**5. Endocrine and metabolic contributions in SARS-CoV-2 infection: ACE-2 downregulation in SARS-CoV-2 as phenocopy of Hartnup disease**

Epidemiological data showed that the elderly and those with co-morbidities (diabetes, obesity, and cardiovascular, respiratory, renal, and lung diseases) are most susceptible to COVID-19 and more likely to suffer from the most severe disease complications [64]. Viral infections mobilize free fatty acids to support capsid-associated membrane formation, which was described for other coronaviruses and is explained, in part, by activating phospholipase A2, a target amenable to pharmacological intervention [65].

Hartnup disease is a condition caused by the body's inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins and other substances they need with a well-balanced diet [27, 66].

Individuals with Hartnup disease have high levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, in other cases, individuals have episodes exhibiting other

**45**

*Renin Angiotensin System, Gut-Lung Cross Talk and Microbiota. Lessons from SARS-CoV…*

signs, which can include skin rashes, difficulty of coordination of movements (cerebellar ataxia), and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by intercurrent infection, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is changed, although the aminoaciduria remains. In affected individuals, signs and

As previously mentioned, the two antagonistic systems ACE, ANG II, AT1R and ACE2, ANII 1–7 are in the "hurricane eye" of SARS-CovV-2 and the non-enzymatic role of ACE-2 give rise to Hartnup disease phenocopy. ACE-2 is also a stabilizing protein (very similar to collectrin in kidney) of the neutral amino acid transporter

In mice with ACE-2 deletion in the small intestine, there was also a decrease in tryptophan absorption secondary to the lower expression of the neutral amino acid transporter accompanied by a phenotype very similar to that of Hartnup's disease phenotypes [69]. This situation can be caused by SARS-COVs and probably explains the gastro intestinal symptoms sometimes associated with those viral infections. In this case, it may be the result of the accumulation of nephrotoxic and pro-inflammatory pulmonary products (indole derivatives) or lack of anti-inflammatory kynurenines (IDO derivatives), as a consequence of dysbiosis at large intestine resulting from the lack of absorption of several neutral and aromatic amino acids

**6. New highlights of possible microbioma association to SARS-CoV-2** 

Concordantly to exposed in this chapter, the SARS-CoV-2 is more than a severe respiratory infection and actually integrate a multisystemic coordination. Metabolic syndrome and microbiome had been associated in intervention from ACE-2. This relation has an explanation that is now much more clarified and that goes through the IDO derivatives (Kynurenines) associated with aryl hydrocarbon receptor

The rationale of the non-enzymatic role of ACE-2 to serotonin and IDO derivatives to kynurenines has an explanation based in the activation of AhR functions by these tryptophan metabolites as they activates anti-inflammatory cytokines that may counteract the SARS-CoV-2 gastrointestinal and pulmonary symptoms characterized by a "cytokine storm" [72]. This can have their origin in the dysbiosis related to the tryptophan catabolism in indol derivatives by unbalanced *Lacobacillus spp* (decreased) specially in high salt microenvironment characteristic of western

Importantly, ACE-2 is highly expressed on the luminal surface of intestinal epithelial cells, functioning as a co-receptor for nutrient uptake, in particular for amino acid resorption from food [75]. Therefore the intestine might also be a major entry site for SARS-CoV-2 and the infection might have been initiated by eating food from the Wuhan market, the putative site of the outbreak. Whether SARS-CoV-2 can indeed infect the human gut epithelium has important implications for fecal–oral transmission and containment of viral spread. Moreover, the ACE-2 tissue distribution in other organs could explain the multi-organ dysfunction observed in patients [66, 71, 76, 77]. Any perturbation in host-microbiota crosstalk

Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviors of their host. A large

can be an initiating or re-enforcing factor in SARS-CoV-2 pathogenesis.

*DOI: http://dx.doi.org/10.5772/intechopen.94325*

mutated in the Hartnup disease [27].

namely tryptophan [70, 71].

pattern diets [71, 73, 74].

**infection**

symptoms most commonly occur in childhood [67, 68].

(AhR) and anti-inflammatory response Th22 [56].

*Renin Angiotensin System, Gut-Lung Cross Talk and Microbiota. Lessons from SARS-CoV… DOI: http://dx.doi.org/10.5772/intechopen.94325*

signs, which can include skin rashes, difficulty of coordination of movements (cerebellar ataxia), and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by intercurrent infection, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is changed, although the aminoaciduria remains. In affected individuals, signs and symptoms most commonly occur in childhood [67, 68].

As previously mentioned, the two antagonistic systems ACE, ANG II, AT1R and ACE2, ANII 1–7 are in the "hurricane eye" of SARS-CovV-2 and the non-enzymatic role of ACE-2 give rise to Hartnup disease phenocopy. ACE-2 is also a stabilizing protein (very similar to collectrin in kidney) of the neutral amino acid transporter mutated in the Hartnup disease [27].

In mice with ACE-2 deletion in the small intestine, there was also a decrease in tryptophan absorption secondary to the lower expression of the neutral amino acid transporter accompanied by a phenotype very similar to that of Hartnup's disease phenotypes [69]. This situation can be caused by SARS-COVs and probably explains the gastro intestinal symptoms sometimes associated with those viral infections. In this case, it may be the result of the accumulation of nephrotoxic and pro-inflammatory pulmonary products (indole derivatives) or lack of anti-inflammatory kynurenines (IDO derivatives), as a consequence of dysbiosis at large intestine resulting from the lack of absorption of several neutral and aromatic amino acids namely tryptophan [70, 71].

