ROLE OF GUT MICROBIOME HOMEOSTASIS, INTEGRITY OF THE INTESTINAL EPITHELIAL CELLS, AND THE (ENDOGENOUS) BUTYRATE IN ENDURING A HEALTHY LONG LIFE.

The influence of gut microbiomes on health has been gaining significance lately. More emphasis is their role in neurological illnesses as several of the metabolites and factors produced by the gut affect the brain via the gut-brain axis. Among all the gut microbiome produced metabolites, butyrate has been considered the most significant. Externally supplemented butyrate though has health benefits, when evaluated thoroughly, it is understood that there have been different pathways involved in the production of butyrate by the gut microbiome with the produced butyrate even being detrimental, though majority are beneficial. Importantly maternal butyrate supplementation has resulted in detrimental effects in the offspring. In this background, a black yeast Aureobasidium pullulans produced biological response modifier beta glucans (BRMGs) has shown beneficial outcome (anti-inflammatory: decrease in IL-6, Ferritin, C-reactive protein in COVID-19, D-Dimer; anti-fibrotic in fatty liver disease; improvement of behaviour and sleep with increase in α-synuclein, melatonin in autism) along with its effect on increasing the butyrate producing bacteria in the gut. Since only advantageous outcome has been reported with this BRMG produced butyrate, it is worth being considered as a yardstick for evaluation of exogenously supplemented and endogenous produced butyrate for their differential effects on host and its offspring.

Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients.

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.

Gut and airway microbiota dysbiosis and their role in COVID-19 and long-COVID.

The gut microbiota plays a crucial role in human health and disease. Gut dysbiosis is known to be associated with increased susceptibility to respiratory diseases and modifications in the immune response and homeostasis of the lungs (the so-called gut-lung axis). Furthermore, recent studies have highlighted the possible role of dysbiosis in neurological disturbances, introducing the notion of the "gut-brain axis." During the last 2 years, several studies have described the presence of gut dysbiosis during coronavirus disease 2019 (COVID-19) and its relationship with disease severity, SARS-CoV-2 gastrointestinal replication, and immune inflammation. Moreover, the possible persistence of gut dysbiosis after disease resolution may be linked to long-COVID syndrome and particularly to its neurological manifestations. We reviewed recent evidence on the association between dysbiosis and COVID-19, investigating the possible epidemiologic confounding factors like age, location, sex, sample size, the severity of disease, comorbidities, therapy, and vaccination status on gut and airway microbial dysbiosis in selected studies on both COVID-19 and long-COVID. Moreover, we analyzed the confounding factors strictly related to microbiota, specifically diet investigation and previous use of antibiotics/probiotics, and the methodology used to study the microbiota (α- and ß-diversity parameters and relative abundance tools). Of note, only a few studies focused on longitudinal analyses, especially for long-term observation in long-COVID. Lastly, there is a lack of knowledge regarding the role of microbiota transplantation and other therapeutic approaches and their possible impact on disease progression and severity. Preliminary data seem to suggest that gut and airway dysbiosis might play a role in COVID-19 and in long-COVID neurological symptoms. Indeed, the development and interpretation of these data could have important implications for future preventive and therapeutic strategies.

Respiratory and Intestinal Microbiota in Pediatric Lung Diseases-Current Evidence of the Gut-Lung Axis.

The intestinal microbiota is known to influence local immune homeostasis in the gut and to shape the developing immune system towards elimination of pathogens and tolerance towards self-antigens. Even though the lung was considered sterile for a long time, recent evidence using next-generation sequencing techniques confirmed that the lower airways possess their own local microbiota. Since then, there has been growing evidence that the local respiratory and intestinal microbiota play a role in acute and chronic pediatric lung diseases. The concept of the so-called gut-lung axis describing the mutual influence of local microbiota on distal immune mechanisms was established. The mechanisms by which the intestinal microbiota modulates the systemic immune response include the production of short-chain fatty acids (SCFA) and signaling through pattern recognition receptors (PRR) and segmented filamentous bacteria. Those factors influence the secretion of pro- and anti-inflammatory cytokines by immune cells and further modulate differentiation and recruitment of T cells to the lung. This article does not only aim at reviewing recent mechanistic evidence from animal studies regarding the gut-lung axis, but also summarizes current knowledge from observational studies and human trials investigating the role of the respiratory and intestinal microbiota and their modulation by pre-, pro-, and synbiotics in pediatric lung diseases.

