4.2 The intestinal homeostasis disorder in COVID-19
It was reported that many COVID-19 patients appeared gastrointestinal symptoms, like diarrhea, abdominal pain and vomiting(Guan et al. , 2020; Holshue et al. , 2020; Jin et al. , 2020). SARS-CoV-2 RNA not only exists in lung, but also in anal swabs and stool specimen(Tang et al. , 2020; Zhang et al. , 2020). ACE2 was confirmed to be expressed in gastrointestinal epithelial cells by sequencing, and it was positively correlated with gene expression related to virus release(Zhang et al. , 2020). Consequently, the gut may be the target of SARS-CoV-2. While the mechanism of gastrointestinal symptoms is not fully understood, current data indicated these histological changes could be caused by the infection of SARS-CoV-2, especially the down-regulation of ACE2 in tissue. The down-regulation of ACE2 expression will lead to the imbalance of RAAS, which causing inflammation in digestive system. It was found that the level of serum Ang Ⅱ increased in the infected patients(Liu et al. , 2020), who have obvious clinical manifestations, such as diarrhea and liver injury with raised enzymes. Nevertheless, no viral inclusion was observed in the liver. Many studies have shown that the RAAS is related with the gut inflammation and gut microbiota. Treatment with Ang Ⅱ may alter selectively gut microbial communities, and induce pathological alterations in gut wall(Sharma et al. , 2019). Previous animal experiments have shown that the expression of ACE2 and Ang (1-7) play an essential role in the gastrointestinal inflammation. The study of Hashimoto has confirmed that transplantation of the altered microbiota from ACE2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis(Hashimotoet al. , 2012). ACE2 interacts with B0AT1 amino acid transporter, which is necessary for polarized surface expression of the transporter in intestinal epithelial cells, and subsequently reduces the levels of tryptophan and other large amino acids, which resulted in alterations in gut inflammation and gut microbiota. Furthermore, systemic ACE2 deficiency would synergize to adversely impact both the microbiome and gut barrier function(Duan et al. , 2019). Meanwhile, inhibition of ACE2 may reduce DSS-induced inflammatory bowel disease (IBD) of mouse(Chen et al. , 2020). Moreover, treatment of the ACEI is able to upregulate ACE2 expression in injured liver(Huang et al. , 2010). In clinical trials, the IBD patients together with ACEI/ARB exposure had fewer hospitalizations, operations and corticosteroid prescriptions compared to matched controls(Jacobs et al. , 2019). All the above evidences have demonstrated that activation of the ACE2/Ang (1-7)/Mas signaling pathway or inhibition of the ACE/Ang Ⅱ/AT1R pathway may be important treatments for gastrointestinal inflammation. Therefore, the imbalance of RAAS caused by SARS-CoV-2 infection may has adverse effects on the gut inflammation and gut microbiota, and gut-liver axis, which may participate in the pathological process of COVID-19 patients with sepsis. We speculate that rebalance of RAAS restore the intestinal homeostasis.