVID-19 in comparison to patients without COVID-19. METHODS: We performed an internal transcribed spacer 2 (ITS2) profiling with the Illumina MiSeq platform on 26 respiratory specimens from patients with COVID-19 as well as from 26 patients with non-COVID-19 pneumonia. RESULTS: Patients with COVID-19 were more likely to be colonized with Candida spp. ARDS was associated with lung dysbiosis characterized by a shift to Candida species colonization and a decrease of fungal diversity. We also observed higher bacterial phylogenetic distance among taxa in colonized patients with COVID-19. In patients with COVID-19 not colonized with Candida spp., ITS2 amplicon sequencing revealed an increase of Ascomycota unassigned spp. and 1 Aspergillus spp.-positive specimen. In addition, we found that corticosteroid therapy was frequently associated with positive Galactomannan cell wall component of Aspergillus spp. among patients with COVID-19. CONCLUSION: Our study underpins that ARDS in patients with COVID-19 is associated with lung dysbiosis and that an increased density of Ascomycota unassigned spp. is present in patients not colonized with Candida spp.


Subject(s)
COVID-19 , COVID-19/complications , Candida/genetics , Critical Illness , Dysbiosis/complications , Dysbiosis/microbiology , Humans , Lung/microbiology , Pandemics , Phylogeny
7.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574011

ABSTRACT

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is now pandemic. While most Covid-19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid-19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure. These severe patients are characterized by hyperinflammation with highly increased pro-inflammatory cytokines including IL-6, IL-17 and TNF-alpha as well as C-reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid-19 and plays a key role in the pathogenesis of Covid-19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid-19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid-19, and these include advanced age, concomitant chronic disease, SARS-CoV-2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid-19 due to decreased commensal microbial metabolites, which cause reduced anti-inflammatory mechanisms and chronic low-grade inflammation. The preconditioned immune dysregulation enables SARS-CoV-2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre-existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid-19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid-19.


Subject(s)
Bacteria/metabolism , COVID-19/microbiology , Gastrointestinal Microbiome , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Dysbiosis/genetics , Dysbiosis/immunology , Dysbiosis/microbiology , Dysbiosis/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
8.
Cells ; 10(12)2021 11 25.
Article in English | MEDLINE | ID: covidwho-1542428

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.


Subject(s)
Arachidonic Acids/therapeutic use , Endocannabinoids/therapeutic use , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Lung/pathology , Polyunsaturated Alkamides/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/microbiology , Animals , Arachidonic Acids/pharmacology , Butyrates/metabolism , Cecum/pathology , Cell Separation , Colon/drug effects , Colon/pathology , Discriminant Analysis , Dysbiosis/complications , Dysbiosis/microbiology , Endocannabinoids/pharmacology , Enterotoxins , Female , Gastrointestinal Tract/drug effects , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphocyte Activation/drug effects , Mice, Inbred C57BL , Pneumonia/drug therapy , Pneumonia/microbiology , Polyunsaturated Alkamides/pharmacology , Respiratory Distress Syndrome/complications , T-Lymphocytes/drug effects
9.
Curr Med Sci ; 41(6): 1087-1095, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1540258

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is often accompanied by gastrointestinal symptoms, which are related to gut microbiota dysbiosis (GMD). Whether washed microbiota transplantation (WMT) is an effective treatment for COVID-19 patients suspected of having GMD by restoring the gut microbiota is unknown. This study is designed to explore the efficacy and safety of WMT in COVID-19 patients suspected of having GMD. METHODS: This is a randomized, multicenter, single-blind prospective study. COVID-19 patients suspected of having GMD will be randomly divided to receive routine treatment only or to receive routine treatment and WMT. The frequency of WMT will be once a day for three consecutive days. Laboratory and imaging examinations will be performed at admission, 1 and 2 weeks after treatment, and on the day of discharge. Then a telephone follow-up will be conducted at 1st week, 2nd week, and 6th month after discharge. The clinical efficacy and safety of WMT in COVD-19 patients suspected of having GMD and the effects of WMT on the organ function, homeostasis, inflammatory response, intestinal mucosal barrier function, and immunity of the patients will be evaluated. RESULTS: By following the proposed protocol, WMT is expected to be efficacious and safe for the treatment of COVID-19 patients suspected of having GMD, and the therapeutic effect is expected to be associated with improvement of the intestinal mucosal barrier function, inflammatory response, and immunity. CONCLUSION: The findings from this study may offer a new approach for the prevention and treatment of COVID-19 patients suspected of having GMD.


