The presence of SARS-CoV-2 gastrointestinal infection has recently been reported by two independent groups from China 1, 2 . Also, liver injury -in part presumably explained by viral infection of liver cells may be present in about 60% of the infected patients 3 . Therefore, patients with chronic liver disease may be vulnerable to the serious clinical consequences of COVID-19 infection. Likewise, emerging clinical data suggest that males with comorbidities, including obesity, are more likely to present severe disease 4, 5 . While the biological mechanisms behind this observation are unclear, it has been speculated that sex-based immunological and or/ hormonal differences may account in part for that.
There is evidence highlighting angiotensin-converting enzyme 2 (ACE2) as one of the host receptors for cell entry of members of the SARS-CoV group, including SARS-CoV-2 6 .
Structural analysis showed several binding motifs between the SARS-CoV spike protein receptor-binding domain and human ACE2 6 . Besides its role in catalyzing the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7, ACE2 is involved in cellular pathways associated with other viral entry into host cells.
Gene expression levels of ACE2 differ across human body . The highest expression levels are in the small intestine and terminal ileum, and ACE2 expression levels in the liver and lung are much lower than that of the gastrointestinal tract. One remarkable aspect of the ACE2 is that the gene maps on the non-pseudoautosomal, that is, the X-specific, region of the chromosome X (Xp22.2). It is largely known that in order to balance the dosage effect of X-linked genes, one of the two X chromosomes is randomly inactivated in females during development; this process is called X inactivation. Nevertheless, while most genes are silenced, about 15% of X-linked human genes escape from inactivation 7 . More importantly, X-escape is not uniform across different tissues. In fact, it was shown that ~10% of gene escape occurs selectively in specific tissues 7 . These molecular aspects are of medical importance because they could explain sex differences in the natural course of human diseases, including COVID-19. 3 A recent systematic survey of the landscape of human X-linked genes inactivation using RNA sequencing-based approaches showed that ACE2 presents remarkable differences in male-female expression levels 8 . Tukiainen et al. suggested that tissue differences in Xescape can directly translate into tissue-specific sex biases in gene expression 8 . Specifically, the study showed not only that ACE2 is among the 82 X-escaping genes but also highlighted that there might be differences in the liver and lung ACE2 expression levels between males and females 8 . Paradoxically, escape of ACE2 from X-inactivation resulted in low levels of expression in the liver, lung, and visceral adipose tissue of women 8 . Conversely, ACE2 expression levels in colon transverse and subcutaneous adipose tissue were significantly higher in females than males 8 .
Collectively, these novel observations may have important clinical implications for COVID-19 infected patients. First, differences between men and women in liver ACE2 expression levels may help to explain potential clinical differences in the course of COVID-19 infection in patients with underlying chronic liver disease. Second, differences between men and women in ACE2 expression levels in gastrointestinal tissues due to escaping from Xinactivation, including colon, could result in different transmission patterns, including fecaloral transmission. Third, gender-linked diferential expression levels in adipose tissue and/or visceral fat, might also shed light into potential differences in the odds of presenting severe complications and in-hospital death associated with comorbidities, including severe obesity.