**2. Intestinal Microbiota and Systemic Protection**

In this context, the involvement of the gut microbiota could play an important role in the COVID-19 phenomenon perhaps not yet sufficiently considered. From a clinical point of view, the elderly patient presents a dysregulation of microbial homeostasis and neurodegeneration that can lead to a condition of greater fragility. This condition manifests itself as a reduced functional reserve, reduced resistance to stress, increased susceptibility to disease, mood, and increased risk of adverse health outcomes [23]. The gut could serve as a reservoir for acute respiratory syndrome COVID-19. Evidence reported that the intestinal microbiota is really altered in SARS-CoV-2 infection [24,25]. In addition, Zuo et al. found that the loss of beneficial species in SARS-CoV-2 persists for a long time in most patients suggesting that exposure to SARS-CoV-2 infection and/or hospitalization may be associated with lasting damage to the intestinal microbiota [25]. In particular, a condition of dysbiosis, perturbations in the structural and, therefore, functional dynamics of the intestinal microbiota, could have a crucial role in COVID-19 disease. Physiologically, the microbiota protects the intestine from colonization of exogenous pathogens and potentially dangerous autochthonous microorganisms. Man has evolved side by side with microbes. The mammalian intestine is colonized by trillions of microorganisms, and most of these are bacteria that evolved together with the host in a symbiotic relationship, ensuring the state of immunosurveillance of the organism. It is well-known that the microbiota can modulate the innate and the adaptive immune system [26–28].

Aging implies an imbalanced immunological response to microbial infection associated with elevated levels of several cytokines, including IL-1, IL-6 and TNFα [29,30]. In addition, changes in the expression of PRRs, activation of such receptors by endogenous ligands associated with cellular damage, and unusual downstream signalling events of PRRs activation have evolved to induce a chronic cytokine secretion [31].

The conditions of the intestinal microbiota and pulmonary changes are closely related to immune responses [32]. Interestingly, SARS-CoV-2 leverages the ACE2 receptor to access the host, and this receptor is expressed in both the respiratory and gut tracts [33]. ACE2 is involved in controlling intestinal inflammation. The direct colonization of intestinal ACE2 receptors through ingestion of the virus is potentially responsible for a range of gastrointestinal tract symptoms associated with COVID-19 [34,35]. Chronic obstructive pulmonary disease is often concomitant with chronic diseases of the gastrointestinal tract. Yet, there is a higher risk of allergic diseases of the airways and use of antibiotics and alteration in the composition of the gut microbiota [36]. Finally, a crosstalk pattern between Bacillus and Lactobacillus in the gut has recently been reported, revealing the extremely complicated interactions of multiple bacterial species in the gut microbiota [37].

The central role of the intestinal microbiota in the development of mucosal immunity is not surprising, as multiple interactions with the external environment take place in the gut and the intestinal epithelial barrier must tolerate the intestinal microbiota which constitutes the majority of the antigens presented to the resident immune cells [38]. Despite this condition, there is no strong activation of a local or systematic immune response. This condition occurs because tolerance is induced due to intestinal epithelial cells (ICE) which are in close contact with the intestinal microbiota and are constantly exposed to a large number of antigens [32,38]. In order to minimize the toxic potential of these antigens, ICEs adopt a number of strategies, such as reducing their TLRs, and modifying the antigenic fractions of the microbiota, to make them less immunogenic. The important role of the gut microbiota in the development of the systemic immune system has been assessed by studies conducted in the model of germ-free mice, i.e., without microbiota, born and kept in sterile conditions. These mice have various immune disorders, abnormal numbers of different types of immune cells, altered cytokines, as well as deficits in the local and systemic lymphoid structure [39].

The gut microbiota is a physical barrier to incoming pathogens through competitive exclusion, i.e., resistance to colonization, via mechanisms such as the occupation of attachment sites, the consumption of nutrients and the production of antimicrobial substances [40]. The interactions between antimicrobial peptides and microbiota are bidirectional. Gut bacteria secrete and consume a wide variety of neuromodulators and neurotransmitters, including serotonin, dopamine, gamma-aminobutyric acid, epinephrine and noradrenaline [41]. In this context, blood levels of serotonin, a metabolite of tryptophan independent of the kynurenine pathway, are lower in patients with severe COVID-19 than in healthy controls, suggesting that during SARS-CoV2 infection tryptophan is facilitated to take the kynurenine route [42].

A plethora of microbiota-derived compounds are produced as intermediates or final products of microbial metabolism and can influence biological functions both in the peripheral and the central nervous system (CNS) through nerve activation, cytokine production, neurotransmitters, and via systemic circulation [41,43]. The metabolites produced by the intestine not only modulate gastrointestinal immunity, but also affect distant organs, such as lung and brain.

A relevant response of the host's immune system following microbial colonization of the gut is the production of immunoglobulin (Ig)A by gut-associated lymphoid tissues. IgA plays a vital role in mucosal homeostasis in the intestine and functions as the dominant antibody [43,44].