Subject(s)
COVID-19/microbiology , COVID-19/therapy , Dysbiosis/microbiology , Dysbiosis/therapy , Fecal Microbiota Transplantation/methods , Gastrointestinal Microbiome , SARS-CoV-2 , Adult , Aged , COVID-19/complications , China , Clinical Protocols , Dysbiosis/etiology , Fecal Microbiota Transplantation/adverse effects , Female , Humans , Living Donors , Male , Middle Aged , Prospective Studies , Safety , Single-Blind Method , Treatment Outcome , Young Adult
10.
Front Immunol ; 12: 765965, 2021.
Article in English | MEDLINE | ID: covidwho-1497082

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an unprecedented global crisis. Although primarily a respiratory illness, dysregulated immune responses may lead to multi-organ dysfunction. Prior data showed that the resident microbial communities of gastrointestinal and respiratory tracts act as modulators of local and systemic inflammatory activity (the gut-lung axis). Evolving evidence now signals an alteration in the gut microbiome, brought upon either by cytokines from the infected respiratory tract or from direct infection of the gut, or both. Dysbiosis leads to a "leaky gut". The intestinal permeability then allows access to bacterial products and toxins into the circulatory system and further exacerbates the systemic inflammatory response. In this review, we discuss the available data related to the role of the gut microbiome in the development and progression of COVID-19. We provide mechanistic insights into early data with a focus on immunological crosstalk and the microbiome's potential as a biomarker and therapeutic target.


Subject(s)
COVID-19/microbiology , Cytokine Release Syndrome/microbiology , Dysbiosis/microbiology , Gastrointestinal Microbiome/immunology , SARS-CoV-2/physiology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Dysbiosis/immunology , Humans , Immunity , Inflammation
11.
Sci Rep ; 11(1): 21297, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1493220

ABSTRACT

The COVID-19 outbreak has caused over three million deaths worldwide. Understanding the pathology of the disease and the factors that drive severe and fatal clinical outcomes is of special relevance. Studying the role of the respiratory microbiota in COVID-19 is especially important as the respiratory microbiota is known to interact with the host immune system, contributing to clinical outcomes in chronic and acute respiratory diseases. Here, we characterized the microbiota in the respiratory tract of patients with mild, severe, or fatal COVID-19, and compared it to healthy controls and patients with non-COVID-19-pneumonia. We comparatively studied the microbial composition, diversity, and microbiota structure between the study groups and correlated the results with clinical data. We found differences in the microbial composition for COVID-19 patients, healthy controls, and non-COVID-19 pneumonia controls. In particular, we detected a high number of potentially opportunistic pathogens associated with severe and fatal levels of the disease. Also, we found higher levels of dysbiosis in the respiratory microbiota of patients with COVID-19 compared to the healthy controls. In addition, we detected differences in diversity structure between the microbiota of patients with mild, severe, and fatal COVID-19, as well as the presence of specific bacteria that correlated with clinical variables associated with increased risk of mortality. In summary, our results demonstrate that increased dysbiosis of the respiratory tract microbiota in patients with COVID-19 along with a continuous loss of microbial complexity structure found in mild to fatal COVID-19 cases may potentially alter clinical outcomes in patients. Taken together, our findings identify the respiratory microbiota as a factor potentially associated with the severity of COVID-19.


Subject(s)
Bacteria/genetics , COVID-19/microbiology , COVID-19/mortality , Dysbiosis/microbiology , Microbiota/genetics , Respiratory System/microbiology , SARS-CoV-2/genetics , Severity of Illness Index , Adolescent , Adult , Aged , COVID-19/pathology , Case-Control Studies , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Phylogeny , RNA, Ribosomal, 16S/genetics , Young Adult
12.
Microbiol Spectr ; 9(2): e0005521, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1467670

