Interaction between gut microbiota and COVID-19 and its vaccines

The whole world has been continuously afflicted by the coronavirus disease 2019 (COVID-19) pandemic for the past 3 years. Many countries have tried many methods to control this virus infection with varying successes and failures. The gut microbiota is a biosystem spanning the entire length of the digestive tract and playing important roles in health and disease. It is much affected by COVID-19. In return it also substantially impacts infection. In particular, the gut microbiota has established a bidirectional interaction with the COVID-19 vaccines, enhancing or reducing vaccine efficacy by virtue of its varying components. Conversely, COVID-19 vaccines also make a substantial impact on the gut microbiota, re-ducing its overall population and biodiversity. It is hoped that by exploring and harnessing this bidirectional interaction we may break new ground and develop new methods to prevent and treat this formidable virus infection.     

COVID-19 and gut immunomodulation

The disease coronavirus disease 2019 (COVID-19) is a severe respiratory illness that has emerged as a devastating health problem worldwide. The disease outcome is heterogeneous, and severity is likely dependent on the immunity of infected individuals and comorbidities. Although symptoms of the disease are primarily associated with respiratory problems, additional infection or failure of other vital organs are being reported. Emerging reports suggest a quite common co-existence of gastrointestinal (GI) tract symptoms in addition to respiratory symptoms in many COVID-19 patients, and some patients show just the GI symptoms. The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut, which is supported by the fact that (1) The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells; (2) About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract; and (3) SARS-CoV-2 can directly infect gut epithelial cells in vitro (gut epithelial cells and organoids) and in vivo (rhesus monkey). The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically, stool samples of COVID-19 patients possess proinflammatory cytokines (interleukin 8), calprotectin (neutrophils activity), and immunoglobulin A antibodies. In addition to direct immune activation by the virus, impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines, hypoxia, and changes in gut microbiota (dysbiosis) due to infection of the respiratory system, which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive. This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms, their association with disease severity, and potential therapeutic interventions.     

Change in gut microbiota for eczema: Implications for novel therapeutic strategies

Eczema is one of the most common inflammatory diseases, often constituting a lifelong burden for afflicted individuals. The complex interaction of host genetic and multiple environmental factors contribute to its pathogenesis. A relationship between maladjustment of gut microbiota and eczema has been brought into the light of day in most previous studies. In eczema preclinical models, specific intestinal microbial species have been demonstrated to prohibit or dwindle immune responsiveness, indicating that these strains among commensal gut bacteria may exert either a morbific or phylactic function in eczema progression. As such, oral probiotics can serve as a medicinal approach for eczema therapy. Given that relative scientific work is still at the early stage, only limited data are available in the field. New sequencing techniques have been fortunately performed to gain access to an extended research on the relationship between gut bacterial flora and human diseases. In the current review, we identified the role of intestinal microbiota in the development of eczema and how specific bacterial strains adjust the immune responsiveness in the midst of disease progression. Probiotics as an applicable treatment for eczema were evaluated in other threads as well.     

Alterations of the gut microbiota in coronavirus disease 2019 and its therapeutic potential

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global health. SARS-CoV-2 infects host cells primarily by binding to angiotensin-converting enzyme 2, which is coexpressed in alveolar type 2 cells and gut epithelial cells. It is known that COVID-19 often presents with gastrointestinal symptoms and gut dysbiosis, mainly characterized by an increase in opportunistic pathogens and a decrease in beneficial commensal bacteria. In recent years, multiple studies have comprehensively explored gut microbiota alterations in COVID-19 and highlighted the clinical correlation between dysbiosis and COVID-19. SARS-CoV-2 causes gastrointestinal infections and dysbiosis mainly through fecal-oral transmission and the circulatory and immune pathways. Studies have shown that the gut microbiota and its metabolites can regulate the immune response and modulate antiviral effects. In addition, the gut microbiota is closely related to gastrointestinal symptoms, such as diarrhea, a common gastrointestinal symptom among COVID-19. Therefore, the contribution of the gut microbiota in COVID-19 should not be overlooked. Strategies targeting the gut microbiota via probiotics, prebiotics and fecal microbiota transplantation should be considered to treat this patient population in the future. However, the specific alterations and mechanisms as well as the contributions of gut microbiota in COVID-19 should be urgently further explored.     