## **6. New highlights of possible microbioma association to SARS-CoV-2 infection**

Concordantly to exposed in this chapter, the SARS-CoV-2 is more than a severe respiratory infection and actually integrate a multisystemic coordination. Metabolic syndrome and microbiome had been associated in intervention from ACE-2. This relation has an explanation that is now much more clarified and that goes through the IDO derivatives (Kynurenines) associated with aryl hydrocarbon receptor (AhR) and anti-inflammatory response Th22 [56].

The rationale of the non-enzymatic role of ACE-2 to serotonin and IDO derivatives to kynurenines has an explanation based in the activation of AhR functions by these tryptophan metabolites as they activates anti-inflammatory cytokines that may counteract the SARS-CoV-2 gastrointestinal and pulmonary symptoms characterized by a "cytokine storm" [72]. This can have their origin in the dysbiosis related to the tryptophan catabolism in indol derivatives by unbalanced *Lacobacillus spp* (decreased) specially in high salt microenvironment characteristic of western pattern diets [71, 73, 74].

Importantly, ACE-2 is highly expressed on the luminal surface of intestinal epithelial cells, functioning as a co-receptor for nutrient uptake, in particular for amino acid resorption from food [75]. Therefore the intestine might also be a major entry site for SARS-CoV-2 and the infection might have been initiated by eating food from the Wuhan market, the putative site of the outbreak. Whether SARS-CoV-2 can indeed infect the human gut epithelium has important implications for fecal–oral transmission and containment of viral spread. Moreover, the ACE-2 tissue distribution in other organs could explain the multi-organ dysfunction observed in patients [66, 71, 76, 77]. Any perturbation in host-microbiota crosstalk can be an initiating or re-enforcing factor in SARS-CoV-2 pathogenesis.

Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviors of their host. A large

*Some RNA Viruses*

SARS-CoV-2 [58].

pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). This initial observational study identified amino acid and fatty acid metabolism as correlates of

ated with unbalanced ACE-ACE-2 system (**Figure 3b**) [38].

immunosuppressive profile be protected from this reciprocal attack?

The children account for less than 2% of identified cases of SARS-CoV-2 [62]. Interestingly, young children, including infants who are more susceptible to other infections, have milder symptoms and less severe SARS-CoV-2. Nevertheless, children seem to have similar rates of becoming infected compared with middle-aged adults following close contact with a person infected with SARS-CoV-2 [33].

Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (Bacillus Calmette–Guérin - BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells [63].

**5. Endocrine and metabolic contributions in SARS-CoV-2 infection: ACE-2 downregulation in SARS-CoV-2 as phenocopy of Hartnup disease**

Epidemiological data showed that the elderly and those with co-morbidities (diabetes, obesity, and cardiovascular, respiratory, renal, and lung diseases) are most susceptible to COVID-19 and more likely to suffer from the most severe disease complications [64]. Viral infections mobilize free fatty acids to support capsid-associated membrane formation, which was described for other coronaviruses and is explained, in part, by activating phospholipase A2, a target amenable to

Hartnup disease is a condition caused by the body's inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins

Individuals with Hartnup disease have high levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, in other cases, individuals have episodes exhibiting other

and other substances they need with a well-balanced diet [27, 66].

In our group, we also demonstrated that a functional variable number of tandem repeats (VNTR) genetic polymorphism of serotonin transporter, whose expression is activated by IL-1, has some relation with the ACE serum levels that can be associ-

Polymorphisms in genes coding for IL-10, TNF-alpha and IL-6 influence circulating levels, and behave as promoters of severe systemic inflammatory response that can probably has an interindividual and gender dependent impact [53]. At the other end of the iceberg, the immunocompromised patients could be protected against SARS-CoV-2, since unlike other common viruses, coronaviruses have not shown to cause more severe disease in immunosuppressed patients, at least statistically significant [60]. Our own immune response appears to be the main driver of lung tissue damage during infection. Starting around the 2nd week of symptoms, patients experience a "storm of cytokines" – autoimmune reaction, where your body over-reacts and in attacking coronavirus, your lungs get caught in the body immunologic response [47, 61]. In the first week of the illness it's the virus itself that's triggering most of your symptoms, but then in severe cases, it's our own inflammatory responses that takes over in causing the most of the damage. So this "storm of cytokines" is killing our immune cells, therefore, could patients with

**44**

pharmacological intervention [65].

array of metabolites drives the crosstalk between the host and its microbiome. The three currently most studied categories of metabolites involved in host-microbiota interactions are short-chain fatty acids produced by bacteria from the fermentation of fibbers, bile acids produced in the liver and transformed by the gut microbiota before re-affecting the host, and tryptophan metabolites, which are the topic of this review [72].

Tryptophan is an essential aromatic amino acid composed of a b carbon connected to the 3 position of an indole group and it is a biosynthetic precursor of a large number of microbial and host metabolites [78]. It's metabolism follows three major pathways in the gastrointestinal tract: the direct transformation of Tryptophan into several molecules, including ligands of the (AhR) by the gut microbiota [78]; the kynurenine pathway in both immune and epithelial cells via IDO-1 [79]; and the serotonin (5-hydroxytryptamine [5-HT]) production pathway in enterochromaffin cells via Tryptophan hydroxylase 1 (TpH1) [72]. The AhR is implicated in lung inflammation [80].

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance.
