In the process of viral invasion, the intestinal microbiota plays a key role, acting as a barrier, interacting directly or indirectly with the virus, and stimulating the innate and adaptive immune responses. Viral infections also have the potential of changing the composition of the gut microbiota [11]. Indeed, during COVID-19, modifications in microbiota composition have been reported [12,13,14,15]. Patients with COVID-19 had a higher number of opportunistic pathogens and depletion of beneficial commensals. On the one hand, the baseline abundance of some pro-inflammatory bacteria such as coprobacilli and Clostridiodes was higher and correlated with a more severe disease course. On the other hand, anti-inflammatory bacteria like Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented. Interestingly, some bacteroides (B. dorei, B. thetaiotaomicron, B. massiliensis, and B. ovatus) downregulate the expression of angiotensin-converting enzyme 2 (ACE2), reducing the possibility of virus-entry thus causing a lower SARS-CoV-2 viral load in fecal samples of patients [13,14,15].

Liu et al. studied the effect of fecal microbiota transplantation in 11 patients who recovered from COVID-19 and who had suffered with gastrointestinal symptoms, gut dysbiosis and alteration of their immune status. Fecal microbiota transplantation restored gut microbiota and alleviated gastrointestinal disorders, but also had an impact on the immune system as demonstrated by changes in the peripheral lymphocyte subset [16]. In addition, there was also an increase in Bifidobacterium and Faecalibacterium and restored Actinobacteria and Proteobacteria. The modulation of gut microbiota was also proven to reduce COVID-19 disease severity, with beneficial effects on gastrointestinal symptoms, too [16]. Additionally, other study groups are investigating the effects of gut microbiota modulation during COVID-19 infection. In particular, studies are focusing on the effects of microbiota in modulating the immune system of the host, particularly in terms of progression of cytokine storm. It is well known that gut microbiota strictly interacts with host immune system. Their relationship is complex and dynamic. Factors such as viral infections can modify this balance, triggering inflammatory and immune diseases [14]. However, many studies focusing on the interaction between immunity and microbiota have tried to sequence and characterize the microbiome’s profile and to investigate on gut–microbiota modulators [13,14,15,16]. Another aspect that has been investigated is the role of KB109, a synthetic peptide, that can act as a microbiota modulator. In two trials it is currently being investigated whether or not it could significantly and positively impact microbiota composition, as a positive effect of COVID-19 disease [17,18,19].

The first reports in scientific literature regarding cardiac involvement during SARS-CoV-2 infection go back to the first months of the pandemic outbreak.

Many authors have described cases of patients with COVID-19 and inflammatory cardiomyopathies, mostly myocarditis [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37] but also pericarditis [38,39,40,41,42,43]. In some cases, the cardiac disease was the first manifestation of the viral infection [21,29,39]. In other patients it was a life-threatening early complication, [24,25,31,38,44], or a fatal one [20]. Moreover, it could clinically display after infection recovery [30,32,35,37,45], or some-times remain subclinical, being detected only after cardiac imaging taking place for other reasons [46]. Manifestation could be cardiac tamponade or constrictive pericarditis, overall varying widely.

Acute myocardial dysfunction during the early course of COVID-19 has been retrospectively reported in 16–36% of patients [47,48]. While the etiology is unclear, it has been suggested that cardiac damage in COVID-19 could be attributed to stress-induced cardiomyopathy and immunological and microvascular damage [49].

The virus can indeed directly infect cardiac cells, entering in the endothelial blood vessels and activating immune response with endothelitis. Moreover, it can dysregulate hormonal pathways and activate proinflammatory responses with the release of many cytokines and the involvement of neutrophils, macrophages, platelets, and lymphocytes, thus provoking a prothrombotic state and a predisposition for clotting. This can happen both in the cardiac micro- and macro-vessels, with potentially many complications [49].

Moreover, it can dysregulate hormonal pathways and activate proinflammatory responses, with the release of many cytokines and the involvement of neutrophils, macrophages, platelets, and lymphocytes, thus provoking a prothrombotic state and a predisposition for clotting. This can happen in the cardiac micro and macrovessels. There are many different possible consequences, which range from the above discussed myocarditis and pericarditis, but also sudden arrythmias, heart failure and cor pulmonaris, plaque rupture. Another manifestation, closely associated with stress-induced mechanisms, is Takotsubo syndrome [49].

Post-mortem examination of hearts revealed potentially COVID-19-related cardio-vascular histopathologic findings, such as macro or microvascular thrombi, inflammation, and presence of intraluminal megakaryocytes. Even if these manifestations have been reported in almost half of autopsies (47.8%), functionally significant myocarditis was identified in only 2% of all cases [50]. Interestingly, when analyzing myocardial biopsies of patients with myocarditis/myopericarditis, no evidence of intracellular virus was reported [51]. Yet, some authors reported the presence of SARS-CoV-2 mRNA in the endomyocardial biopsies of patients with clinically suspected myocarditis, both testing positive [52] or negative for COVID-19 by nasopharyngeal swab [53]. SARS-CoV-2 particles were found in the cardiac macrophages or in the endothelial cells [54] but not directly in cardiomyocytes; some authors have thus suggested that the cardiovascular damage was caused by overall immune activation, rather than by direct viral induced damage [55].

The above discussed evidence has contributed to identifying and describing the “acute COVID-19 cardiovascular syndrome” (ACoVCS) in adults [56]. Yet, even though it has been identified as a clinical entity, its pathogenesis still remains largely unknown. Molecular mimicry and endothelial dysfunction have been hypothesized, but more studies are needed to confirm these results [51].

Even if our review focuses on adult patients, it is interesting to note that the ACoVCS presents some similarities with the “multisystem inflammatory syndrome in children” (MIS-C) described by Most, that has been reported in children with SARS-CoV-2 infection [56]. At a cardiac level, the MIS-C can present itself with coronary dilatation, which resembles Kawasaki disease [55,56]. Other manifestations can be elevated troponin, cardiogenic shock, and reduced biventricular function. In this study, all children tested negative for SARS-CoV-2 by polymerase chain reaction (PCR) test, but they also had specific IgG antibodies. The authors thus concluded that MIS-C could depend on a post-infectious inflammatory state that occurs several weeks after a primary infection [56].

There is much more evidence on the association between COVID-19 and cardiovascular complications, such as myocarditis, pericarditis, fulminant myocarditis with arrhythmias, as described above, but there is a gap of knowledge in understanding the different pathogenic mechanisms [9]. Fox et al. analyzed myocardial biopsies of COVID-19 patients with myocarditis and found an increased number of CD68 + cells (that indicate monocyte/macrophage lineage), compared to myocarditis which are not associated to COVID-19 infection [57]. Similar observations have been reported by other authors as well [52]. The significance of these data has not been clarified yet and the possible association with prognosis and mortality is unclear. Lethal complications of myocarditis (such as end stage heart failure, cardiogenic shock, etc.) have also been observed in patients with COVID-19 infection [51]. Sawalha et al. noticed that cardiac tamponade was present in 20% of echocardiograms in patients with COVID-19 infection. Moreover, patients who died usually also had a serious acute respiratory distress syndrome as well [58].