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.