COVID-19 and the Microbiome: The Gut-Lung Connection

The world is currently experiencing a major pandemic due to COVID-19, a disease caused by SARS-CoV-2 infection. This virus is highly transmissible and clinically presents with a wide range of manifestations. The microbiome has a profound effect on the development of host immunity and susceptibility to infection. In severe COVID-19 patients, alterations of the gut and lung microbiome were detected. Emerging evidence indicates bidirectional crosstalk through a gut-lung axis, in which microbial metabolites, such as short-chain fatty acids, play pivotal roles in human health. In this review we will discuss the gut and lung microbiome in health and during viral infection, with a focus on SARS-CoV-2 infection. © 2022 Elsevier Inc. All rights reserved.

Cerrado and Pantanal fruit flours affect gut microbiota composition in healthy and post-COVID-19 individuals: an in vitro pilot fermentation study.

Cerrado and Pantanal plants can provide fruits with high nutritional value and antioxidants. This study aims to evaluate four fruit flours (from jatobá pulp, cumbaru almond, bocaiuva pulp and bocaiuva almond) and their effects on the gut microbiota in healthy (HD) and post-COVID-19 individuals (PC). An in vitro batch system was carried out, the microbiota was analysed by 16S rRNA amplicon sequencing and the short-chain fatty acids ratio was determined. Furthermore, the effect of jatobá pulp flour oil (JAO) on cell viability, oxidative stress and DNA damage was investigated in a myelo-monocytic cell line. Beyond confirming a microbiota imbalance in PC, we identified flour-specific effects: (i) reduction of Veillonellaceae with jatobá extract in PC samples; (ii) decrease in Akkermansia with jatoba and cumbaru flours; (iii) decreasing trend of Faecalibacterium and Ruminococcus with all flours tested, with the exception of the bocaiuva almond in HD samples for Ruminococcus and (iv) increase in Lactobacillus and Bifidobacterium in PC samples with bocaiuva almond flour. JAO displayed antioxidant properties protecting cells from daunorubicin-induced cytotoxicity, oxidative stress and DNA damage. The promising microbiota-modulating abilities of some flours and the chemopreventive effects of JAO deserve to be further explored in human intervention studies.

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.

Plant Polysaccharides Modulate Immune Function via the Gut Microbiome and May Have Potential in COVID-19 Therapy.

Plant polysaccharides can increase the number and variety of beneficial bacteria in the gut and produce a variety of active substances, including short-chain fatty acids (SCFAs). Gut microbes and their specific metabolites have the effects of promoting anti-inflammatory activity, enhancing the intestinal barrier, and activating and regulating immune cells, which are beneficial for improving immunity. A strong immune system reduces inflammation caused by external viruses and other pathogens. Coronavirus disease 2019 (COVID-19) is still spreading globally, and patients with COVID-19 often have intestinal disease and weakened immune systems. This article mainly evaluates how polysaccharides in plants can improve the immune system barrier by improving the intestinal microecological balance, which may have potential in the prevention and treatment of COVID-19.

Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome through Modulation of Microbiome in the Gut-Lung Axis.

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.

Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids (SCFAs) were depleted in SARS-CoV-2-infected patients. We aimed to characterize a functional profile of the gut microbiome in patients with COVID-19 before and after disease resolution. METHODS: We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (at up to 6 times points) during hospitalization and beyond 1 month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. RESULTS: Compared with non-COVID-19 controls, patients with COVID-19 with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for SCFA and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in patients with COVID-19. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in patients with COVID-19 before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT- proB-type natriuretic peptide, and C-reactive protein (all P < .05). CONCLUSIONS: Gut microbiome of patients with COVID-19 displayed impaired capacity for SCFA and L-isoleucine biosynthesis that persisted even after disease resolution. These 2 microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.

The Role of Bifidobacteria in Predictive and Preventive Medicine: A Focus on Eczema and Hypercholesterolemia.