Gastrointestinal mucosal immunity and COVID-19

As the gastrointestinal tract may also be a crucial entry or interaction site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the role of the gut mucosal immune system as a first-line physical and immunological defense is critical. Furthermore, gastrointestinal involvement and symptoms in coronavirus disease 2019 (COVID-19) patients have been linked to worse clinical outcomes. This review discusses recent data on the interactions between the virus and the immune cells and molecules in the mucosa during the infection. By carrying out appropriate investigations, the mucosal immune system role in SARS-CoV-2 infection in therapy and prevention can be established. In line with this, COVID-19 vaccines that stimulate mucosal immunity against the virus may have more advantages than the others.     

Potential role of the microbiome in liver injury during COVID-19: Further research is needed

Although different studies have associated coronavirus disease 2019 (COVID-19) with the occurrence of liver injury, the hepatic injury route during the COVID-19 course is not yet fully understood. In order to better understand the mechanisms of the disease, the human gut microbiota has been the subject of extensive discussion in the context of COVID-19 pathophysiology. However, many questions remain, including the risks of liver injury due to COVID-19 specific populations. Further research in this field could allow the discovery of new personalized treatment strategies aimed at improving the microbiota composition, thereby reducing COVID-19 severity and its complications in different populations. In this article, we discussed basic mechanisms of severe acute respiratory syndrome coronavirus 2 infection and recent evidence on the relationship between COVID-19, the gut microbiome and liver injury as well as proposed recommendations for further research.     

Diabetes and COVID-19: A pooled analysis related to disease severity and mortality

Globally, COVID-19 has become a major concern for the diabetic community. We conducted a pooled analysis and constructed a forest plot for the association between diabetes and COVID-19 progression in 47 studies. A random effects meta-analysis (Mantel–Haenszel method) was conducted to estimate the outcomes effect size as odds ratios (OR) and 95% confidence intervals (CI) using Review Manager Software version 5.3. COVID-19 patients with diabetes have a significantly higher risk of disease severity (OR = 2.20, 95% CI = 1.69–2.86, p < 0.00001) and associated mortality outcomes (OR = 2.52, 95% CI = 1.93–3.30, p =  < 0.00001).     

Role of diet and gut microbiota on colorectal cancer immunomodulation

Colorectal cancer(CRC) is one of the most commonly diagnosed cancers, and it is characterized by genetic and epigenetic alterations, as well as by inflammatory cell infiltration among malignant and stromal cells. However, this dynamic infiltration can be influenced by the microenvironment to promote tumor proliferation, survival and metastasis or cancer inhibition. In particular, the cancer microenvironment metabolites can regulate the inflammatory cells to induce a chronic inflammatory response that can be a predisposing condition for CRC retention. In addition, some nutritional components might contribute to a chronic inflammatory condition by regulating various immune and inflammatory pathways. Besides that, diet strongly modulates the gut microbiota composition,which has a key role in maintaining gut homeostasis and is associated with the modulation of host inflammatory and immune responses. Therefore, diet has a fundamental role in CRC initiation, progression and prevention. In particular,functional foods such as probiotics, prebiotics and symbiotics can have a potentially positive effect on health beyond basic nutrition and have antiinflammatory effects. In this review, we discuss the influence of diet on gut microbiota composition, focusing on its role on gut inflammation and immunity.Finally, we describe the potential benefits of using probiotics and prebiotics to modulate the host inflammatory response, as well as its application in CRC prevention and treatment.     

