The upper respiratory tract microbiome and its role in human health: barrier function.

The human respiratory tract is a complex system characterized by a series of niches colonized with specific microbial communities. Until recently, researchers were mostly interested in lung microbiomes associated with acute and chronic infections. The upper respiratory tract microbiota has gained attention during COVID-19 (COronaVIrus Disease 2019) pandemic because it was suspected to influence the course and the outcome of viral infections. Aim. In this two-part review (see part 1, Pul'monologiya. 2022;32 (5): 745-754), we summarize current knowledge of the microbial communities at each upper respiratory tract location, considering the proposed barrier function of the respiratory microbiome. Conclusion. Based on the evidence presented in this review, we can see how the respiratory microbiome is involved in the pathogenesis of viral respiratory infections, including SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2).Copyright © Starikova E.V. et al., 2022.

The gut microbiome and severity of SARS-CoV-2 infection: what is the link?

In the recent years, studies of the human microbiome have aroused great interest. Several evidences suggest a connection between the gut microbiome and the human immune response at the pulmonary level, which has been defined as the "gut-lung axis". The clinical symptoms of COVID-19 are varied and include gastrointestinal manifestations such as diarrhea, which has been linked to alterations in the gut microbiome;imbalance of the immune response;and delayed viral clearance. The aim of this narrative review was to address the role of the gut microbiome in the respiratory health and in particular, its association with the severity of COVID-19. The gut microbiome plays several important roles therefore;its balance is determinant for the human health, due to its relationship with several essential physiological processes, including maturation of both of the innate and the adaptive immune responses. Intestinal dysbiosis has an impact on the respiratory mucosa, and in turn on infection of the intestinal epithelial cells by SARS-CoV-2, which can induce intestinal inflammation and gastrointestinal symptoms. All these symptoms could contribute to an altered inflammatory immune response to SARS-CoV-2, favoring infection, dissemination and severity of the disease. Knowledge about the roles of the gut microbiome and its interactions in the context of SARS-CoV-2 infection could help to find biomarkers involved in COVID-19-related dysbiosis, as well as to determine the possible therapeutic targets for treatment of these patients. © 2022, Egyptian Association for Medical Mycologists (EAMM). All rights reserved.

The upper respiratory tract microbiome and its role in human health: biotopes and variability

Human respiratory tract is a complex system with a specific microbiological profile. Until recently, researchers were mostly interested in lung microbial communities associated with acute and chronic infections. The upper respiratory tract microbiota has gained attention during COVID-19 pandemic as it was proposed to be one of the factors affecting the course and the outcome of viral infections. The aim. In this review, we summarized the current knowledge about microbial communities in each section of the upper respiratory tract, considering the proposed barrier function of the respiratory microbiome. Conclusion. The facts provided in the first part of this review give a modern perspective on the structure of microbial communities of each part of the upper respiratory tract and factors that affect their variability. Copyright © 2022 Medical Education. All rights reserved.

Microbial Dysbiosis and Epithelial Dysfunction in Vitamin A-Deficient Lungs

Once believed to be sterile, recent studies now show microbes inhabiting healthy lungs that are dysregulated in patients with chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), and SARS-CoV-2 infection. Other studies have shown an increase in pulmonary disease and recurrent respiratory infections in malnourished patients. According to the World Health Organization, vitamin A deficiency (VAD) is now a major public health issue in low-income communities and many developing countries. While VAD has been shown to alter gene expression and tissue morphology in humans and mice, research suggests the lung microbiome plays an intimate role in the metabolic regulation, pathogen inhibition, and inflammatory responses in the lung. Whether dysbiosis is a cause or consequence of chronic respiratory conditions, or whether retinoic acid (RA) - the bioactive metabolite of Vitamin A - is essential for lung microbiome homeostasis, remains unknown. Therefore, we hypothesize that dietary VAD leads to epithelial remodeling which promotes microbial dysbiosis;the dysbiosis then perpetuates epithelial remodeling via host-microbe interactions. Our preliminary results show anatomical/pathological changes to the epithelium in VAD adult mouse lungs compared to controls (VAS). Using our Nkx2- 1creERT2/dnRAR Rosa26 tdTomato transgenic mouse model that selectively induces VAD in the adult lung epithelium following tamoxifen injections, our data supports the hypothesis that host epithelial aberration associated with dietary VAD is induced locally in the lung and not via distal or systemic mechanisms. Our data also indicates the onset of dysbiosis in adult mouse lungs as early as three weeks post-diet modulation as observed through changes in microbial composition in VAD mice compared to controls. Finally, our bulk RNAseq analysis of host and microbial gene signatures has uncovered mechanisms associated with microbial metabolic functions, ciliopathy, host cellular polarity, and immune response to infection, that are dysregulated in the absence of vitamin A. Further, we have also identified altered transcriptional activity of microbes that are traditionally symbiotic or pathobiotic under normal homeostasis. This work indicates the presence of specific host-microbe interactions that are essential for lung homeostasis and protection against lung infection and disease that are dysregulated or lost in the absence of dietary vitamin A.

Targeting the Pulmonary Microbiota to Fight against Respiratory Diseases.

