Potential contribution of beneficial microbes to face the COVID-19 pandemic

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COVID-19 affecting intestinal tract

An outbreak of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome (SARS-CoV-2), has rapidly spread from China to almost all over the world affecting over 13,200,000 people across 199 countries by early July 2020. By that time, more than 577,000 people were lost to the virus (John Hopkins University, 2020). The SARS-CoV-2 coronavirus is part of a family of viruses, known as coronaviruses, common in nature, with many potential natural primary, intermediate, and final hosts (Wang et al., 2020). These viruses cause respiratory infections, such as the severe acute respiratory syndrome – SARS (whose agent is SARS-CoV) and the Middle East respiratory syndrome – MERS (whose agent is MERS-CoV).

In the past, human coronaviruses (HCoVs) have been considered to be relatively harmless respiratory pathogens till the outbreaks SARS and MERS (Yin & Wunderink, 2018). Due to the fact that SARS-CoV-2 is 96% identical at the whole-genome level to a bat coronavirus, the domestication and/or consumption of wildlife animal was pointed as the possible origin for the disease (Wu et al., 2020). COVID-19 has emerged as a multifaceted, multi-system and multiorgan disorder ranging from non-specific flulike symptoms, to pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure and death (Baud et al., 2020; Chen et al., 2020; Infusino et al., 2020). Other described clinical findings are: septic shock, metabolic acidosis and coagulation dysfunction (Infusino et al., 2020).

Fortunately, most patients have mild symptoms and present good prognosis (Chen et al., 2020). Coronavirus entry is mediated by the viral spike (S) glycoprotein. Then, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) (Bosch et al., 2003). Binding to ACE2 allows the virus to invade cells in the oropharyngeal epithelia and the development of lung injury and hyperinflammation (Rivellese & Prediletto, 2020; Xu, Zhong, et al., 2020). At the pulmonary level ACE2 is expressed on the epithelial cells of alveoli, trachea, bronchi, bronchial serous glands, alveolar monocytes and macrophages (Yin & Wunderink, 2018). It has been postulated that different concentrations and/or activation of ACE2 at the pulmonary level can be a reason for higher incidence of COVID-19 in adults, compared to children (Fanos et al., 2020). Interestingly, Zhang et al. (2020) showed that ACE2 is not only highly expressed in the lung AT2 cells, esophagus upper and stratified epithelial cells but also in absorptive enterocytes from ileum and colon. These results indicated along with respiratory systems, that the digestive system is a potential route for 2019-nCov infection.

A shrinking microbiota: An immunocompromised individual

In this way, the ACE2 has a specific function in intestinal tract, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. In additional, ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Then, ACE2 is key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis (Hashimoto et al., 2012). The role of non-pharmacological substances such as probiotics and nutraceuticals can be an interesting option considering the long time necessary to find, evaluate and produce drugs that are able to interfere with SARS-CoV-2 pathway (Infusino et al., 2020). This review aims to discuss the possible correlation between COVID-19 infection and microbiota. In addition, we show scientific evidence on the possible role of consumption of fermented foods, as well as probiotics and prebiotics in promoting mucosal immunity to better face a possible infection.

The most common symptoms of COVID-19 at the onset of illness are fever, cough, fatigue, myalgia, dyspnea, headache, stomachache, pains in the rib cage, loss of taste and smell, skin problems like hives or chills on the toes, neurological problems and gastrointestinal (GI) symptoms, such as diarrhea and nausea (Huang et al., 2020). Tissue tropism of coronavirus in the intestinal tract was first described by Leung et al. (2003) for the SARS-CoV responsible for the SARS outbreak in Hong Kong in March 2003. It was reported the presence of active viral replication in the small and large intestine of the patients, and also evidence of virus accumulation inside endoplasmic reticulum of enterocytes (Leung et al., 2003). A lot of evidence shows that human-to-human transmission occurs in close contact, mainly transmitted through respiratory droplets, aerosols and direct contact. Many findings suggest that the intestine could also have a relevant role both in the COVID-19 evolution and as a possible route of infection, so an oral fecal route has also been evaluated. Viral RNA from SARS-CoV2 can be found in stools of previously infected patient, even after negativization in the exam from the respiratory tract. According to Zhang et al. (2020) enteric symptom of diarrhea would be associated with the invaded ACE2-expressing enterocytes. Even so more studies are needed to confirm this hypothesis.

Jin et al. (2020) evaluated patients with COVID-19 in the Zhejiang province. 11.4% of these patients (average age of 46.14 years) presented with at least one GI symptom (nausea, vomiting or diarrhea), and GI symptoms were recorded on admission, precluding the influence of other medical therapy and external factors. Li et al. (2020) evaluated 95 cases with SARS-CoV-2 caused coronavirus disease 2019. Among them, 58 cases exhibited GI symptoms (diarrhea, anorexia, and nausea) of which 11.6% occurred on admission and 49.5% developed during hospitalization. However, the authors did not correlated the drug administration and GI symptoms. They found presence of SARS-CoV-2 in faecal samples in 52.4% of patients and SARS-CoV-2 RNA was detected in oesophagus, stomach, duodenum, and rectum specimens for both two severe patients. In addition, patients with GI symptoms revealing oesophagus bleeding with erosions and ulcers. The more detailed information on the characteristics of COVID-19 is found for adult and elder people, but for children is still scarce. A recent publication showed five children with non-respiratory symptoms as the first manifestation were hospitalized from the emergency department at the Wuhan Children’s Hospital and were later confirmed to have COVID-19.

