Table 1: The differences in the weighted number of the binding motifs for colon-specific miRNA within various coding regions of SARS-CoV-2 RNA genome. All weighted numbers are averaged by variants of the groups and normalized by “Wuhan” RNA length. “Diff” columns contain differences between the averaged values of the corresponding groups. “FDR” columns contain adjusted p-values of Mann-Whitney U tests comparing the weighted numbers of virus variants of the corresponding groups. of miRNAs expressed in the intestinal tissue (p ≤ 2.50 · 10−2). Coronaviruses are generally perceived as Acute Respiratory Infections (ARIs), and the viral production in the lungs provides for a reservoir underlining the virus spread. In addition to the lungs, SARS-CoV-2 is capable of replication in many other organs and tissues [40], the main of which is an intestine, where the virus may reside for up to three month [41]. Prolonged period of intestinal replication provides sufficient time for evolutionary forces to work on the population of the viruses within the same host, with the host factors serving as the drivers for such evolution. Arguably, binding of host miRNAs represents such a force. Resultant viral populations may be returned to circulating pool of the viruses either through the fecal-oral route [42] or during secondary viremia in the immunocompromised hosts capable of supporting internal reinfection of the lungs [43,44], and subsequent airborne spread. It has been shown that the initial version of Omicron variant shared a high similarity with the variants of the SARS-CoV-2 virus found in rodents, particularly in mice [45]. Therefore, it has been hypothesized that one of the ancestral variants of SARS-CoV-2, from approximately mid-2020 [46], has entered the population of rodents and has evolved within these animals for quite some time till reemerging in humans [47,48]. An alternative theory suggests a longterm virus evolution within an immunocompromised patient, predominantly in the intestines [49]. An observation described in this study highlights the significance of the intestinal site for the pathogenesis of COVID-19. Although pneumonia and respiratory complications account for the most of the morbidity and mortality of COVID-19, extrapulmonary manifestations of COVID-19 infection include prominently diarrhea, as well as nausea, emesis, anorexia, abdominal pain, and heartburn [41]. These complications are observed in 10%-20% of patients with COVID-19 [50], which does not exclude the possibility of asymptomatic gastrointestinal infections with SARS-CoV-2. Moreover, the latent persistence of SARS-CoV-2 in the intestine may be one of the contributors to the long COVID [51]. A dramatic decrease in miRNA binding sites was especially pronounced in BA.2-like SARS-CoV-2 variants. To a large extent, this drop was due to the mutations within the region encoding the NSP4 protein, which promotes the formation of double-membrane vesicles serving as a scaffold for replication/transcriptional complexes [52] of the virus. Additionally, attachment to NSP4 protects viral RNA from intracellular immunity [53]. Along with dramatic changes in S-protein, the miRNA-driven alterations of NSP4, acquired during prolonged replication with the intestine, may have contributed to the current global dominance of the descendants of the BA.2 variant [54]. Findings highlight the possibility that intestinal tissue may significantly impact evolution of the SARS-CoV-2 genome and may play a pivotal role in the long COVID.