Altered gut microbial metabolites could mediate the effects of risk factors in Covid-19.

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.

Viral Infections, the Microbiome, and Probiotics.

Viral infections continue to cause considerable morbidity and mortality around the world. Recent rises in these infections are likely due to complex and multifactorial external drivers, including climate change, the increased mobility of people and goods and rapid demographic change to name but a few. In parallel with these external factors, we are gaining a better understanding of the internal factors associated with viral immunity. Increasingly the gastrointestinal (GI) microbiome has been shown to be a significant player in the host immune system, acting as a key regulator of immunity and host defense mechanisms. An increasing body of evidence indicates that disruption of the homeostasis between the GI microbiome and the host immune system can adversely impact viral immunity. This review aims to shed light on our understanding of how host-microbiota interactions shape the immune system, including early life factors, antibiotic exposure, immunosenescence, diet and inflammatory diseases. We also discuss the evidence base for how host commensal organisms and microbiome therapeutics can impact the prevention and/or treatment of viral infections, such as viral gastroenteritis, viral hepatitis, human immunodeficiency virus (HIV), human papilloma virus (HPV), viral upper respiratory tract infections (URTI), influenza and SARS CoV-2. The interplay between the gastrointestinal microbiome, invasive viruses and host physiology is complex and yet to be fully characterized, but increasingly the evidence shows that the microbiome can have an impact on viral disease outcomes. While the current evidence base is informative, further well designed human clinical trials will be needed to fully understand the array of immunological mechanisms underlying this intricate relationship.

Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential.

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.

Cross-talk between immune system and microbiota in COVID-19.

INTRODUCTION: Human gut microbiota plays a crucial role in providing protective responses against pathogens, particularly by regulating immune system homeostasis. There is a reciprocal interaction between the gut and lung microbiota, called the gut-lung axis (GLA). Any alteration in the gut microbiota or their metabolites can cause immune dysregulation, which can impair the antiviral activity of the immune system against respiratory viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. AREAS COVERED: This narrative review mainly outlines emerging data on the mechanisms underlying the interactions between the immune system and intestinal microbial dysbiosis, which is caused by an imbalance in the levels of essential metabolites. The authors will also discuss the role of probiotics in restoring the balance of the gut microbiota and modulation of cytokine storm. EXPERT OPINION: Microbiota-derived signals regulate the immune system and protect different tissues during severe viral respiratory infections. The GLA's equilibration could help manage the mortality and morbidity rates associated with SARS-CoV-2 infection.

Host factors facilitating SARS-CoV-2 virus infection and replication in the lungs.

SARS-CoV-2 is the virus causing the major pandemic facing the world today. Although, SARS-CoV-2 primarily causes lung infection, a variety of symptoms have proven a systemic impact on the body. SARS-CoV-2 has spread in the community quickly infecting humans from all age, ethnicities and gender. However, fatal outcomes have been linked to specific host factors and co-morbidities such as age, hypertension, immuno-deficiencies, chronic lung diseases or metabolic disorders. A major shift in the microbiome of patients suffering of the coronavirus disease 2019 (COVID-19) have also been observed and is linked to a worst outcome of the disease. As many co-morbidities are already known to be associated with a dysbiosis of the microbiome such as hypertension, diabetes and metabolic disorders. Host factors and microbiome changes are believed to be involved as a network in the acquisition of the infection and the development of the diseases. We will review in detail in this manuscript, the immune response toward SARS-CoV-2 infection as well as the host factors involved in the facilitation and worsening of the infection. We will also address the impact of COVID-19 on the host's microbiome and secondary infection which also worsen the disease.

The Role of the Gut-Liver Axis in Metabolic Dysfunction-Associated Fatty Liver Disease.

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.

The microbiome in atopic patients and potential modifications in the context of the severe acute respiratory syndrome coronavirus 2 pandemic.

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.

The Role of Bacterial and Fungal Human Respiratory Microbiota in COVID-19 Patients.

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic with millions of infected patients. Alteration in humans' microbiota was also reported in COVID-19 patients. The alteration in human microbiota may contribute to bacterial or viral infections and affect the immune system. Moreover, human's microbiota can be altered due to SARS-CoV-2 infection, and these microbiota changes can indicate the progression of COVID-19. While current studies focus on the gut microbiota, it seems necessary to pay attention to the lung microbiota in COVID-19. This study is aimed at reviewing respiratory microbiota dysbiosis among COVID-19 patients to encourage further studies on the field for assessment of SARS-CoV-2 and respiratory microbiota interaction.