Interestingly, that two of these patients had acute gastroenteritis symptoms. Viral replication in the intestine determines an exponential increase in the viral load in the digestive mucosa, leading to a loss of barrier integrity and a strong production of cytokines hypothesis. Dysbiosis microbiome may create an inflammatory environment that the coronavirus can exploit. Gut-related inflammatory proteins, cytokines, are amplified by more cytokines when coronavirus hits. The combined inflammation may ignite a “cytokine storm”—a runaway immune reaction that can cause more damage than the virus itself, including multiorgan injury (Yang et al., 2020). A recent Chinese study identified marker bacterial related with COVID-19 susceptibility. Based on the COVID-19 patient data, they constructed a blood proteomic risk score (PRS) for the prediction of COVID-19 progression to clinically severe phase. Then, Ruminococcus gnavus was positively correlated with inflammation, while Clostridia spp. was negatively correlated. They also found a strong association between these bacteria, the PRS, and COVID-19 severity, but only in older age groups.

In additional, they looked at a subgroup of 301 noninfected people over a three-year period. Intriguingly, they found that microbiome alterations occurred before the change was reflected by the PRS, making it plausible that dysbiosis causes the protein alterations and not the other way around. Then, dietary strategies for the promotion of the gut microbiota, and thus the strengthening of the immune system associated with the gut, include increased consumption of fiber and prebiotics, beer), or the microorganisms are not viable (sourdough bread, pasteurized sauerkraut), while others may contain living microorganisms, such as yoghurt, yoghurt with probiotics, kefir or kombucha. On the other hand, in some of them, the microbiological composition is known in advance (yoghurt, yoghurt with probiotics), while in others it is not possible to know which microorganisms are present in a given batch (kefir, kombucha, sauerkraut).

Probiotics in the prevention of respiratory disease

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al., 2014), whereas prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit, including carbohydrate and non-carbohydrate substances (Gibson et al., 2017). Probiotics can be found in food supplements or in foods, fermented (yoghurt, fermented oats) or not (fruit juices), being yoghurt the most widely used food as a vehicle for probiotics (Syngai et al., 2016). The most widely used probiotics in supplements belong to the genera Lactobacillus, Bifidobacterium, Saccharomyces, and Bacillus, while Lactobacillus and Bifidobacterium are almost exclusively used in foods. The characteristics that a probiotic strain must display are: identity (genera, species, and strain denomination); to be viable in the supplement or response against RNA viral infections, such as SARS-CoV-2. Their review emphasized the contribution of vitamins omega-3 polyunsaturated fatty acids, selenium, zinc, and iron to combat viral infections. Diet fiber might also be beneficial in this context because diets with high fiber content (30 g/d) are associated with lower levels of inflammatory markers (King et al., 2007). Infusino et al.

(2020) emphasized also the importance of polyphenols (flavonoids, phenolic acids, stilbenes, lignans) to provide health benefits maintaining a proper redox homeostasis. The excess body weight per se can cause a mechanical difficulty to the lung ventilation process, aggravated by the decrease in muscle strength of the diaphragm and intercostal muscles. In obese individuals it is observed an increased number of ACE2-expressing cells due to more adipose tissue present (Jia et al., 2020). The overproduction of proinflammatory cytokines observed in COVID-19 can be especially harmful for obese patients, since obesity is a condition of systemic lowgrade inflammation. Pneumonia will be present in mild or more aggressive COVID-19, affecting adults or children (WHO, 2020), as a consequence the lungs will become inflamed and filled with fluid leading to breathing difficulties causing shortness of breath that can culminate to ARDS that can be fatal.

The healthy lung has its specific microbiota obtained by microaspiration and inhalation which can be composed by bacteria, molds and virus. The dynamic of microorganisms that access the lung will be determined by three factors: immigration, elimination, and the relative growth rates of its members (Bassis et al., 2015). The prominent genera in healthy subjects include Prevotella, Veillonella and Streptococcus, however the Veillonella spp. and Prevotella spp. can also be associatedm with the presence of inflammatory cells in the lung (Bassis et al., 2015; Fanos et al., 2020; Larsen et al., 2014). On the other hand, Pseudomonas spp. is rare in a healthy lung and Proteobacteria can be found in the respiratory tract of intubated preterm newborns (Fanos et al., 2020). In ARDS, the lung microbiota becomes rich in bacteria from the gut, such as Bacteroidetes and Enterobacteriaceae gut probably because of condition of hyper-permeable gut what facilitates bacterial translocation through the colon wall and reach the lung (Fanos et al., 2020). Dysbiosis in gut microbiota has been implicated in several lung diseases, including allergy, asthma and cystic fibrosis (Anand & Mande, 2018). shows the lesions in the pulmonary and intestinal epithelium resulting of the prevalence of pathogens microorganisms that contribute to an inflammatory environment, in which it may be explored by SARS-CoV-2 in both microbiota.

Author: Adriane E.C. Antunes , Gabriel Vinderola , Douglas Xavier-Santos , Katia Sivieri