肠道微生物在非酒精性脂肪肝发生发展中的作用机制

非酒精性脂肪肝是代谢综合征的肝脏表现,可发展为肝硬化和肝癌。非酒精性脂肪肝的病因尚未明确,近年来宿主肠道微生物在非酒精性脂肪肝的发生、发展及治疗中的作用越来越受到重视。目前认为人类肠道是一个内在重要的代谢及免疫器官,肠道微生物的组成可影响宿主代谢,改变肠道通透性,引起炎症及一系列免疫反应。本文就肠道微生物在非酒精性脂肪肝的病理生理过程中的作用机制进行综述。     

Functional analysis of gut microbiota and immunoinflammation in children with autism spectrum disorders

Background and AimsRecent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms.MethodsThirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot.ResultsWe observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children.ConclusionsWe suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.     

Anti-PF4 antibodies associated with disease severity in COVID-19

Severe COVID-19 is characterized by a prothrombotic state associated with thrombocytopenia, with microvascular thrombosis being almost invariably present in the lung and other organs at postmortem examination. We evaluated the presence of antibodies to platelet factor 4 (PF4)–polyanion complexes using a clinically validated immunoassay in 100 hospitalized patients with COVID-19 with moderate or severe disease (World Health Organization score, 4 to 10), 25 patients with acute COVID-19 visiting the emergency department, and 65 convalescent individuals. Anti-PF4 antibodies were detected in 95 of 100 hospitalized patients with COVID-19 (95.0%) irrespective of prior heparin treatment, with a mean optical density value of 0.871 ± 0.405 SD (range, 0.177 to 2.706). In contrast, patients hospitalized for severe acute respiratory disease unrelated to COVID-19 had markedly lower levels of the antibodies. In a high proportion of patients with COVID-19, levels of all three immunoglobulin (Ig) isotypes tested (IgG, IgM, and IgA) were simultaneously elevated. Antibody levels were higher in male than in female patients and higher in African Americans and Hispanics than in White patients. Anti-PF4 antibody levels were correlated with the maximum disease severity score and with significant reductions in circulating platelet counts during hospitalization. In individuals convalescent from COVID-19, the antibody levels returned to near-normal values. Sera from patients with COVID-19 induced higher levels of platelet activation than did sera from healthy blood donors, but the results were not correlated with the levels of anti-PF4 antibodies. These results demonstrate that the vast majority of patients with severe COVID-19 develop anti-PF4 antibodies, which may play a role in the clinical complications of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), the most devastating pandemic to have plagued the world in more than a century (1). Although effective vaccines have been developed and deployed at an unprecedented pace on a global scale (2–5), morbidity and mortality remain at alarming levels, particularly in areas with limited access or resistance to vaccination. Furthermore, the virus, because of its RNA nature, continues to evolve and generate novel variants that escape from neutralizing antibodies and other immunologic mechanisms of protection elicited by current vaccines (6–8). Thus, a further delineation of the mechanisms of COVID-19 disease remains a high priority, as it may foster the development of increasingly effective therapeutic strategies.The clinical spectrum of COVID-19 is broad, ranging from an asymptomatic state to severe disease leading to multisystemic involvement and death (9–11). The lung is the most frequently targeted organ, with the development of acute respiratory distress syndrome for which patients may require mechanical ventilation. Among the distinctive features of COVID-19 are vascular changes affecting the lung as well as other organs. Although clinically apparent thrombosis of major vessels can occur in severely ill patients with COVID-19 (12, 13), disseminated microthrombosis affecting multiple organs is an almost invariable finding at postmortem examination, particularly in the lungs, where diffuse platelet microthrombi are associated with alveolar damage (14–16). In addition, mortality in COVID-19 is associated with progressive thrombocytopenia, apparently as a consequence of disseminated platelet activation and consumption rather than of immune-mediated platelet destruction or splenic sequestration (9, 17). Thus, even in the absence of clinically apparent thrombosis, systemic microvascular thrombosis with thrombocytopenia may represent a common pathological mechanism underlying multiple organ failures in fatal COVID-19.The simultaneous presence of thrombosis and thrombocytopenia is the hallmark of heparin-induced thrombocytopenia (HIT), a dramatic clinical syndrome associated with heparin treatment especially in patients recovering from cardiac or orthopedic surgery (18). The pathogenic mechanism of the HIT syndrome involves the elicitation of autoantibodies that target partially cryptic epitopes in the α-chemokine platelet factor 4 (PF4 or CXCL4), which are fully revealed upon binding to heparin or other polyanionic molecules. Severe thrombosis associated with thrombocytopenia and anti-PF4–polyanion (anti-PF4) antibodies has also recently been reported as a rare complication of adenovirus-vectored anti–SARS-CoV2 vaccines, such as AZD1222 and Ad26.COV2.S, and defined as vaccine-induced thrombosis with thrombocytopenia (VITT) (19–22).Given the simultaneous occurrence of thrombosis, especially systemic microthrombosis, and thrombocytopenia in patients with severe COVID-19, we investigated the presence of anti-PF4 antibodies in the serum of patients with COVID-19.     