ABSTRACT

Bacterial-viral interactions in saliva have been associated with morbidity and mortality for respiratory viruses such as influenza and SARS-CoV. However, such transkingdom relationships during SARS-CoV-2 infection are currently unknown. Here, we aimed to elucidate the relationship between saliva microbiota and SARS-CoV-2 in a cohort of newly hospitalized COVID-19 patients and controls. We used 16S rRNA sequencing to compare microbiome diversity and taxonomic composition between COVID-19 patients (n = 53) and controls (n = 59) and based on saliva SARS-CoV-2 viral load as measured using reverse transcription PCR (RT-PCR). The saliva microbiome did not differ markedly between COVID-19 patients and controls. However, we identified significant differential abundance of numerous taxa based on saliva SARS-CoV-2 viral load, including multiple species within Streptococcus and Prevotella. IMPORTANCE Alterations to the saliva microbiome based on SARS-CoV-2 viral load indicate potential biologically relevant bacterial-viral relationships which may affect clinical outcomes in COVID-19 disease.


Subject(s)
Bacteria/classification , COVID-19/pathology , Microbial Interactions/physiology , SARS-CoV-2/isolation & purification , Saliva/microbiology , Bacteria/genetics , Dysbiosis/microbiology , Female , Humans , Male , Microbiota/genetics , Middle Aged , Nasopharynx/microbiology , RNA, Ribosomal, 16S/genetics , Viral Load
13.
Am J Chin Med ; 49(2): 237-268, 2021.
Article in English | MEDLINE | ID: covidwho-1365230

ABSTRACT

Intestinal flora is essential for maintaining host health and plays a unique role in transforming Traditional Chinese Medicine (TCM). TCM, as a bodyguard, has saved countless lives and maintained human health in the long history, especially in this COVID-19 pandemic. Pains of diseases have been removed from the effective TCM therapy, such as TCM preparation, moxibustion, and acupuncture. With the development of life science and technology, the wisdom and foresight of TCM has been more displayed. Furthermore, TCM has been also inherited and developed in innovation to better realize the modernization and globalization. Nowadays, intestinal flora transforming TCM and TCM targeted intestinal flora treating diseases have been important findings in life science. More and more TCM researches showed the significance of intestinal flora. Intestinal flora is also a way to study TCM to elucidate the profound theory of TCM. Processing, compatibility, and properties of TCM are well demonstrated by intestinal flora. Thus, it is no doubt that intestinal flora is a core in TCM study. The interaction between intestinal flora and TCM is so crucial for host health. Therefore, it is necessary to sum up the latest results in time. This paper systematically depicted the profile of TCM and the importance of intestinal flora in host. What is more, we comprehensively summarized and discussed the latest progress of the interplay between TCM and intestinal flora to better reveal the core connotation of TCM.


Subject(s)
Drugs, Chinese Herbal/therapeutic use , Dysbiosis/microbiology , Gastrointestinal Microbiome , Medicine, Chinese Traditional , Autoimmune Diseases/microbiology , Autoimmune Diseases/therapy , COVID-19 , Cardiovascular Diseases/microbiology , Cardiovascular Diseases/therapy , Diabetes Mellitus/microbiology , Diabetes Mellitus/therapy , Electroacupuncture , Gastrointestinal Diseases/microbiology , Gastrointestinal Diseases/therapy , Humans , Metabolic Diseases/microbiology , Metabolic Diseases/therapy , Neoplasms/microbiology , Neoplasms/therapy , Non-alcoholic Fatty Liver Disease/microbiology , Non-alcoholic Fatty Liver Disease/therapy , Obesity/microbiology , Obesity/therapy , Renal Insufficiency, Chronic/microbiology , Renal Insufficiency, Chronic/therapy , SARS-CoV-2
14.
mBio ; 12(4): e0177721, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1360545

