ons is well-known. In specific, abnormally low levels of tryptophan are observed within the blood and brain of Ace2 KO mice [27,60,61]. Interestingly, such alterations may be rescued by the oral administration from the dipeptide glycyl-tryptophan (Gly-Trp) [27], a tryptophan precursor whose absorption will not call for the intestinal expression of ACE2. Moreover, human subjects bearing an SLC6A19 loss-of-function mutation develop a disorder called Hartnup disease, characterized notably by the co-occurrence of neuropsychiatric symptoms and low blood levels of neutral amino acids [62,63]. In addition to SLC6A19, we also found that in SARS-CoV2-infected enterocytes, ACE2 co-regulates with quite a few critical genes of your dopamine/trace amines synthetic pathways. Essentially the most statistically significant correlation hyperlinks with ACE2 were observed for SLC7A9 and MAOB, two genes respectively involved in the intestinal absorption of L-DOPA and the catabolism of both tryptamine and -PEA. As a matter of reality, dopamine and trace amines have been involved within the pathophysiology of bipolar disorder [646] and schizophrenia [670]. We also performed an unsupervised correlation analysis allowing identification of the top-25 genes 5-HT7 Receptor review exhibiting the closest correlation links with ACE2 in SARS-CoV2-infectedInt. J. Mol. Sci. 2021, 22,10 ofenterocytes. MAOB belonged to this short list of genes, reinforcing the notion that in human enterocytes, SARS-CoV2-induced dysregulation of ACE2 may well be accompanied by alterations on the dopamine/trace amines metabolic pathways. Only a couple of system biology metabolomics analyses have already been performed so far on blood samples from COVID-19 sufferers. Strikingly, one such study showed that amongst the metabolites exhibiting altered blood levels in COVID-19 sufferers (n = 33), the highest scores of statistical enrichment were observed for metabolites connected to neutral amino acids metabolic pathways (notably tryptophan, proline and/or lysine metabolic pathways) (Figure S3A) [71]. In this dataset, neutral amino acids which include tryptophan, alanine, glycine, serine and glutamine have been discovered to be down-regulated in the blood of COVID-19 patients, irrespective in the presence of high or moderate levels of systemic inflammation (Figure S3B,C). Raw information regarding the blood levels of tyrosine are regrettably not accessible within this report. On the other hand, a further metabolomics study [72] in which a larger cohort of patients was analyzed (n = 50) clearly demonstrated decreased blood levels of neutral amino acids (which includes tryptophan and tyrosine) in either extreme or CDK16 medchemexpress non-severe COVID-19 sufferers when compared with healthy subjects (Table S3). Interestingly also, this study reported a statistically significant reduce in dopamine sulfate (dopamine 3-O-sulfate) inside the blood of non-severe COVID-19 patients as compared with healthful controls (Table S3). Of note, measuring trace amines in biological fluids calls for procedures which might be much more sensitive than mass spectrometry. Similarly, the blood of wholesome subjects consists of high amounts of dopamine-sulfate but only low levels of L-DOPA (which nonetheless boost following food intake) [38]. These technical issues might clarify the current lack of data concerning such molecules within the context of COVID-19. General, given that SARS-CoV2 was shown to chronically infect human enterocytes in vivo, our findings raise the possibility that in sufferers with long COVID, a dysfunction of ACE2 in human enterocytes could possibly alter the blood levels