SARS-CoV-2 infection of intestinal cells mainly has the following two characteristics. First, the immune response induced by SARS-CoV-2 is different. Under in vitro conditions, SARS-CoV-2 was observed to infect human intestinal epithelial cells and mesenteric cells, leading to their apoptosis (19). The replication efficiency of SARS-CoV-2 is lower than that of SARS-CoV. The cytopathology induced in human intestinal epithelium is relatively less, and it induces a stronger innate immune response, including more powerful interferon and pro-inflammatory response (20). Second, lung infections can be accompanied by gastrointestinal infections, which can lead to recurrence of the disease. For patients who experienced recurrence, the phylogenetic analysis of the full-length SARS-CoV-2 genome in the gastrointestinal tract showed that the virus detected in the positive retest evolved from the original parent virus (21). Some patients still have a positive stool test when the throat swab test is concealed (22–24).This suggests that SARS-CoV-2 exists and replicates at a low level in the intestine for a long time (21). This is because in the early stage of new coronavirus infection, it is difficult for a small number of patients to quickly obtain immunity to SARS-CoV-2 and produce targeted IgM or IgG, which eventually causes the virus to persist in the gastrointestinal tract for a long time (25, 26). A recent study pointed out that the virus can hide in the mesenteric tissue and infect the lungs through the vasculature, causing disease (27).

We know that the renal angiotensin system (RAS) regulates systemic or local body functions and plays an important role in regulating blood pressure, electrolytes, organ functions, etc. (28). RAS is regulated by the opposing actions of two key carboxypeptidases, angiotensin-converting enzyme (ACE) and ACE2 (29, 30). Angiotensin II (AngII) is a vasoactive substance that can raise blood pressure. AngII is a vasoconstrictor, its overproduction causes inflammation (31, 32), and ACE2 is an enzyme that converts AngII, the main biologically active molecule of RAS, into Ang 1-7 (33, 34). The physiological significance is to exert anti-inflammatory and anti-remodeling effects (35). Recent reports showed that the S protein of COVID-19 would use the same receptor ACE2 as SARS-CoV to infect the host (36–39). Furthermore, the expression of ACE2 protein was downregulated after the virus infects the host (7). The lack of ACE2 was due to the internalization of the SARS-CoV-2–ACE2 complex, which limited the role of ACE2 as the carboxypeptidase of AngII and desarginine-bradykinin and other polypeptide hormones (40, 41). Based on this, we speculate that COVID-19 will cause the downregulation of ACE2 in the intestinal mucosal cells during the infection process, leading to the disorder of the RAS system and the decline of the anti-inflammatory ability of the intestinal mucosa ( Figure 1 ). This is one of the reasons why people infected with the new coronavirus have intestinal symptoms.

There are very few reports about SARS-CoV-2 infection leading to viremia (42, 43). Recently, in a case, researchers isolated and cultured a live SARS-CoV-2 virus strain from the stool of an advanced patient and believed that SARS-CoV-2 might be able to migrate from the lungs to the blood circulation to the digestive tract (44). We agree with this view, but when viremia is present, patients often have severe systemic inflammation and cytokine storms (45). We believe viremia may be a stage that causes intestinal symptoms in patients, but it is not the main cause of intestinal damage.

In the early stage of SARS-CoV-2 infection, the body’s immediate immune response to the virus can effectively clear up the virus (46). Stimulation of innate immune cells leads to secretion of inflammatory mediators, which together with complement system exert antiviral effects in the early stage (47). Viruses evolved to have various strategies to circumvent the innate immune response. For example, viruses can evade the complement system by removing antibody–antigen complexes from cell surfaces, decreasing Fc receptor expression, or by mimicking the complement regulatory component (48, 49). Studies have shown that the replication efficiency of SARS-CoV-2 is lower, and the natural immune response (including the activation of type I and type III interferons) induced in human intestinal tissue is stronger than SARS-CoV (20). Due to the complex virus–innate immune interaction, the immune system may sometimes delay recovery, eventually leading to the patient’s disease progression and even death (46).