ABSTRACT

Viral infection of the respiratory tract can be associated with propagating effects on the airway microbiome, and microbiome dysbiosis may influence viral disease. Here, we investigated the respiratory tract microbiome in coronavirus disease 2019 (COVID-19) and its relationship to disease severity, systemic immunologic features, and outcomes. We examined 507 oropharyngeal, nasopharyngeal, and endotracheal samples from 83 hospitalized COVID-19 patients as well as non-COVID patients and healthy controls. Bacterial communities were interrogated using 16S rRNA gene sequencing, and the commensal DNA viruses Anelloviridae and Redondoviridae were quantified by qPCR. We found that COVID-19 patients had upper respiratory microbiome dysbiosis and greater change over time than critically ill patients without COVID-19. Oropharyngeal microbiome diversity at the first time point correlated inversely with disease severity during hospitalization. Microbiome composition was also associated with systemic immune parameters in blood, as measured by lymphocyte/neutrophil ratios and immune profiling of peripheral blood mononuclear cells. Intubated patients showed patient-specific lung microbiome communities that were frequently highly dynamic, with prominence of Staphylococcus. Anelloviridae and Redondoviridae showed more frequent colonization and higher titers in severe disease. Machine learning analysis demonstrated that integrated features of the microbiome at early sampling points had high power to discriminate ultimate level of COVID-19 severity. Thus, the respiratory tract microbiome and commensal viruses are disturbed in COVID-19 and correlate with systemic immune parameters, and early microbiome features discriminate disease severity. Future studies should address clinical consequences of airway dysbiosis in COVID-19, its possible use as biomarkers, and the role of bacterial and viral taxa identified here in COVID-19 pathogenesis. IMPORTANCE COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory tract, results in highly variable outcomes ranging from minimal illness to death, but the reasons for this are not well understood. We investigated the respiratory tract bacterial microbiome and small commensal DNA viruses in hospitalized COVID-19 patients and found that each was markedly abnormal compared to that in healthy people and differed from that in critically ill patients without COVID-19. Early airway samples tracked with the level of COVID-19 illness reached during hospitalization, and the airway microbiome also correlated with immune parameters in blood. These findings raise questions about the mechanisms linking SARS-CoV-2 infection and other microbial inhabitants of the airway, including whether the microbiome might regulate severity of COVID-19 disease and/or whether early microbiome features might serve as biomarkers to discriminate disease severity.


Subject(s)
Bacteria/classification , Dysbiosis/microbiology , Lung/microbiology , Nasopharynx/microbiology , Oropharynx/microbiology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Anelloviridae/classification , Anelloviridae/genetics , Anelloviridae/isolation & purification , Bacteria/genetics , Bacteria/isolation & purification , COVID-19/pathology , Female , Humans , Lymphocyte Count , Male , Microbiota , Middle Aged , RNA, Ribosomal, 16S/genetics , Severity of Illness Index
15.
PLoS One ; 16(6): e0253293, 2021.
Article in English | MEDLINE | ID: covidwho-1280625

ABSTRACT

BACKGROUND: Human microbiotas are communities of microorganisms living in symbiosis with humans. They play an important role in the host immune response to respiratory viral infection. However, evidence on the human microbiome and coronavirus disease (COVID-19) relationship is insufficient. The aim of this systematic literature review was to evaluate existing evidence on the association between the microbiome and COVID-19 in humans and summarize these data in the pandemic era. METHODS: We conducted a systematic literature review on the association between the microbiome and COVID-19 in humans by searching PubMed, Embase, and the Cochrane Library, CINAHL, and Web of Science databases for articles in English published up to October 31, 2020. The results were analyzed qualitatively. This study is registered with PROSPERO (CRD42020195982). RESULTS: Of the 543 articles identified by searching databases, 16 in line with the research objectives were eligible for qualitative review: eight sampled the microbiome using stool, four using nasopharyngeal or throat swab, three using bronchoalveolar lavage fluid, and one using lung tissue. Fecal microbiome dysbiosis and increased opportunistic pathogens were reported in COVID-19 patients. Several studies suggested the dysbiosis in the lung microbiome of COVID-19 patients with an abundance of opportunistic pathogens using lower respiratory tract samples. The association between COVID-19 severity and the human microbiome remains uncertain. CONCLUSION: The human fecal and respiratory tract microbiome changed in COVID-19 patients with opportunistic pathogen abundance. Further research to elucidate the effect of alternation of the human microbiome in disease pathogenesis is warranted.