Bifidobacteria colonize the human gastrointestinal tract early on in life, their interaction with the host starting soon after birth. The health benefits are strain specific and could be due to the produced polysaccharides. The consumption of probiotics may prevent obesity, irritable bowel syndrome, eczema or atopic dermatitis, and asthma. Non-replicative strains of Bifidobacterium longum (NCC3001 and NCC2705) promote the differentiation of normal human epidermal keratinocytes (NHEKs), inducing a high expression of differentiation markers (keratin -KRT1-, and transglutaminase -TGM1-) and pro-regeneration markers (cathepsins), including ß-defensin-1, which plays an important role in modulating the cutaneous immune response. Strains belonging to the genera Bifidobacterium and Lactobacillus can increase tight-junction proteins in NHEKs and enhance barrier function. Bifidobacteria and lactobacilli may be used as prophylactic or therapeutic agents towards enteric pathogens, antibiotic-associated diarrhea, lactose intolerance, ulcerative colitis, irritable bowel syndrome, colorectal cancer, cholesterol reduction, and control of obesity and metabolic disorders. Bifidobacterium bifidum showed an in vitro capability of lowering cholesterol levels thanks to its absorption into the bacterial membrane. Several strains of the species Lactobacillus acidophilus, L. delbrueckii subsp. bulgaricus, L. casei, and L. gasseri led to a reduced amount of serum cholesterol due to their ability to assimilate cholesterol (in vitro). Lactococcus lactis KF147 and Lactobacillus plantarum Lp81 have also been shown to reduce cholesterol levels by 12%. Clarifying the specific health mechanisms of Bifidobacterium and Lactobacillus strains in preventing high-cost pathologies could be useful for delineating effective guidelines for the treatment of infants and adults.

Main Clinical Features of COVID-19 and Potential Prognostic and Therapeutic Value of the Microbiota in SARS-CoV-2 Infections.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has become a pandemic, infecting more than 4,000,000 people worldwide. This review describes the main clinical features of COVID-19 and potential role of microbiota in COVID-19. SARS-CoV and SARS-CoV-2 have 79.5% nucleotide sequence identity and use angiotensin-converting enzyme 2 (ACE2) receptors to enter host cells. The distribution of ACE2 may determine how SARS-CoV-2 infects the respiratory and digestive tract. SARS and COVID-19 share similar clinical features, although the estimated fatality rate of COVID-19 is much lower. The communication between the microbiota and SARS-CoV-2 and the role of this association in diagnosis and treatment are unclear. Changes in the lung microbiota were identified in COVID-19 patients, and the enrichment of the lung microbiota with bacteria found in the intestinal tract is correlated with the onset of acute respiratory distress syndrome and long-term outcomes. ACE2 regulates the gut microbiota by indirectly controlling the secretion of antimicrobial peptides. Moreover, the gut microbiota enhances antiviral immunity by increasing the number and function of immune cells, decreasing immunopathology, and stimulating interferon production. In turn, respiratory viruses are known to influence microbial composition in the lung and intestine. Therefore, the analysis of changes in the microbiota during SARS-CoV-2 infection may help predict patient outcomes and allow the development of microbiota-based therapies.

Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide, seriously endangering human health. In addition to the typical symptoms of pulmonary infection, patients with COVID-19 have been reported to have gastrointestinal symptoms and/or intestinal flora dysbiosis. It is known that a healthy intestinal flora is closely related to the maintenance of pulmonary and systemic health by regulating the host immune homeostasis. Role of the "gut-lung axis" has also been well-articulated. This review provides a novel suggestion that intestinal flora may be one of the mediators of the gastrointestinal responses and abnormal immune responses in hosts caused by SARS-CoV-2; improving the composition of intestinal flora and the proportion of its metabolites through probiotics, and personalized diet could be a potential strategy to prevent and treat COVID-19. More clinical and evidence-based medical trials may be initiated to determine the strategy.

Microbiota Modulating Nutritional Approaches to Countering the Effects of Viral Respiratory Infections Including SARS-CoV-2 through Promoting Metabolic and Immune Fitness with Probiotics and Plant Bioactives.

Viral respiratory infections (VRIs) can spread quickly and cause enormous morbidity and mortality worldwide. These events pose serious threats to public health due to time lags in developing vaccines to activate the acquired immune system. The high variability of people's symptomatic responses to viral infections, as illustrated in the current COVID-19 pandemic, indicates the potential to moderate the severity of morbidity from VRIs. Growing evidence supports roles for probiotic bacteria (PB) and prebiotic dietary fiber (DF) and other plant nutritional bioactives in modulating immune functions. While human studies help to understand the epidemiology and immunopathology of VRIs, the chaotic nature of viral transmissions makes it difficult to undertake mechanistic study where the pre-conditioning of the metabolic and immune system could be beneficial. However, recent experimental studies have significantly enhanced our understanding of how PB and DF, along with plant bioactives, can significantly modulate innate and acquired immunity responses to VRIs. Synbiotic combinations of PB and DF potentiate increased benefits primarily through augmenting the production of short-chain fatty acids (SCFAs) such as butyrate. These and specific plant polyphenolics help to regulate immune responses to both restrain VRIs and temper the neutrophil response that can lead to acute respiratory distress syndrome (ARDS). This review highlights the current understanding of the potential impact of targeted nutritional strategies in setting a balanced immune tone for viral clearance and reinforcing homeostasis. This knowledge may guide the development of public health tactics and the application of functional foods with PB and DF components as a nutritional approach to support countering VRI morbidity.