The mucosal immune system of the respiratory tract possesses an effective "defense barrier" against the invading pathogenic microorganisms; therefore, the lungs of healthy organisms are considered to be sterile for a long time according to the strong pathogens-eliminating ability. The emergence of next-generation sequencing technology has accelerated the studies about the microbial communities and immune regulating functions of lung microbiota during the past two decades. The acquisition and maturation of respiratory microbiota during childhood are mainly determined by the birth mode, diet structure, environmental exposure and antibiotic usage. However, the formation and development of lung microbiota in early life might affect the occurrence of respiratory diseases throughout the whole life cycle. The interplay and crosstalk between the gut and lung can be realized by the direct exchange of microbial species through the lymph circulation, moreover, the bioactive metabolites produced by the gut microbiota and lung microbiota can be changed via blood circulation. Complicated interactions among the lung microbiota, the respiratory viruses, and the host immune system can regulate the immune homeostasis and affect the inflammatory response in the lung. Probiotics, prebiotics, functional foods and fecal microbiota transplantation can all be used to maintain the microbial homeostasis of intestinal microbiota and lung microbiota. Therefore, various kinds of interventions on manipulating the symbiotic microbiota might be explored as novel effective strategies to prevent and control respiratory diseases.

Identification of Lung and Blood Microbiota Implicated in COVID-19 Prognosis.

The implications of the microbiome on Coronavirus disease 2019 (COVID-19) prognosis has not been thoroughly studied. In this study we aimed to characterize the lung and blood microbiome and their implication on COVID-19 prognosis through analysis of peripheral blood mononuclear cell (PBMC) samples, lung biopsy samples, and bronchoalveolar lavage fluid (BALF) samples. In all three tissue types, we found panels of microbes differentially abundant between COVID-19 and normal samples correlated to immune dysregulation and upregulation of inflammatory pathways, including key cytokine pathways such as interleukin (IL)-2, 3, 5-10 and 23 signaling pathways and downregulation of anti-inflammatory pathways including IL-4 signaling. In the PBMC samples, six microbes were correlated with worse COVID-19 severity, and one microbe was correlated with improved COVID-19 severity. Collectively, our findings contribute to the understanding of the human microbiome and suggest interplay between our identified microbes and key inflammatory pathways which may be leveraged in the development of immune therapies for treating COVID-19 patients.

Staphylococcus aureus ventilator-associated pneumonia in patients with COVID-19: clinical features and potential inference with lung dysbiosis.

BACKGROUND: Hospitalized patients with COVID-19 admitted to the intensive care unit (ICU) and requiring mechanical ventilation are at risk of ventilator-associated bacterial infections secondary to SARS-CoV-2 infection. Our study aimed to investigate clinical features of Staphylococcus aureus ventilator-associated pneumonia (SA-VAP) and, if bronchoalveolar lavage samples were available, lung bacterial community features in ICU patients with or without COVID-19. METHODS: We prospectively included hospitalized patients with COVID-19 across two medical ICUs of the Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy), who developed SA-VAP between 20 March 2020 and 30 October 2020 (thereafter referred to as cases). After 1:2 matching based on the simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score, cases were compared with SA-VAP patients without COVID-19 (controls). Clinical, microbiological, and lung microbiota data were analyzed. RESULTS: We studied two groups of patients (40 COVID-19 and 80 non-COVID-19). COVID-19 patients had a higher rate of late-onset (87.5% versus 63.8%; p = 0.01), methicillin-resistant (65.0% vs 27.5%; p < 0.01) or bacteremic (47.5% vs 6.3%; p < 0.01) infections compared with non-COVID-19 patients. No statistically significant differences between the patient groups were observed in ICU mortality (p = 0.12), clinical cure (p = 0.20) and microbiological eradication (p = 0.31). On multivariable logistic regression analysis, SAPS II and initial inappropriate antimicrobial therapy were independently associated with ICU mortality. Then, lung microbiota characterization in 10 COVID-19 and 16 non-COVID-19 patients revealed that the overall microbial community composition was significantly different between the patient groups (unweighted UniFrac distance, R2 0.15349; p < 0.01). Species diversity was lower in COVID-19 than in non COVID-19 patients (94.4 ± 44.9 vs 152.5 ± 41.8; p < 0.01). Interestingly, we found that S. aureus (log2 fold change, 29.5), Streptococcus anginosus subspecies anginosus (log2 fold change, 24.9), and Olsenella (log2 fold change, 25.7) were significantly enriched in the COVID-19 group compared to the non-COVID-19 group of SA-VAP patients. CONCLUSIONS: In our study population, COVID-19 seemed to significantly affect microbiological and clinical features of SA-VAP as well as to be associated with a peculiar lung microbiota composition.

Targeting the gut-lung microbiota axis by means of a high-fibre diet and probiotics may have anti-inflammatory effects in COVID-19 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 is a 2019 novel coronavirus, which only in the European area has led to more than 300,000 cases with at least 21,000 deaths. This manuscript aims to speculate that the manipulation of the microbial patterns through the use of probiotics and dietary fibers consumption may contribute to reduce inflammation and strengthen the immune system response in COVID-19 infection. The reviews of this paper are available via the supplemental material section.

Initial Real-Life Experience from a Designated COVID-19 Centre in Athens, Greece: a Proposed Therapeutic Algorithm.

We report our initial experience with the management of a mixed group of patients with COVID-19 infection, admitted and treated in a designated COVID-19 centre in the Athens Metropolitan area over a 4-week period. The SARS-CoV-2 pandemic presented a huge challenge to the Greek National Healthcare System and healthcare workers. Their response so far has been miraculously effective. Since there are essentially no therapeutic guidelines yet for this disease, we relied mainly on our medical intuition, our empathy for our patients and team work to do the best possible for 49 people with this infection. We present the therapeutic algorithm we gradually developed (on the job) and applied in our patients, based on continuous creative brainstorming and monitoring of the literature.