Subject(s)
COVID-19/microbiology , Dysbiosis/microbiology , Microbiota , Nasopharynx/microbiology , Bronchoalveolar Lavage Fluid , Dysbiosis/virology , Feces/microbiology , Gastrointestinal Microbiome , Humans
16.
Front Immunol ; 12: 660179, 2021.
Article in English | MEDLINE | ID: covidwho-1264332

ABSTRACT

The complex interplay between the gut microbiota, the intestinal barrier, the immune system and the liver is strongly influenced by environmental and genetic factors that can disrupt the homeostasis leading to disease. Among the modulable factors, diet has been identified as a key regulator of microbiota composition in patients with metabolic syndrome and related diseases, including the metabolic dysfunction-associated fatty liver disease (MAFLD). The altered microbiota disrupts the intestinal barrier at different levels inducing functional and structural changes at the mucus lining, the intercellular junctions on the epithelial layer, or at the recently characterized vascular barrier. Barrier disruption leads to an increased gut permeability to bacteria and derived products which challenge the immune system and promote inflammation. All these alterations contribute to the pathogenesis of MAFLD, and thus, therapeutic approaches targeting the gut-liver-axis are increasingly being explored. In addition, the specific changes induced in the intestinal flora may allow to characterize distinctive microbial signatures for non-invasive diagnosis, severity stratification and disease monitoring.


Subject(s)
Gastrointestinal Microbiome/immunology , Intestinal Mucosa/immunology , Liver/immunology , Metabolic Syndrome/immunology , Non-alcoholic Fatty Liver Disease/immunology , Animals , CCR5 Receptor Antagonists/therapeutic use , Dysbiosis/immunology , Dysbiosis/microbiology , Humans , Imidazoles/therapeutic use , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Liver/metabolism , Liver/pathology , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Sulfoxides/therapeutic use
17.
Sci Rep ; 11(1): 10103, 2021 05 12.
Article in English | MEDLINE | ID: covidwho-1226438

ABSTRACT

COVID-19 infection may predispose to secondary bacterial infection which is associated with poor clinical outcome especially among critically ill patients. We aimed to characterize the lower respiratory tract bacterial microbiome of COVID-19 critically ill patients in comparison to COVID-19-negative patients. We performed a 16S rRNA profiling on bronchoalveolar lavage (BAL) samples collected between April and May 2020 from 24 COVID-19 critically ill subjects and 24 patients with non-COVID-19 pneumonia. Lung microbiome of critically ill patients with COVID-19 was characterized by a different bacterial diversity (PERMANOVA on weighted and unweighted UniFrac Pr(> F) = 0.001) compared to COVID-19-negative patients with pneumonia. Pseudomonas alcaligenes, Clostridium hiranonis, Acinetobacter schindleri, Sphingobacterium spp., Acinetobacter spp. and Enterobacteriaceae, characterized lung microbiome of COVID-19 critically ill patients (LDA score > 2), while COVID-19-negative patients showed a higher abundance of lung commensal bacteria (Haemophilus influenzae, Veillonella dispar, Granulicatella spp., Porphyromonas spp., and Streptococcus spp.). The incidence rate (IR) of infections during COVID-19 pandemic showed a significant increase of carbapenem-resistant Acinetobacter baumannii (CR-Ab) infection. In conclusion, SARS-CoV-2 infection and antibiotic pressure may predispose critically ill patients to bacterial superinfection due to opportunistic multidrug resistant pathogens.


Subject(s)
Bacteria/isolation & purification , COVID-19/microbiology , Dysbiosis/microbiology , Lung/microbiology , Aged , Bronchoalveolar Lavage Fluid/microbiology , COVID-19/diagnosis , Critical Illness , Dysbiosis/complications , Female , Humans , Male , Microbiota , Middle Aged , SARS-CoV-2/isolation & purification
18.
Commun Biol ; 4(1): 480, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1182874

ABSTRACT

The relationship between gut microbes and COVID-19 or H1N1 infections is not fully understood. Here, we compared the gut mycobiota of 67 COVID-19 patients, 35 H1N1-infected patients and 48 healthy controls (HCs) using internal transcribed spacer (ITS) 3-ITS4 sequencing and analysed their associations with clinical features and the bacterial microbiota. Compared to HCs, the fungal burden was higher. Fungal mycobiota dysbiosis in both COVID-19 and H1N1-infected patients was mainly characterized by the depletion of fungi such as Aspergillus and Penicillium, but several fungi, including Candida glabrata, were enriched in H1N1-infected patients. The gut mycobiota profiles in COVID-19 patients with mild and severe symptoms were similar. Hospitalization had no apparent additional effects. In COVID-19 patients, Mucoromycota was positively correlated with Fusicatenibacter, Aspergillus niger was positively correlated with diarrhoea, and Penicillium citrinum was negatively correlated with C-reactive protein (CRP). In H1N1-infected patients, Aspergillus penicilloides was positively correlated with Lachnospiraceae members, Aspergillus was positively correlated with CRP, and Mucoromycota was negatively correlated with procalcitonin. Therefore, gut mycobiota dysbiosis occurs in both COVID-19 patients and H1N1-infected patients and does not improve until the patients are discharged and no longer require medical attention.