In colonic epithelial cells expressing ACE2 positively, viral infection was significantly enhanced (50). After endocytosis, the positive-sense RNA highjacked cellular machinery for viral RNA and viral-specific protein synthesis. Viral particles were then assembled in the cellular cytoplasm and released into the gastrointestinal (GI) tract (51). In the lungs, due to the presence of ACE2 receptors, blood vessels in the lungs can easily become targets, triggering microthrombosis, immune complex deposition, and excessive humoral immune responses, leading to subsequent hypoxic damage to various important organs (52). From this, we speculate that the virus spreads through fecal–oral transmission to reach the gastrointestinal tract. In the intestine, virus particles reach ACE2-positive intestinal epithelial cells under the protection of the mucus layer (15). Infection of intestinal epithelial cells leads to the release of virus particles. The virus particles then reach the rich vascular network in the submucosa, eventually leading to local inflammation of the intestinal tract and secondary intestinal damage. In in vitro experiments, SARS-CoV-2 can infect and replicate effectively in isolated human intestinal tissues by releasing infectious virus particles, and the innate immune response induced in human intestinal tissues is stronger than SARS-CoV (53). Here, we will discuss the inflammatory response mechanism caused by SARS-CoV-2 infection that may lead to intestinal cell damage.

Increased levels of cytokines often occur in critically ill patients with COVID-19, including IL-6, IL-2R, IL-10, and tumor necrosis factor-α (54). An autopsy report showed that in patients with fatal new coronary pneumonia, there was a widespread systemic inflammation involving the gastrointestinal tract, and neutrophils and reticular structures persist. However, SARS-CoV-2 infected cells were only occasionally seen in the late stage of new coronary pneumonia. This suggested a maladaptive immune response (55). In this maladaptive immune response, the direct cytopathological effects of SARS-CoV-2 induced apoptosis (a highly inflammatory form of programmed cell death) and release endogenous danger signals (56), which were local and remote recognition by epithelial cells, macrophages, and endothelial cells. A cascade of local inflammation ensued, characterized by secretion of pro-inflammatory cytokines and chemokines that attracted monocytes, macrophages, and T cells that mediated extensive pathology, culminating in tissue damage (57). When local inflammation occurs, macrophages frequently communicate with SARS-CoV-2 targets through chemokines and phagocytic signals (58), and inflammation may upregulate ACE2 expression on macrophages (59), further amplifying viral sensing and tissue injury (57). Postmortem analyses of secondary lymph nodes and spleen implicated CD169+ macrophages that contain viral nucleocapsid protein as mediators of activation-induced cell death (AICD) of lymphocytes (60). A recent study pointed out that SARS-CoV-2 induces IL-1 production in macrophages and mast cells (MCs), thereby inducing gene expression and activating other pro-inflammatory cytokines. Since IL-1 is toxic, IL-1 produced by ubiquitous MCs and macrophages activated by SARS-CoV-2 also causes gastrointestinal diseases. In addition, IL-1 also promotes the release of nitric oxide and the release of inflammatory arachidonic acid products such as prostaglandin and thromboxane A2 (61). All these effects will promote the generation and development of cytokine storms and lead to secondary intestinal damage.

In addition, patients with severe new-onset coronary pneumonia have significantly higher levels of IL-6 than patients with mild pneumonia (50). This may be because certain viral products (such as human immunodeficiency virus TAT protein transactivator) enhanced the DNA binding activity of nuclear factor κB (NF-κB) and nuclear factor IL-6 (NF-IL-6), thereby increasing IL-6 mRNA transcription (62, 63). IL-6 is usually synthesized locally in the acute phase of inflammation and mediates the multidirectional effects of immune response and hematopoiesis (63). This cytokine also promotes the specific differentiation of normal CD4+ T cells, which is necessary for T-helper 17 (Th17) to differentiate from simple CD4+ T cells, and is related to immune tolerance, autoimmunity and chronic inflammatory diseases (64). The other reason is a potential dysregulation of the AngII–AT1R pathway downstream of ACE2. AngII not only acted as a vasoconstrictor, but also acted as a pro-inflammatory cytokine through AT1R (65). SARS-CoV-2 activated NF-κB and STAT3 through the AngI–AT1R pathway after SARS-CoV-2 infection, and then activated IL-6 amplifier (IL-6 Amp), which was a mechanism for STAT3 to overactivate NF-κB and led to various inflammations and autoimmune diseases (66). A meta-analysis showed that the inflammatory cytokines including IL-6, IL-10, and TNF-α were intensively increased in patients with diarrhea (67). Therefore, there is excessive activation of IL-1, IL-6, and NF-κB in the intestinal system, leading to various damages to the gastrointestinal tract.