Gut microbiota: A new insight into lung diseases.

The human gut microbiota is a complex ecosystem involved in the metabolism, immunity, and health of the host. The microbiome plays a key role in the development of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of host-microbe symbiosis. Lung diseases are usually accompanied by dysbiosis of the intestinal flora and an immune-inflammatory response. The intestinal flora and its metabolites are directly or indirectly involved in the immune regulation of the host in lung disease. However, the exact mechanism of action of the gut-lung axis crosstalk remains unclear. This review is aimed to summarize the latest advances in gut microbiota and their metabolites in typical lung diseases, such as pulmonary hypertension, COPD, and lung cancer. Especially COVID-19, a problem troubling the world, is also discussed in it. Moreover, it is concentrated on the action mechanisms between the identified gut microbiota or their metabolites and the specific lung diseases, and on the link among the gut microbiota, its metabolites, and immune regulation, which could be used as a breakthrough to find new mechanisms and targets for some diseases without specific therapeutic drugs in clinic. It is also discussed a new therapeutic tool "drug-bacterial interaction" and the potential of therapeutic applications in clinic. This review would provide a clear direction for future research on gut microbiota and lung diseases, and propose a new therapeutic strategy targeting "drug-bacterial interaction" in clinic.

Mapping the output of the global literature on the links between gut microbiota and COVID-19.

BACKGROUND: The term "human microbiota" refers to populations of microorganisms that live harmoniously in co-existence with humans. They contribute significantly to the host's immunological response when confronted with a respiratory viral infection. However, little is known about the relationship between the human microbiome and COVID-19. Therefore, our objective is to perform a bibliometric analysis to explore the overall structure and hotspots of research activity on the links between microbiota and COVID-19 at the global level. METHODS: The research literature on the microbiota and COVID-19 published between 2020 and 2022 was obtained from the Scopus database. Bibliometric analysis and network visualization were performed with VOSviewer. RESULTS: Of the 701 publications selected, the USA contributed the most (n = 157, 22.40%), followed by China (n = 118, 16.83%) and Italy (n = 82, 11.70%). Hotspots in this field were "COVID-19 is associated with an altered upper respiratory tract microbiome," "the effect of antibiotics on the gut microbiome," as well as "patient nutrition and probiotic therapy in COVID-19." CONCLUSIONS: The links between microbiota and COVID-19 remain an urgent concern at present, and the use of probiotics or/and antibiotics during the pandemic needs to be further improved. This landscape analysis of the links between the microbiota and COVID-19 will provide a basis for future research.

The Relationship Between Pediatric Gut Microbiota and SARS-CoV-2 Infection.

This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3-7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non-COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non-COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non-COVID-19 and CTRLs and by a specific ß-diversity. Its profile appeared enriched in Faecalibacterium, Fusobacterium, and Neisseria and reduced in Bifidobacterium, Blautia, Ruminococcus, Collinsella, Coprococcus, Eggerthella, and Akkermansia, compared with CTRLs (p < 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non-COVID-19 cohorts highlighted a reduction of Abiotrophia in the COVID-19 cohort (p < 0.05). The GM of MIS-C cohort was characterized by an increase of Veillonella, Clostridium, Dialister, Ruminococcus, and Streptococcus and a decrease of Bifidobacterium, Blautia, Granulicatella, and Prevotella, compared with CTRLs. Stratifying for disease severity, the GM associated to "moderate" COVID-19 was characterized by lower α-diversity compared with "mild" and "asymptomatic" and by a GM profile deprived in Neisseria, Lachnospira, Streptococcus, and Prevotella and enriched in Dialister, Acidaminococcus, Oscillospora, Ruminococcus, Clostridium, Alistipes, and Bacteroides. The ML models identified Staphylococcus, Anaerostipes, Faecalibacterium, Dorea, Dialister, Streptococcus, Roseburia, Haemophilus, Granulicatella, Gemmiger, Lachnospira, Corynebacterium, Prevotella, Bilophila, Phascolarctobacterium, Oscillospira, and Veillonella as microbial markers of COVID-19. The KEGG ortholog (KO)-based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, Bacteroides and Sutterella correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, Faecalibacterium was a specific marker of pediatric COVID-19 GM. The durable modification of patients' GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. Faecalibacterium and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2-infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19-related GM.