The lung-gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes.

Bacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host's defense against viral respiratory infections. The gut microbiota's composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota's composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung-gut axis in coronavirus disease 2019.

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.

OBJECTIVE: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus. METHODS: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma. RESULTS: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. CONCLUSION: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Impact of Microbiota: A Paradigm for Evolving Herd Immunity against Viral Diseases.

Herd immunity is the most critical and essential prophylactic intervention that delivers protection against infectious diseases at both the individual and community level. This process of natural vaccination is immensely pertinent to the current context of a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection around the globe. The conventional idea of herd immunity is based on efficient transmission of pathogens and developing natural immunity within a population. This is entirely encouraging while fighting against any disease in pandemic circumstances. A spatial community is occupied by people having variable resistance capacity against a pathogen. Protection efficacy against once very common diseases like smallpox, poliovirus or measles has been possible only because of either natural vaccination through contagious infections or expanded immunization programs among communities. This has led to achieving herd immunity in some cohorts. The microbiome plays an essential role in developing the body's immune cells for the emerging competent vaccination process, ensuring herd immunity. Frequency of interaction among microbiota, metabolic nutrients and individual immunity preserve the degree of vaccine effectiveness against several pathogens. Microbiome symbiosis regulates pathogen transmissibility and the success of vaccination among different age groups. Imbalance of nutrients perturbs microbiota and abrogates immunity. Thus, a particular population can become vulnerable to the infection. Intestinal dysbiosis leads to environmental enteropathy (EE). As a consequence, the generation of herd immunity can either be delayed or not start in a particular cohort. Moreover, disparities of the protective response of many vaccines in developing countries outside of developed countries are due to inconsistencies of healthy microbiota among the individuals. We suggested that pan-India poliovirus vaccination program, capable of inducing herd immunity among communities for the last 30 years, may also influence the inception of natural course of heterologous immunity against SARS-CoV-2 infection. Nonetheless, this anamnestic recall is somewhat counterintuitive, as antibody generation against original antigens of SARS-CoV-2 will be subdued due to original antigenic sin.

COVID-19: Can the symptomatic SARS-CoV-2 infection affect the homeostasis of the gut-brain-microbiota axis?

COVID-19 is associated with acute and lethal pneumonia, causing the severe acute respiratory syndrome (SARS), which is not confined to the respiratory tract, as demonstrated by clinical evidence of the involvement of multiple organs, including the central nervous system (CNS). In this context, we hypothesized that both oligosymptomatic and symptomatic patients present an imbalance in the microbiota-gut (immune system) and nervous system axis, worsening the clinical picture. The brain constantly receives a direct and indirect influence from the intestine, more specifically from the immune system and intestinal microbiota. The presence of SARS-CoV-2 in the intestine and CNS, can contribute to both neurological disorders and gut immune system imbalance, events potentialized by an intestinal microbiota dysbiosis, aggravating the patient's condition and causing more prolonged harmful effects.

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System.

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.

Immunological co-ordination between gut and lungs in SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a major pandemic called coronavirus disease 2019 (COVID-19) that has created unprecedented global health emergencies, and emerged as a serious threat due to its strong ability for human-to-human transmission. The reports indicate the ability of SARS-CoV-2 to affect almost any organ due to the presence of a receptor known as angiotensin converting enzyme 2 (ACE2) across the body. ACE2 receptor is majorly expressed in the brush border of gut enterocytes along with the ciliated cells and alveolar epithelial type II cells in the lungs. The amino acid transport function of ACE2 has been linked to gut microbial ecology in gastrointestinal (GI) tract, thereby suggesting that COVID-19 may, to some level, be linked to the enteric microbiota. The significant number of COVID-19 patients shows extra-pulmonary symptoms in the GI tract. Many subsequent studies revealed viral RNA of SARS-CoV-2 in fecal samples of COVID-19 patients. This presents a new challenge in the diagnosis and control of COVID-19 infection with a caution for proper sanitation and hygiene. Here, we aim to discuss the immunological co-ordination between gut and lungs that facilitates SARS-CoV-2 to infect and multiply in the inflammatory bowel disease (IBD) and non-IBD patients.