Previous studies showed that the incidence of gastrointestinal symptoms in patients with COVID-19 was approximately 61%. Symptoms such as diarrhea, vomiting, and abdominal pain were reported (5). If the presence of SARS-CoV-2 is detected in the gastrointestinal tract tissue, this usually means that the symptoms are severe. Another study also showed that the incidence of abdominal pain in patients entering the intensive care unit was significantly higher than that in patients who did not need to enter the intensive care unit (68). SARS-CoV in 2003 used the human ACE2 receptor to infect the host, and a considerable number of patients developed gastrointestinal symptoms (69). Recent studies reported that SARS-CoV-2 used ACE2 receptors more effectively than SARS-CoV (70). Therefore, we cannot ignore the effect of SARS-CoV-2 on ACE2 in the gastrointestinal tract.

ACE2 regulates the expression of the intestinal neutral amino acid transporter, which is very important for the composition of intestinal microbiota (71). Therefore, diarrhea and other gastrointestinal symptoms in patients with COVID-19 are likely to be related to the downregulation of ACE2 expression. Here, we summarize the possible causes and mechanisms of the effects of COVID-19 on the gastrointestinal tract. Studies showed that the transepithelial absorption of amino acids through intestinal epithelial cells referred to the sequential transport process through the lumen, brush border, and basolateral membrane, and the step of amino acids passing through the lumen required the mediation of various amino acid transporters.

Studies reported that sodium-dependent neutral amino acid transporter B(0)AT1 was expressed in small intestinal cells and plays an important role in amino acid absorption, while the expression and function of B(0)AT1 depend on the existence of ACE2 (72). Hartnup disease is a rare autosomal recessive disease caused by B(0)AT1 gene mutation (73, 74). The disease causes obvious symptoms of diarrhea. Tatsuo et al. found that there was no change in the morphology and ultrastructure of the small intestine and large intestine in ACE2 knockout mice. However, after stimulation with sodium dextran sulfate (SDS), the intestines of ACE2 knockout mice showed more obvious inflammation, weight loss, and severe diarrhea (71). B(0)AT1 cannot be expressed in the intestines of ACE2 knockout mice, but dietary tryptophan is mainly absorbed through the B(0)AT1/ACE2 transport pathway on the surface of the intestinal epithelium. As a result, the level of plasma tryptophan decreased significantly, while the deficiency of tryptophan and its metabolite nicotinamide decreased the activity of the mTOR pathway (71, 75). The mTOR pathway regulates the expression of antimicrobial peptides that affect intestinal microbiota. Changes in antimicrobial peptides will affect the ecology of large and small intestinal microbiota and cause local enteritis and diarrhea (71). Combined with a recent autopsy report of COVID-19 patients, intestinal injury was not obvious to the naked eye, and the small intestine showed phased dilatation and stenosis. Intestinal injury was probably caused by intestinal inflammation. The Susanna Nikolaus team studied 500 patients with inflammatory bowel disease and found that tryptophan deficiency promotes the development of inflammatory bowel disease and exacerbates disease activity (76). Therefore, we infer that the gastrointestinal symptoms in some patients with COVID-19 may be due to the downregulation of ACE2 expression, which affects the disturbance of tryptophan absorption and local enteritis caused by the ecology of intestinal microbiota through the above pathway ( Figure 2 ). B(0)AT1 was also shown to interact with another coronavirus receptor, aminopeptidase N (APN) (77). All these findings suggest that B(0)AT1 may have a certain regulatory effect on the ability of some coronaviruses to infect the intestine.

A recent study pointed out that several biosynthetic pathways, including the tryptophan biosynthetic pathway, will change in COVID-19 patients. This may be mainly caused by intestinal microbes. The study also found the depletion of several low-water-soluble long-chain fatty acids or fatty alcohols, such as arachidic acid, behenic acid, and 1-hexadecanol, in the feces of COVID-19 patients (78). The abovementioned microorganism-derived metabolites are closely related to regulating the host’s inflammatory response and promoting tolerance and drug resistance to viral pathogens (79, 80). Understanding how SARS-CoV-2 causes changes in the intestinal microbiota and fecal metabolites is of great significance to the study of the mechanism of SARS-CoV-2 causing gastrointestinal symptoms.

