Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation.
digestive inflammation
gut microbiota
holobiont
microbiome
protease activity profiling
serine proteases
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
08
01
2020
revised:
27
03
2020
accepted:
28
03
2020
pubmed:
21
4
2020
medline:
20
1
2021
entrez:
21
4
2020
Statut:
ppublish
Résumé
Serine proteases have been long recognized to coordinate many physiological processes and play key roles in regulating the inflammatory response. Accordingly, their dysregulation has been regularly associated with several inflammatory disorders and suggested as a central mechanism in the pathophysiology of digestive inflammation. So far, studies addressing the proteolytic homeostasis in the gut have mainly focused on host serine proteases as candidates of interest, while largely ignoring the potential contribution of their bacterial counterparts. The human gut microbiota comprises a complex ecosystem that contributes to host health and disease. Yet, our understanding of microbially produced serine proteases and investigation of whether they are causally linked to IBD is still in its infancy. In this review, we highlight recent advances in the emerging roles of host and bacterial serine proteases in digestive inflammation. We also discuss the application of available tools in the gut to monitor disease-related serine proteases. An exhaustive representation and understanding of such functional potential would help in closing existing gaps in mechanistic knowledge.
Identifiants
pubmed: 32307770
doi: 10.1096/fj.202000031RR
doi:
Substances chimiques
Serine Proteases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
7270-7282Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
Références
Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12:720-727.
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. 2018;390:2769-2778.
Chudy-Onwugaje KO, Christian KE, Farraye FA, Cross RK. A state-of-the-art review of new and emerging therapies for the treatment of IBD. Inflamm Bowel Dis. 2019;25:820-830.
Zhang M, Sun K, Wu Y, Yang Y, Tso P, Wu Z. Interactions between intestinal microbiota and host immune response in inflammatory bowel disease. Front Immunol. 2017;8:942.
Dickson I. Gut microbiota: diagnosing IBD with the gut microbiome. Nat Rev Gastroenterol Hepatol. 2017;14:195.
Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019;20:970-979.
Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514-521.
Vergnolle N. Protease inhibition as new therapeutic strategy for GI diseases. Gut. 2016;65:1215-1224.
Puente XS, Sánchez LM, Gutiérrez-Fernández A, Velasco G, López-Otín C. A genomic view of the complexity of mammalian proteolytic systems. BiochemSoc Trans. 2005;2:331-334.
Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucl Acids Res. 2018;46:624-632.
Drag M, Salvesen GS. Emerging principles in protease-based drug discovery. Nat Rev Drug Discov. 2010;9:690-701.
Neurath H, Walsh K. Role of proteolytic enzymes in biological regulation (a review). PNAS. 1976;73:3825-3832.
Siegel RM. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol. 2006;6:308-317.
Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8:221-233.
Motta JP, Magne L, Descamps D, et al. Modifying the protease antiprotease pattern by Elafin overexpression protects mice from colitis. Gastroenterology. 2011;140:1272-1282.
Motta JP, Bermúdez-Humarán LG, Deraison C, et al. Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. Sci Transl Med. 2012;4:158ra144.
Edgington-Mitchell LE. Pathophysiological roles of proteases in gastrointestinal disease. Am J Physiol Gastrointest Liver Physiol. 2016;310:234-239.
Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol. 2008;153:263-282.
Di Cera E. Serine proteases. IUBMB Life. 2009;61:510-515.
Gurumallesh P, Alagu K, Ramakrishnan B, Muthusamy S. A systematic reconsideration on proteases. Int J Biol Macromol. 2018;128:254-267.
Mönttinen HAM, Ravantti JJ, Poranen MM. Structural comparison strengthens the higher-order classification of proteases related to chymotrypsin. PLoS ONE. 2019;14:e0216659.
Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell. 2002;10:443-455.
Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol. 2002;2:401-409.
Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50:326-336.
López-Otín C, Bond JS. Proteases: multifunctional enzymes in life and disease. J Biol Chem. 2008;283:30433-30437.
Pham CT. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. 2006;6:541-550.
Verdoes M, Verhelst SH. Detection of protease activity in cells and animals. Biochim Biophys Acta. 2016;1864:130-142.
Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov. 2006;5:785-799.
Belaaouaj A. Neutrophil elastase-mediated killing of bacteria: lessons from targeted mutagenesis. