What do we know about the renin angiotensin system and inflammatory bowel disease?

References

• Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001;38(6):1246–1249.
   PubMed Web of Science ®Google Scholar
• Santos RAS, Sampaio WO, Alzamora AC, et al. The ACE2/Angiotensin-(1-7)/mas axis of the renin-angiotensin system: focus on angiotensin-(1-7). Physiol Rev. 2018;98(1):505–553.
   PubMed Web of Science ®Google Scholar
• Garg M, Angus PW, Burrell LM, et al. Review article: the pathophysiological roles of the renin-angiotensin system in the gastrointestinal tract. Aliment Pharmacol Ther. 2012;35(4):414–428.
   PubMed Web of Science ®Google Scholar
• Castrop H, Höcherl K, Kurtz A, et al. Physiology of kidney renin. Physiol Rev. 2010;90(2):607–673.
   PubMed Web of Science ®Google Scholar
• Feng Y. ANG II-independent prorenin/(pro)renin receptor signaling pathways in the central nervous system. Am J Physiol Heart Circ Physiol. 2015;309(5):H731–3.
   PubMed Web of Science ®Google Scholar
• Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238–33243.
   PubMed Web of Science ®Google Scholar
• Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(1):45–51.
   PubMedGoogle Scholar
• Santos RAS, Simoes E Silva AC, Maric C, et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100(14):8258.
   PubMed Web of Science ®Google Scholar
• Kuba K, Imai Y, Ohto-Nakanishi T, et al. Trilogy of ACE2: a peptidase in the renin–angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol Ther. 2010;128(1):119–128.
   PubMed Web of Science ®Google Scholar
• English WR, Corvol P, Murphy G. LPS activates ADAM9 dependent shedding of ACE from endothelial cells. Biochem Biophys Res Commun. 2012;421(1):70–75.
   PubMed Web of Science ®Google Scholar
• Salmenkari H, Issakainen T, Vapaatalo H, et al. Local corticosterone production and angiotensin-I converting enzyme shedding in a mouse model of intestinal inflammation. World J Gastroenterol. 2015;21(35):10072–10079.
   PubMed Web of Science ®Google Scholar
• Lundström A, Ziegler L, Havervall S, et al. Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers. J Med Virol. 2021;93(10):5908–5916.
   PubMed Web of Science ®Google Scholar
• Yugandhar VG, Clark MA. Angiotensin III: a physiological relevant peptide of the renin angiotensin system. Peptides (NY). 2013. 46:26–32.
   PubMed Web of Science ®Google Scholar
• Swanson GN, Hanesworth JM, Sardinia MF, et al. Discovery of a distinct binding site for angiotensin II (3–8), a putative angiotensin IV receptor. Regul Pept. 1992;40(3):409–419.
   PubMedGoogle Scholar
• Lautner RQ, Villela DC, Fraga-Silva RA, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–1111.
   PubMed Web of Science ®Google Scholar
• Singh KD, Karnik SS. Angiotensin receptors: structure, function, signaling and clinical applications. J Cell Signal. 2016 Jun;1(2):111.
   Google Scholar
• Matavelli LC, Siragy HM. AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol. 2015;65(3):226–232.
   PubMed Web of Science ®Google Scholar
• Zizzo MG, Caldara G, Bellanca A, et al. PD123319, angiotensin II type II receptor antagonist, inhibits oxidative stress and inflammation in 2, 4-dinitrobenzene sulfonic acid-induced colitis in rat and ameliorates colonic contractility. Inflammopharmacology. 2020;28(1):187–199.
   PubMed Web of Science ®Google Scholar
• Bayes-Genis A, Barallat J, Richards AM. A Test in Context: neprilysin: function, Inhibition, and Biomarker. J Am Coll Cardiol. Elsevier USA. 2016;68(6):639–653
   Google Scholar
• Sargın ZG, Erin N, Tazegul G, et al. Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis. PLoS One. 2017 Dec 12;12(12):e0189526.
   PubMed Web of Science ®Google Scholar
• Takai S, Jin D, Miyazaki M. New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: chymase as an Important Target to Prevent Organ Damage. J Pharmacol Sci. 2010;113(4):301–309.
   PubMed Web of Science ®Google Scholar
• Leo CH, Jelinic M, Gooi JH, et al. A vasoactive role for endogenous relaxin in mesenteric arteries of male mice. PLoS One. 2014;9(9). DOI:10.1371/journal.pone.0107382.
   Web of Science ®Google Scholar
• Ng HH, Leo CH, Parry LJ, et al. Relaxin as a Therapeutic Target for the Cardiovascular Complications of Diabetes. Front Pharmacol. 2018;9. DOI:10.3389/fphar.2018.00501.
   Web of Science ®Google Scholar
• Chow BSM, Kocan M, Shen M, et al. AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts: impact on the therapeutic targeting of renal and cardiac fibrosis. J Am Soc Nephrol. 2019;30(11):2191–2207.
   PubMed Web of Science ®Google Scholar
• Samuel CS, Bodaragama H, Chew JY, et al. Serelaxin is a more efficacious antifibrotic than enalapril in an experimental model of heart disease. Hypertension. 2014;64(2):315–322.
   PubMed Web of Science ®Google Scholar
• Khedr S, Deussen A, Kopaliani I, et al. Effects of tryptophan-containing peptides on angiotensin-converting enzyme activity and vessel tone ex vivo and in vivo. Eur J Nutr. 2018;57(3):907–915.
   PubMed Web of Science ®Google Scholar
• Nikolaus S, Schulte B, Al-Massad N, et al. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology. 2017;153(6):1504–1516.e2.
   PubMed Web of Science ®Google Scholar
• Kim CJ, Kovacs-Nolan JA, Yang C, et al. l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. J Nutr Biochem. 2010;21(6):468–475.
   PubMed Web of Science ®Google Scholar
• Hashimoto T, Perlot T, Rehman A, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487(7408):477–481.
   PubMed Web of Science ®Google Scholar
• Lavoie JL, Sigmund CD. Minireview: overview of the Renin-Angiotensin System—An Endocrine and Paracrine System. Endocrinology. 2003;144(6):2179–2183.
   PubMed Web of Science ®Google Scholar
• Hallersund P, Elfvin A, Helander HF, et al. The expression of renin-angiotensin system components in the human gastric mucosa. J Renin Angiotensin Aldosterone Syst. 2011;12(1):54–64.
   PubMed Web of Science ®Google Scholar
• Carl-Mcgrath S, Grntzdrffer I, Lendeckel U, et al. Angiotensin II-generating enzymes, angiotensin-converting enzyme (ACE) and mast cell chymase (CMA1), in gastric inflammation may be regulated by H. pylori and associated cytokines. Pathology. 2009;41(5):419–427.
   PubMed Web of Science ®Google Scholar
• Brzozowski T, Ptak-Belowska A, Kwiecien S, et al. Novel concept in the mechanism of injury and protection of gastric mucosa: role of renin-angiotensin system and active metabolites of angiotensin. Curr Med Chem. 2012;19(1):55–62.
   PubMed Web of Science ®Google Scholar
• Weidemann BJ, Voong S, Morales-Santiago FI, et al. Dietary sodium suppresses digestive efficiency via the renin-angiotensin system. Sci Rep. 2015;5. DOI:10.1038/srep11123.
   PubMed Web of Science ®Google Scholar
• Bruneval P, Hinglais N, Alhenc-Gelas F, et al. Angiotensin I converting enzyme in human intestine and kidney. Histochemistry. 1986;85(1):73–80
   PubMedGoogle Scholar
• Hamming I, Timens W, Bulthuis MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637.
   PubMed Web of Science ®Google Scholar
• Harmer D, Gilbert M, Borman R, et al. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 2002;532(1–2):107–110.
   PubMed Web of Science ®Google Scholar
• Trejdosiewicz LK, Malizia G, Oakes J, et al. Expression of the common acute lymphoblastic leukaemia antigen (CALLA gp100) in the brush border of normal jejunum and jejunum of patients with coeliac disease. J Clin Pathol. 1985;38(9):1002–1006.
   PubMed Web of Science ®Google Scholar
• Hirasawa K, Sato Y, Hosoda Y, et al. Immunohistochemical localization of angiotensin II receptor and local renin-angiotensin system in human colonic mucosa. J Histochem Cytochem. 2002;50(2):275–282.
   PubMed Web of Science ®Google Scholar
• Shorning BY, Jardé T, McCarthy A, et al. Intestinal renin–angiotensin system is stimulated after deletion of Lkb1. Gut. 2012;61(2):202–213.
   PubMed Web of Science ®Google Scholar
• Ryuzaki M, Miyashita K, Sato M, et al. Activation of the intestinal tissue renin-angiotensin system by transient sodium loading in saltsensitive rats. J Hypertens. 2022;40(1):33–45.
   PubMed Web of Science ®Google Scholar
• Wong TP, Ho KY, Ekw N, et al. Upregulation of ACE2-ANG-(1-7)-mas axis in jejunal enterocytes of type 1 diabetic rats: implications for glucose transport. Am J Physiol Endocrinol Metab. 2012;303(5):E669–E681.
   Web of Science ®Google Scholar
• Kowalczuk S, Bröer A, Tietze N, et al. A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J. 2008;22(8):2880–2887.
   PubMed Web of Science ®Google Scholar
• Qin WH, Liu CL, Jiang YH, et al. Gut ACE2 expression, tryptophan deficiency, and inflammatory responses the potential connection that should not be ignored during SARS-CoV-2 Infection. Cell Mol Gastroenterol Hepatol; 2021;12(4):1514–1516.e4.
   Google Scholar
• Fändriks L. The angiotensin II type 2 receptor and the gastrointestinal tract. JRAAS - J Renin-Angiotensin-Aldosterone Sys. 2010;11(1):43–48
   Google Scholar
• Oliveira LP, Guimarães VHD, Oliveira JR, et al. Genetic deletion of the angiotensin-(1–7) receptor Mas leads to alterations in gut villi length modulating TLR4/PI3K/AKT and produces microbiome dysbiosis. Neuropeptides. 2020;82:102056.
   Web of Science ®Google Scholar
• Garg M, Royce SG, Tikellis C, et al., Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target? Gut. 2020. 69(5): 841–854.
   PubMed Web of Science ®Google Scholar
• Pais R, Rievaj J, Larraufie P, et al. Angiotensin II Type 1 receptor-dependent GLP-1 and PYY secretion in mice and humans. Endocrinology. 2016;157(10):3821–3831.
   PubMed Web of Science ®Google Scholar
• Andoh A, Deguchi Y, Inatomi O, et al. Immunohistochemical study of chymase-positive mast cells in inflammatory bowel disease. Oncol Rep. 2006;16(1):103–107.
   Web of Science ®Google Scholar
• Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769–2778.
   PubMed Web of Science ®Google Scholar
• Maaser C, Sturm A, Vavricka SR, et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019;13(2):144–164K.
   PubMed Web of Science ®Google Scholar
• Cooper HS, Murthy SN, Shah RS, et al. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69(2):238–249.
   PubMed Web of Science ®Google Scholar
• Spencer AU, Yang H, Haxhija EQ, et al. Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition. Dig Dis Sci. 2007;52(4):1060.
   PubMed Web of Science ®Google Scholar
• Inokuchi Y, Morohashi T, Kawana I, et al. Amelioration of 2,4,6-trinitrobenzene sulphonic acid induced colitis in angiotensinogen gene knockout mice. Gut. 2005;54(3):349–356.
   PubMed Web of Science ®Google Scholar
• Katada K, Yoshida N, Suzuki T, et al. Dextran sulfate sodium-induced acute colonic inflammation in angiotensin II type 1a receptor deficient mice. Inflamm Res. 2008;57(2):84–91.
   PubMed Web of Science ®Google Scholar
• Mizushima T, Sasaki M, Ando T, et al. Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis. Am J Physiol Gastrointest Liver Physiol. 2010;298(2):G255–G266.
   Web of Science ®Google Scholar
• Shi Y, Liu T, He L, et al. Activation of the renin-angiotensin system promotes colitis development. Sci Rep. 2016;6(1):6.
   PubMedGoogle Scholar
• He L, Du J, Chen Y, et al. Renin-angiotensin system promotes colonic inflammation by inducing T H 17 activation via JAK2/STAT pathway. Am J Physiol Gastrointest Liver Physiol. 2019;316(6):G774–G784.
   PubMed Web of Science ®Google Scholar
• Wengrower D, Zannineli G, Pappo O, et al. Prevention of Fibrosis in Experimental Colitis by Captopril: the Role of tgf--beta1. 2004;10(5):536–545.
   Google Scholar
• Jahovic N, Ercan F, Gedik N, et al. The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats. Regul Pept. 2005;130(1–2):67–74.
   PubMedGoogle Scholar
• Koga H, Yang H, Adler J, et al. Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: development of a unique mode of treatment. Surgery. 2008;144(2):259–268.
   PubMed Web of Science ®Google Scholar
• Sueyoshi R, Ignatoski KMW, Daignault S, et al. Angiotensin converting enzyme-inhibitor reduces colitis severity in an il-10 knockout model. Dig Dis Sci. 2013;58(11):3165–3177.
   PubMed Web of Science ®Google Scholar
• Lee C, Chun J, Hwang SW, et al. Enalapril inhibits nuclear factor-κB signaling in intestinal epithelial cells and peritoneal macrophages and attenuates experimental colitis in mice. Life Sci. 2014;95(1):29–39.
   PubMed Web of Science ®Google Scholar
• Okawada M, Wilson MW, Larsen SD, et al. Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models. Pediatr Surg Int. 2016;32(12):1103–1114.
   PubMed Web of Science ®Google Scholar
• Salmenkari H, Holappa M, Forsgard RA, et al. Orally administered angiotensin-converting-enzyme-inhibitors captopril and isoleucine-proline-proline have distinct effects on local renin-angiotensin system and corticosterone synthesis in dextran sulfate sodium-induced colitis in mice. J Physiol Pharmacol. 2017;68(3):355–362.
   PubMed Web of Science ®Google Scholar
• Salmenkari H, Pasanen L, Linden J, et al. Beneficial anti-inflammatory effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in the treatment of dextran sulfate sodium-induced colitis in mice. J Physiol Pharmacol. 2018;69(4).
   Web of Science ®Google Scholar
• Kabel AM, Atef A, Borg HM, et al. Perindopril/ambrosin combination mitigates dextran sulfate sodium-induced colitis in mice: crosstalk between toll-like receptor 4, the pro-inflammatory pathways, and SIRT1/PPAR-γ signaling. Pharmaceuticals (Basel). 2022;15(5):600.
   PubMedGoogle Scholar
• Björkman E, Edebo A, Casselbrant A, et al. The renin-angiotensin system in the esophageal mucosa of healthy subjects and patients with reflux disease. Scand J Gastroenterol. 2013;48(2):147–159.
   PubMed Web of Science ®Google Scholar
• Wengrower D, Zanninelli G, Latella G, et al. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats. Can J Gastroenterol. 2012;26(1):33–39.
   PubMed Web of Science ®Google Scholar
• Liu TJ, Shi YY, Wang EB, et al. AT1R blocker losartan attenuates intestinal epithelial cell apoptosis in a mouse model of Crohn’s disease. Mol Med Rep. 2016;13(2):1156–1162.
   PubMed Web of Science ®Google Scholar
• Hachiya KHY-L, MasuyaLee MP-I, KurodaHsueh NP-R, et al. Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking Predominant role of Haemophilus influenzae in the MCP-1/CCR2 pathway association of conjunctivitis, acute otitis media and acute bacterial paranasal sinusitis in children. Sci Rep. 2021;11(1)
   Google Scholar
• Santiago OI, Rivera E, Ferder L, et al. An angiotensin II receptor antagonist reduces inflammatory parameters in two models of colitis. Regul Pept. 2007;146(1–3):250–259.
   PubMedGoogle Scholar
• Arab HH, Al-Shorbagy MY, Abdallah DM, et al. Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease. PLoS One. 2014;9(5):e97193.
   PubMed Web of Science ®Google Scholar
• Arumugam S, Sreedhar R, Thandavarayan RA, et al. Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium. Cytokine. 2015;74(2):305–312.
   PubMed Web of Science ®Google Scholar
• Guerra GCB, Araújo AA, Lira GA, et al. Telmisartan decreases inflammation by modulating TNF-α, IL-10, and RANK/RANKL in a rat model of ulcerative colitis. Pharmacol Rep. 2015;67(3):520–526.
   PubMed Web of Science ®Google Scholar
• Saber S, Basuony M, Eldin AS. Telmisartan ameliorates dextran sodium sulfate-induced colitis in rats by modulating NF-κB signalling in the context of PPARγ agonistic activity. Arch Biochem Biophys. 2019;671:185–195.
   PubMed Web of Science ®Google Scholar
• Okawada M, Koga H, Larsen SD, et al. Use of enterally delivered angiotensin II type Ia receptor antagonists to reduce the severity of colitis. Dig Dis Sci. 2011;56(9):2553–2565.
   PubMed Web of Science ®Google Scholar
• Nagib MM, Tadros MG, Elsayed MI, et al. Anti-inflammatory and anti-oxidant activities of olmesartan medoxomil ameliorate experimental colitis in rats. Toxicol Appl Pharmacol. 2013;271(1):106–113.
   PubMed Web of Science ®Google Scholar
• Saber S, Khalil RM, Abdo WS, et al. Olmesartan ameliorates chemically-induced ulcerative colitis in rats via modulating NFκB and Nrf-2/HO-1 signaling crosstalk. Toxicol Appl Pharmacol. 2019;364:120–132.
   PubMed Web of Science ®Google Scholar
• Patel RB, Prajapati KD, Sonara BM, et al. Ameliorative potential of aliskiren in experimental colitis in mice. Eur J Pharmacol. 2014;737:70–76.
   PubMed Web of Science ®Google Scholar
• Khajah MA, Fateel MM, v AK, et al. Anti-inflammatory action of angiotensin 1-7 in experimental colitis. PLoS One. 2016 Mar 10;11(3):e0150861.
   Web of Science ®Google Scholar
• Khajah MA, Fateel MM, v AK, et al. Anti-inflammatory action of angiotensin 1-7 in experimental colitis may be mediated through modulation of serum cytokines/chemokines and immune cell functions. Dev Comp Immunol. 2017;74:200–208.
   PubMed Web of Science ®Google Scholar
• Kumar A, Priyamvada S, Soni V, et al. Angiotensin II Inhibits P-glycoprotein in Intestinal Epithelial Cells. Acta Physiol (Oxf). 2020;228(1):e13332.
   PubMed Web of Science ®Google Scholar
• Sturiale S, Barbara G, Qiu B, et al. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proc Natl Acad Sci U S A. 1999;96(20):11653–11658.
   PubMed Web of Science ®Google Scholar
• Liu WX, Wang Y, Sang LX, et al. Chymase inhibitor TY-51469 in therapy of inflammatory bowel disease. World J Gastroenterol. 2016;22(5):1826–1833.
   PubMed Web of Science ®Google Scholar
• Wei X, Li X, Du J, et al. Vitamin D deficiency exacerbates colonic inflammation due to activation of the local renin–angiotensin system in the colon. Dig Dis Sci. 2021;66(11):3813–3821.
   PubMed Web of Science ®Google Scholar
• Del Pinto R, Pietropaoli D, Chandar AK, et al. Association between inflammatory bowel disease and vitamin d deficiency: a systematic review and meta-analysis. Inflamm Bowel Dis. 2015;21(11):2708–2717.
   PubMed Web of Science ®Google Scholar
• Garg M, Rosella O, Lubel JS, et al. Association of circulating vitamin D concentrations with intestinal but not systemic inflammation in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(12):2634–2643.
   PubMed Web of Science ®Google Scholar
• Tian T, Wang Z, Zhang J. Pathomechanisms of Oxidative stress in inflammatory bowel disease and potential antioxidant therapies. Oxid Med Cell Longev. 2017;2017:1–18.
   Web of Science ®Google Scholar
• Verstockt B, Verstockt S, Abdu Rahiman S, et al. Intestinal receptor of SARS-CoV-2 in inflamed IBD tissue seems downregulated by HNF4A in ileum and upregulated by interferon regulating factors in colon. J Crohns Colitis. 2021;15(3):485–498.
   PubMed Web of Science ®Google Scholar
• Biagioli M, Marchianò S, Roselli R, et al. GLP-1 mediates regulation of colonic ACE2 expression by the bile acid receptor GPBAR1 in inflammation. Cells. 2022;11(7):1187.
   PubMed Web of Science ®Google Scholar
• Garg M, Burrell LM, Velkoska E, et al. Upregulation of circulating components of the alternative renin-angiotensin system in inflammatory bowel disease: a pilot study. JRAAS - Journal of the Renin-Angiotensin-Aldosterone System. 2015;16(3):559–569.
   PubMed Web of Science ®Google Scholar
• Jaszewski R, Tolia V, Ehrinpreis MN, et al. Increased colonic mucosal angiotensin I and II concentrations in Crohn’s colitis. Gastroenterology. 1990;98(6):1543–1548.
   PubMed Web of Science ®Google Scholar
• Hume GE, Doecke JD, Huang N, et al. Altered expression of angiotensinogen and mediators of angiogenesis in ileal crohn’s disease. J Gastrointestin Liver Dis. 2016;25(1):39–48.
   PubMed Web of Science ®Google Scholar
• Nowak JK, Lindstrøm JC, Kalla R, et al. Age, Inflammation, and disease location are critical determinants of intestinal expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in inflammatory bowel disease. Gastroenterology. 2020;159(3):1151–1154.e2.
   PubMed Web of Science ®Google Scholar
• Burgueno JF, Reich A, Hazime H, et al. Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD. Inflamm Bowel Dis. 2020;26(6):797–808.