Some recent cases reported repeated diarrhea, gastrointestinal bleeding, and acute mesenteric thrombosis in patients infected with the new coronavirus (81, 82). According to a recent study, bowel abnormalities were a common finding (31%) during abdominal imaging of patients with COVID-19, and patients who required laparotomy often had histological ischemia due to small blood vessel thrombosis (83). An imaging study showed that in patients without COVID-19, the left flexure colon and sigmoid colon were at the highest risk of ischemic colitis, while the distal rectal segment usually survived due to its double blood supply, and in patients with COVID-19, seven cases have reported thickening of the colon/rectum. This difference in the location of the disease also reveals the relationship between intestinal ischemic injury and SARS-CoV-2 infection (83, 84). A case report also confirmed that the gastrointestinal bleeding of patients with COVID-19 was caused by SARS-CoV-2 infection (85), and it was considered to be a thrombotic dysfunction caused by excessive inflammation, hypoperfusion, and even direct inflammation (86). Recent studies also reported patients who died of thrombotic diseases, or were infected with the new coronavirus with venous thromboembolism (VTE) and peripheral arterial thrombosis (60, 87, 88). Here, we summarize the relevant mechanisms of intestinal coagulation diseases caused by SARS-CoV-2.

ACE2 and TMPRSS2 (a serine protease) are expressed in endothelial cells (89, 90), and the S protein of the virus can also induce the downregulation of ACE2 (7). The downregulation of ACE2 is related to the local increase of Ang II (7). The increase of Ang- has a pro-inflammatory effect, leading to increased blood tumor necrosis factor-α and interleukin-6 levels (91). Both cytokines promote the rupture of the endothelial barrier (92) and reduce the level of Ang-(1-7) (93), leading to the occurrence of sepsis (94). Sepsis increases the level of inflammatory factors in the blood. Many cytokines are related to the production of blood’s procoagulant state. For example, the increase of IL-6 level is related to the increase of fibrinogen level (95). Increased levels of cytokines also led to tissue damage, thrombotic microangiopathy, endotheliitis, and endothelial dysfunction (96). The direct attack of SARS-CoV-2 on the vascular endothelium eventually led to a vicious cycle between sepsis and increased cytokine levels. The damage of vascular endothelial cells and the increase of cytokines in the blood together led to the hypercoagulable state of the blood, which induced the occurrence of intestinal coagulation diseases.

In addition, studies showed that SARS-CoV-2 connected through the ACE2 receptor and enters cells, causing local inflammation and activating endothelial cells (97). The activation of lung endothelial cells led to the shedding of ACE1, which was described as the massive release of ACE1 from the cell membrane, followed by a rapid increase in the level of AngII, leading to inflammation, coagulation and capillary leakage (98). Here, we make an assumption: ACE1 shedding may also occur in infected intestinal endothelial cells. When the free ACE1 in the blood disappears, AngII will also drop to a very low level. Decreased levels of AngII can induce ACE2 synthesis, and may cause more SARS-CoV-2 to enter tissue cells (99) ( Figure 3 ).

The increased levels of D-dimer and fibrinogen in many patients with COVID-19 may not only be a common cause of peripheral and pulmonary thrombosis, but also be the main cause of intestinal hypercoagulability and ischemic events (100, 101). Among patients hospitalized with COVID-19, the proportion of patients with D-Dimer increased as high as 47% (102). Compared with patients with coagulopathy, the most typical manifestation of patients with COVID-19 was increased D-dimer concentration (101). IL-6 induced mononuclear cells to express tissue factor, which in turn caused coagulation activation and thrombin generation. TNF-α and IL-1 are the main mediators that inhibit the endogenous anticoagulation pathway (103). Therefore, it is necessary to detect the levels of D-dimer and IL-6, TNF-α, and IL-1 to prevent and predict the intestinal coagulation disease of COVID-19. Polyphosphates are derived from microorganisms; activate platelets, mast cells, and factor 12 (FXII) in the coagulation pathway; and play other downstream roles in enhancing the procoagulant reaction of the endogenous coagulation pathway (104). The imbalance of gastrointestinal microbiota and the influence of gastrointestinal microbiota metabolites on the complications of intestinal thrombosis is also a point worth studying.