Correlation of gut microbiota and metabolic functions with the antibody response to the BBIBP-CorV vaccine.

Increasing evidence indicates that gut microbiota may play a key role in vaccination immunity. Here, we investigate whether the human gut microbiota and metabolic function correlate with the BBIBP-CorV vaccine response. A total of 207 participants who received the BBIBP-CorV vaccine are enrolled. The gut microbiome and metabolic functions are investigated using metagenomic sequencing and metabolomic assays. We find that BBIBP-CorV vaccination is accompanied by altered microbiome composition and functional pathways, and the gut microbiome and its functional profiles correlate with the vaccine response. The levels of short-chain fatty acids (SCFAs) are much higher in the high antibody response group compared to the low response group, and several SCFAs display a positive correlation with the antibody response. Our study highlights that the gut microbiome and its function is associated with the BBIBP-CorV vaccine response, providing evidence for further exploration of microbiome modulation to improve COVID-19 vaccine efficacy.

Remembrance of infections past.

Host-derived metabolite trains the microbiota to develop colonization resistance.

Obesity and the Brain.

Innate and adaptive immunity are essential for neurodevelopment and central nervous system (CNS) homeostasis; however, the fragile equilibrium between immune and brain cells can be disturbed by any immune dysregulation and cause detrimental effects. Accumulating evidence indicates that, despite the blood-brain barrier (BBB), overactivation of the immune system leads to brain vulnerability that increases the risk of neuropsychiatric disorders, particularly upon subsequent exposure later in life. Disruption of microglial function in later life can be triggered by various environmental and psychological factors, including obesity-driven chronic low-grade inflammation and gut dysbiosis. Increased visceral adiposity has been recognized as an important risk factor for multiple neuropsychiatric conditions. The review aims to present our current understanding of the topic.

Chronic Systemic Low-Grade Inflammation and Modern Lifestyle: The Dark Role of Gut Microbiota on Related Diseases with a Focus on COVID-19 Pandemic.

Inflammation is a physiological, beneficial, and auto-limiting response of the host to alarming stimuli. Conversely, a chronic systemic low-grade inflammation (CSLGI), known as a long-time persisting condition, causes damage to the organs and host tissues, representing a major risk for chronic diseases. Currently, a high global incidence of chronic inflammatory diseases is observed, often linked to the lifestyle-related changes that occurred in the last decade. The main lifestyle-related factors are proinflammatory diet, psychological stress, tobacco smoking, alcohol abuse, physical inactivity, and indoor living and working with its related consequences such as indoor pollution, artificial light exposure, and low vitamin D production. Recent scientific evidence found that gut microbiota (GM) has a main role in shaping the host's health, particularly as CSLGI mediator. Based on the lastest discoveries regarding the remarkable GM activity, in this manuscript we focus on the elements of actual lifestyle that influence the composition and function of the intestinal microbial community in order to elicit the CSLGI and its correlated pathologies. In this scenario, we provide a broad review of the interplay between modern lifestyle, GM, and CSLGI with a special focus on the COVID symptoms and emerging long-COVID syndrome.