Gut microbiota in a population highly affected by obesity and type 2 diabetes and susceptibility to COVID-19

Coronavirus disease 2019 (COVID-19) is a disease produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is currently causing a catastrophic pandemic affecting humans worldwide. This disease has been lethal for approximately 3.12 million people around the world since January 2020. Globally, among the most affected countries, Mexico ranks third in deaths after the United States of America and Brazil. Although the high number of deceased people might also be explained by social aspects and lifestyle customs in Mexico, there is a relationship between this high proportion of deaths and comorbidities such as high blood pressure (HBP), type 2 diabetes, obesity, and metabolic syndrome. The official epidemiological figures reported by the Mexican government have indicated that 18.4% of the population suffers from HBP, close to 10.3% of adults suffer from type 2 diabetes, and approximately 36.1% of the population suffers from obesity. Disbalances in the gut microbiota (GM) have been associated with these diseases and with COVID-19 severity, presumably due to inflammatory dysfunction. Recent data about the association between GM dysbiosis and metabolic diseases could suggest that the high levels of susceptibility to SARS-CoV-2 infection and COVID-19 morbidity in the Mexican population are primarily due to the prevalence of type 2 diabetes, obesity, and metabolic syndrome.     

Positive QuantiFERON test and the severity of COVID-19 disease: A prospective study

BackgroundA strong negative correlation is reported between the Bacille Calmette Guerin (BCG) index and COVID-19 mortality. The present study explored if frequent exposure to strong Th1 antigens like Mycobacteria or Salmonella have any effect on the progression of the disease in COVID-19 patients.MethodsThis prospective comparative study comprised of 3 groups of 20 each of mild or asymptomatic COVID-19 patients (A), severely ill patients (S) and healthy volunteers with a COVID Negative report (H).ResultsQuantiFERON TB Gold (QFT) which is interferon gamma release assay (IGRA) against Mtb antigen was used to quantify immunity status of patients against the tuberculosis. Group S showed positive QFT in only 15% patients as against 50% QFT positive patients in group A and H. All fourteen patients in group S with QFT negative report died while 5 of six survived patients showed positive QFT report either on initial or repeat testing done at 6 weeks. The sixth survived patient was QFT negative but showed high antibody titre against H antigen (TH) on Widal test. All severely ill group S patients showed huge reduction of IGRA even to the mitogen stimulus thus suggesting gross general unresponsiveness of T cells. Presence of BCG scar showed no correlation with prevalence or progression of the disease.ConclusionPopulation in an endemic area of tuberculosis and typhoid with good community exposure to these antigen is likely to withstand COVID -19 better and show reduced mortality following it.     

Glucose metabolism: Focus on gut microbiota,the endocannabinoid system and beyond

The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D.     

Therapies aimed at the gut microbiota and inflammation: antibiotics, prebiotics, probiotics, synbiotics, anti-inflammatory therapies

Several recent observations have raised the possibility that disturbances in the gut microbiota and/or a low-grade inflammatory state may contribute to symptomatology and the etiology of irritable bowel syndrome (IBS). Consequent on these hypotheses, several therapeutic categories have found their way into the armamentarium of those who care for IBS sufferers. These agents include probiotics, prebiotics, antibiotics, and anti-inflammatory agents.