*2.2. Microbiota and Lung*

The lung microbiota is less relevant in quantity than the gastrointestinal microbiota; however, it is originally colonized by the oropharynx and by microaspirations of the gastrointestinal tract. The predominant bacterial phyla both in the lungs and gut are the same, Firmicutes and Bacteroidetes [70]. The fungal component is also prominent, which is known to communicate with bacteria. The gut and lung microbiota are in parallel throughout life, although dietary changes affect not only the gut microbiota but also the lung microbiome [71,72]. Bidirectional crosstalk has been demonstrated in animal

experiments [73]. Members of the gut microbiome induce immune tolerance and block the colonization of pathogens through the activation of the immune system and the direct and indirect actions of the microbiota. When the immune system "learns" to recognize the enemy from the microbiome, the effect can also occur in a distant organ [74]. Various studies have shown that lung infections are associated and mutually influenced with a change in the gut microbiota [75] (Figure 1).

**Figure 1.** Schematic representation of the bidirectional link between lung and gut. The gut microbiota influences lung health through a cross dialogue between the gut microbiota and the lungs, the "gut– lung axis". The functional state of the elderly, dysbiotic condition, immune compromise, nutritional deficiencies constitute as a whole, a condition of extreme vulnerability.

COVID-19 represents a further aggravation of the inflammatory problem as ageassociated inflammation causes macrophage dysfunction and tissue damage. An increase in circulating bacterial toxins implies a reduction in the gene expression of tight junctions and lethal lung damage [71]. Aging is characterized by a particular condition, the so-called "chronic age-related inflammation". This condition is genetically preordained and is a chronic inflammatory process with a shift in the profile of proinflammatory cytokines at the level of the various districts with the presence of greater amounts of histamine, IL-1 and TNF cytokines and chemotactic factors. In the elderly, it is a consequence of the long-term antigenic load with a continuous involvement of the immune system. The functional degradation of the immune system that occurs with aging is linked to changes in immune-competitive cells and other cells. The changes affect the size of cells, but also their functions and population size. In the elderly, chemotaxis, phagocytosis and antigen presentation worsen in a context of high level of proinflammatory cytokines. Excessive cytokine production leads to chronic overstimulation of the immune system [72].

Like the gastrointestinal tract, lungs are at the forefront of immunity as they are constantly attacked by a wide variety of external environmental stimuli. The microbiome of the lungs plays a crucial role in shaping and harmonizing lung immunity. As in the intestine, the lung microbiota has the task of strengthening innate and adaptive immunity, releasing factors that support respiratory functions and defend the lungs from pathogens [75]. Intestinal dysbiosis has been implicated in various lung diseases, such as asthma and cystic fibrosis. Diet alters the microbiome. So, an altered lung microbiome predicts disease progression in interstitial lung disease [76,77].

Studies have reported the role of fibre-rich diets in modulating innate immunity, supported by a reduction in inflammatory marker levels [77]. A diet rich in fibre influences and modifies not only the intestinal microbiota, but also the lung microbiota, supporting the role of nutrition on lung immunity [77–79].

The depletion of some species of the intestinal microbiota due to the intake of antibiotics influences lung diseases and allergic inflammation [80,81]. In mice it has been observed that influenza virus infection in the respiratory tract increases Enterobacteriaceae and reduces Lactobacilli and Lactococci in the gut microbiota [82]. Dysbiosis in the lung microbiota after LPS administration is accompanied by disorders of the intestinal microbiota due to the movement of bacteria from their lung into the bloodstream [83].

Lactobacilli and Bifidobacteria are beneficial probiotics that exert a trophic effect on the intestinal mucosa. They can promote host defence against infections and reduce hypersensitivity reactions to commensal bacteria and antigens. Specific selected probiotic strains are capable of modulating the expression of proinflammatory molecules and anti-inflammatory properties. The anti-inflammatory and preventive abilities of specific probiotic mixtures have been described [84–86]. Interestingly, M1 macrophages, which produce proinflammatory cytokines, such as IL-6, and M2 macrophages which produce anti-inflammatory cytokines, such as IL-10, can be modulated by specific probiotic treatments [85]. Finally, already various studies have reported that respiratory viral infections can affect the gut microbiome condition, including pulmonary influenza virus and respiratory syncytial infections [73,87].