   PubMed Web of Science ®Google Scholar
• Patankar JV, Chiriac MT, Lehmann M, et al. Severe acute respiratory syndrome coronavirus 2 attachment receptor angiotensin-converting enzyme 2 is decreased in crohn’s disease and regulated by microbial and inflammatory Signaling. Gastroenterology. 2021;160(3):925–928.e4.
   PubMed Web of Science ®Google Scholar
• Jacobs JD, Wagner T, Gulotta G, et al., Impact of angiotensin ii signaling blockade on clinical outcomes in patients with inflammatory bowel Disease. Dig Dis Sci. 2019. 64(7): 1938–1944.
   PubMed Web of Science ®Google Scholar
• Mantaka A, Tsoukali E, Fragkaki M, et al., Is there any role of renin-angiotensin system inhibitors in modulating inflammatory bowel disease outcome? Eur J Gastroenterol Hepatol. 2021. 33(3): 364–371.
   PubMed Web of Science ®Google Scholar
• Fairbrass KM, Hoshen D, Gracie DJ, et al. Effect of ACE inhibitors and angiotensin II receptor blockers on disease outcomes in inflammatory bowel disease. Gut. BMJ Publishing Group. 2021. 218–219. • This study provides clinical evidence for RAS inhibition in IBD
   Google Scholar
• D’Amico F, Baumgart DC, Danese S, et al. Diarrhea During COVID-19 infection: pathogenesis, epidemiology, prevention, and management. Clin Gastroenterol Hepatol. 2020;18:1663–1672.
   PubMed Web of Science ®Google Scholar
• Jackson CB, Farzan M, Chen B, et al. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 2021;23:1. 2021;23:3–20.
   Web of Science ®Google Scholar
• Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280.e8.
   PubMed Web of Science ®Google Scholar
• Zhang H, Kang Z, Gong H, et al. Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process. Gut. 2020;69(6):1010–1018.
   Web of Science ®Google Scholar
• Suárez-Fariñas M, Tokuyama M, Wei G, et al. Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2–related Disease. Gastroenterology. 2021;160(1):287–301.e20.
   PubMed Web of Science ®Google Scholar
• Taxonera C, Sagastagoitia I, Alba C, et al. 2019 novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases. Aliment Pharmacol Ther. 2020;52(2):276–283.
   PubMed Web of Science ®Google Scholar
• Aziz M, Fatima R, Haghbin H, et al. The incidence and outcomes of COVID-19 in IBD patients: a rapid review and meta-analysis. Inflamm Bowel Dis. 2020;26(10):e132–e133.
   PubMed Web of Science ®Google Scholar
• Corrias A, Cortes GM, Bardanzellu F, et al. Risk, course, and effect of SARS-CoV-2 Infection in children and adults with chronic inflammatory bowel diseases. Children (Basel). 2021;9(1):8.
   PubMedGoogle Scholar
• Li W, Moore MJ, Vasllieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:6965
   Web of Science ®Google Scholar
• Monteleone G, Ardizzone S. Are patients with inflammatory bowel disease at increased risk for covid-19 infection? J Crohns Colitis. 2020;14(9):1334–1336. Oxford University Press.
   PubMed Web of Science ®Google Scholar
• Zoufaly A, Poglitsch M, Aberle JH, et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir Med. 2020;8(11):1154–1158.
   PubMed Web of Science ®Google Scholar
• Thomas T, Stefanoni D, Reisz JA, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020;5(14). DOI:10.1172/jci.insight.140327.
   Web of Science ®Google Scholar
• Lionetto L, Ulivieri M, Capi M, et al. Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: an observational cohort study. Biochim Biophys Acta Mol Basis Dis. 2021;1867(3):166042.
   Web of Science ®Google Scholar
• Ghiboub M, Verburgt CM, Sovran B, et al. Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases. Nutrients. 2020;12(9):1–21.
   Web of Science ®Google Scholar
• Hanif K, Bid HK, Konwar R. Reinventing the ACE inhibitors: some old and new implications of ACE inhibition. Hypertens Res. 2010;33(1):1. 2009;33:11–21.
   PubMed Web of Science ®Google Scholar
• Li X, Lu C, Yang Y, et al. Site-specific targeted drug delivery systems for the treatment of inflammatory bowel disease. Biomed Pharmacother. 2020;129:110486.
   PubMed Web of Science ®Google Scholar
• Verma A, Zhu P, Xu K, et al. Angiotensin-(1–7) expressed from lactobacillus bacteria protect diabetic retina in mice. Transl Vis Sci Technol. 2020;9(13):20.
   PubMed Web of Science ®Google Scholar