**4. Focus on Platelets, Microbiota and SARS-CoV-2**

Platelets play an important role in a variety of regulatory and degenerative processes [102]. Platelets participate in inflammation by producing a variety of pro-inflammatory molecules [103]. COVID-19 is associated with increased production of large immature platelets, as megakaryocytes respond to increased platelet consumption. Circulating IL-1β, IL-6 and IL-8 are not regulated in chronic systemic and silent inflammation and also have receptors on platelets [103]. Platelet hyperactivation is observed in aging. And it is unclear whether such hyperactivity is the cause or effect of various other vascular disorders in the elderly [104]. Platelets can interact with viruses through a variety of receptors, including TLRs. The role of platelets in haemostasis is well known, and hypercoagulability is an important sign of inflammation. In particular, IL-1β, IL-6 and IL-8 are critically involved in the formation of abnormal clots, erythrocyte pathology and platelet hyperactivation. The most relevant changes were detected when all three cytokines caused platelet hyperactivation

and spread with vessel damage and thrombogenic effects [105]. Interestingly, a metabolite of the gut microbiota, called phenylacetylglutamine, was recently identified as being able to enhance platelet activation-related phenotypes, thus favouring platelet hyperactivation. This metabolite could therefore increase the thrombotic capacity and increase the risk of cardiovascular complications [106]. In this context, a targeted control of the microbiota could counter the development of such cardiovascular diseases.

Numerous cases of thrombocytopenia have been detected in patients with COVID-19 and three mechanisms have been hypothesized to explain the phenomenon: (i) the virus can directly infect bone marrow cells and inhibit platelet synthesis. The cytokine storm destroys progenitor cells and leads to reduced platelet production; (ii) the immune system destroys platelets; (iii) platelets aggregate in the lungs, resulting in the consumption of microthrombi and platelets [107]. The production of cytokines induced by a dysbiotic microbiota, the activating effect that inflammatory stimuli exert on platelets, MCs and astrocytes, allow the release of further pro-inflammatory molecules, involving an amplification of the harmful effect, micro-thrombi and, considering the location of MCs near the nerves, even possible neurological and brain damage, up to psychopathological conditions, anxiety and depressive syndromes [108]. Finally, it has recently been shown that the lung contributes to platelet biogenesis [109]. Therefore, platelets play a crucial role in the pathogenesis of SARS-CoV-2, as they release various types of molecules through the different stages of the disease. Platelets may have important potential to contribute to the thrombus-inflammation that occurs in SARS-CoV-2, and an inhibition of pathways related to platelet activation could significantly improve outcomes during COVID-19. It has been shown that *L. plantarum*, *L. rhamnosus* and *L. acidophilus* can control any platelet activation [110] (Figure 2).

**Figure 2.** Drawing illustrating the crosstalk between the various players discussed in the paper. In the elderly subject there is a state of fragility of the lung and intestinal microbiota, with loss of the integrity of the epithelial barriers, and chronic silent inflammatory state. Activated mast cells produce a wide variety of cytokines, chemokines and other inflammatory mediators that extensively influence and condition the gut and lung microbiota composition in a vicious cycle; these mediators also affect platelets which, in turn, are affected by microbial metabolites.