Diagnostic, Prognostic, and Therapeutic Roles of Gut Microbiota in COVID-19: A Comprehensive Systematic Review.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) emerged in late December 2019. Considering the important role of gut microbiota in maturation, regulation, and induction of the immune system and subsequent inflammatory processes, it seems that evaluating the composition of gut microbiota in COVID-19 patients compared with healthy individuals may have potential value as a diagnostic and/or prognostic biomarker for the disease. Also, therapeutic interventions affecting gut microbial flora may open new horizons in the treatment of COVID-19 patients and accelerating their recovery. Methods: A systematic search was conducted for relevant studies published from December 2019 to December 2021 using Pubmed/Medline, Embase, and Scopus. Articles containing the following keywords in titles or abstracts were selected: "SARS-CoV-2" or "COVID-19" or "Coronavirus Disease 19" and "gastrointestinal microbes" or "dysbiosis" or "gut microbiota" or "gut bacteria" or "gut microbes" or "gastrointestinal microbiota". Results: Out of 1,668 studies, 22 articles fulfilled the inclusion criteria and a total of 1,255 confirmed COVID-19 patients were examined. All included studies showed a significant association between COVID-19 and gut microbiota dysbiosis. The most alteration in bacterial composition of COVID-19 patients was depletion in genera Ruminococcus, Alistipes, Eubacterium, Bifidobacterium, Faecalibacterium, Roseburia, Fusicathenibacter, and Blautia and enrichment of Eggerthella, Bacteroides, Actinomyces, Clostridium, Streptococcus, Rothia, and Collinsella. Also, some gut microbiome alterations were associated with COVID-19 severity and poor prognosis including the increment of Bacteroides, Parabacteroides, Clostridium, Bifidobacterium, Ruminococcus, Campylobacter, Rothia, Corynebacterium, Megasphaera, Enterococcus, and Aspergillus spp. and the decrement of Roseburia, Eubacterium, Lachnospira, Faecalibacterium, and the Firmicutes/Bacteroidetes ratio. Conclusion: Our study showed a significant change of gut microbiome composition in COVID-19 patients compared with healthy individuals. This great extent of impact has proposed the gut microbiota as a potential diagnostic, prognostic, and therapeutic strategy for COVID-19. There is much evidence about this issue, and it is expected to be increased in near future.

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.

Correlation Analysis between Gut Microbiota Alterations and the Cytokine Response in Patients with Coronavirus Disease during Hospitalization.

The role of the intestinal microbiota in coronavirus disease 2019 (COVID-19) is being elucidated. Here, we analyzed the temporal changes in microbiota composition and the correlation between inflammation biomarkers/cytokines and microbiota in hospitalized COVID-19 patients. We obtained stool specimens, blood samples, and patient records from 22 hospitalized COVID-19 patients and performed 16S rRNA metagenomic analysis of stool samples over the course of disease onset compared to 40 healthy individual stool samples. We analyzed the correlation between the changes in the gut microbiota and plasma proinflammatory cytokine levels. Immediately after admission, differences in the gut microbiota were observed between COVID-19 patients and healthy subjects, mainly including enrichment of the classes Bacilli and Coriobacteriia and decrease in abundance of the class Clostridia. The bacterial profile continued to change throughout the hospitalization, with a decrease in short-chain fatty acid-producing bacteria including Faecalibacterium and an increase in the facultatively anaerobic bacteria Escherichia-Shigella. A consistent increase in Eggerthella belonging to the class Coriobacteriia was observed. The abundance of the class Clostridia was inversely correlated with interferon-γ level and that of the phylum Actinobacteria, which was enriched in COVID-19, and was positively correlated with gp130/sIL-6Rb levels. Dysbiosis was continued even after 21 days from onset. The intestines tended to be an aerobic environment in hospitalized COVID-19 patients. Because the composition of the gut microbiota correlates with the levels of proinflammatory cytokines, this finding emphasizes the need to understand how pathology is related to the temporal changes in the specific gut microbiota observed in COVID-19 patients. IMPORTANCE There is growing evidence that the commensal microbiota of the gastrointestinal and respiratory tracts regulates local and systemic inflammation (gut-lung axis). COVID-19 is primarily a respiratory disease, but the involvement of microbiota changes in the pathogenesis of this disease remains unclear. The composition of the gut microbiota of patients with COVID-19 changed over time during hospitalization, and the intestines tended to be an aerobic environment in hospitalized COVID-19 patients. These changes in gut microbiota may induce increased intestinal permeability, called leaky gut, allowing bacteria and toxins to enter the circulatory system and further aggravate the systemic inflammatory response. Since gut microbiota composition correlates with levels of proinflammatory cytokines, this finding highlights the need to understand how pathology relates to the gut environment, including the temporal changes in specific gut microbiota observed in COVID-19 patients.