Subject(s)
COVID-19/physiopathology , Dysbiosis/microbiology , Gastrointestinal Microbiome/physiology , Influenza, Human/physiopathology , Adult , Aged , Bacteria/classification , Bacteria/genetics , COVID-19/virology , Feces/microbiology , Female , Fungi/classification , Fungi/genetics , Gastrointestinal Microbiome/genetics , Humans , Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/virology , Male , Middle Aged , SARS-CoV-2/physiology , Sequence Analysis, DNA/methods
19.
Front Cell Infect Microbiol ; 11: 590874, 2021.
Article in English | MEDLINE | ID: covidwho-1158345

ABSTRACT

Gut microbiome alterations may play a paramount role in determining the clinical outcome of clinical COVID-19 with underlying comorbid conditions like T2D, cardiovascular disorders, obesity, etc. Research is warranted to manipulate the profile of gut microbiota in COVID-19 by employing combinatorial approaches such as the use of prebiotics, probiotics and symbiotics. Prediction of gut microbiome alterations in SARS-CoV-2 infection may likely permit the development of effective therapeutic strategies. Novel and targeted interventions by manipulating gut microbiota indeed represent a promising therapeutic approach against COVID-19 immunopathogenesis and associated co-morbidities. The impact of SARS-CoV-2 on host innate immune responses associated with gut microbiome profiling is likely to contribute to the development of key strategies for application and has seldom been attempted, especially in the context of symptomatic as well as asymptomatic COVID-19 disease.


Subject(s)
COVID-19/pathology , Dysbiosis/microbiology , Gastrointestinal Microbiome/immunology , Gastrointestinal Tract/microbiology , Immunity, Innate/immunology , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Bacteria/metabolism , COVID-19/therapy , Cardiovascular Diseases/pathology , Diabetes Mellitus, Type 2/pathology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/metabolism , Gene Expression/genetics , Humans , Leukocyte L1 Antigen Complex/biosynthesis , Obesity/pathology , Probiotics/pharmacology , SARS-CoV-2/immunology , Severity of Illness Index
20.
Curr Opin Allergy Clin Immunol ; 21(3): 245-251, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1153254

ABSTRACT

PURPOSE OF REVIEW: Data regarding the effects of coronavirus disease 2019 (COVID-19) on host-microbiome alteration and subsequent effects on susceptibility and clinical course of COVID-19, especially in atopic patients, are currently limited. Here, we review the studies regarding the microbiome of atopic patients with other respiratory infections and discuss the potential role of probiotics as therapeutic targets for COVID-19 to decrease its susceptibility and severity of COVID-19. RECENT FINDINGS: Respiratory tract virus infection affects the gut and airway microbiome structures and host's immune function. Diverse factors in atopic diseases affect the airway and gut microbiome structures, which are expected to negatively influence host health. However, response to respiratory virus infection in atopic hosts depends on the preexisting microbiome and immune responses. This may explain the inconclusiveness of the effects of COVID-19 on the susceptibility, morbidity, and mortality of patients with atopic diseases. Beneficial probiotics may be a therapeutic adjuvant in COVID-19 infection as the beneficial microbiome can decrease the viral load in the early phase of respiratory virus infection and improve the morbidity and mortality. SUMMARY: Application of probiotics can be a potential adjuvant treatment in respiratory virus infection to improve host immune responses and disturbed microbiome structures in atopic patients. Further related studies involving COVID-19 are warranted in near future.


Subject(s)
COVID-19 , Dysbiosis , Gastrointestinal Microbiome/immunology , Hypersensitivity , Pandemics , Probiotics/therapeutic use , SARS-CoV-2/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/microbiology , COVID-19/therapy , Dysbiosis/epidemiology , Dysbiosis/immunology , Dysbiosis/microbiology , Dysbiosis/therapy , Humans , Hypersensitivity/epidemiology , Hypersensitivity/immunology , Hypersensitivity/microbiology , Hypersensitivity/therapy
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