Traditional Chinese medicine against COVID-19: Role of the gut microbiota.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and it has become a public health concern worldwide. In addition to respiratory symptoms, some COVID­19 patients also show various gastrointestinal symptoms and even consider gastrointestinal symptoms to be the first manifestation. A large amount of evidence has shown that SARS-CoV-2 infection could disrupt the gut microbiota balance, and disorders of the gut microbiota could aggravate the condition of COVID-19 patients. Therefore, maintaining the gut microbiota balance is expected to become a potential new therapeutic target for treating COVID-19. Traditional Chinese medicine (TCM) has significant effects in all stages of the prevention and treatment of COVID-19. It can adjust the gut microbiota and is an ideal intestinal microecological regulator. This review summarizes the advantages and clinical efficacy of TCM in the treatment of COVID-19 and expounds on the relationship between TCM and the gut microbiota, the relationship between COVID-19 and the gut microbiota, the mechanism of gut microbiota disorders induced by SARS-CoV-2, the relationship between cytokine storms and the gut microbiota, and the role and mechanism of TCM in preventing and treating COVID-19 by regulating the gut microbiota to provide new research ideas for TCM in the prevention and treatment of COVID-19.

Progressive deterioration of the upper respiratory tract and the gut microbiomes in children during the early infection stages of COVID-19.

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.

Gut microbiota, inflammation, and molecular signatures of host response to infection.

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.

Zinc and gut microbiota in health and gastrointestinal disease under the COVID-19 suggestion.

Microelements represent an emerging resource for medicine and its preventive branch. Zinc is the second most abundant element in our organism with peculiar physiologic functions and pathophysiologic implications in systemic and gastrointestinal (GI) diseases. It interacts very often with gut microbiota (GM) and can affect natural course of GI diseases through a bidirectional relationship with intestinal bugs. We aimed to review literature data regarding zinc chemistry, role in health, and GI diseases in man with a special focus on its interaction with GM. We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: zinc, microelements, gut microbiota, gut health, and COVID-19. Zinc has a rapid and simple metabolism and limited storage within our body. Its efficacy on immune system modulation reflects on improved response to pathogens, reduced inflammatory response, and improved atopic/allergic reactions. Zinc is also involved in cell cycle regulation (namely, apoptosis) with potential anti-cancerogenic effects. All these effects are in a "symbiotic" relationship with GM. Finally, zinc shows preliminary viral antireplicative effects. Zinc seems to gain more and more evidences on its efficacy in allergic, atopic and infectious diseases treatment, and prevention. COVID-19 can be the booster for research on future applications of zinc as perfect "postbiotic" in medicine.

Respiratory tract infections and gut microbiome modifications: A systematic review.

Respiratory tract infections (RTIs) are extremely common and can cause gastrointestinal tract symptoms and changes to the gut microbiota, yet these effects are poorly understood. We conducted a systematic review to evaluate the reported evidence of gut microbiome alterations in patients with a RTI compared to healthy controls (PROSPERO: CRD42019138853). We systematically searched Medline, Embase, Web of Science, Cochrane and the Clinical Trial Database for studies published between January 2015 and June 2021. Studies were eligible for inclusion if they were human cohorts describing the gut microbiome in patients with an RTI compared to healthy controls and the infection was caused by a viral or bacterial pathogen. Dual data screening and extraction with narrative synthesis was performed. We identified 1,593 articles and assessed 11 full texts for inclusion. Included studies (some nested) reported gut microbiome changes in the context of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (n = 5), influenza (H1N1 and H7N9) (n = 2), Tuberculosis (TB) (n = 4), Community-Acquired Pneumonia CAP (n = 2) and recurrent RTIs (rRTI) (n = 1) infections. We found studies of patients with an RTI compared to controls reported a decrease in gut microbiome diversity (Shannon) of 1.45 units (95% CI, 0.15-2.50 [p, <0.0001]) and a lower abundance of taxa (p, 0.0086). Meta-analysis of the Shannon value showed considerable heterogeneity between studies (I2, 94.42). Unbiased analysis displayed as a funnel plot revealed a depletion of Lachnospiraceae, Ruminococcaceae and Ruminococcus and enrichment of Enterococcus. There was an important absence in the lack of cohort studies reporting gut microbiome changes and high heterogeneity between studies may be explained by variations in microbiome methods and confounder effects. Further human cohort studies are needed to understand RTI-induced gut microbiome changes to better understand interplay between microbes and respiratory health.

The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19.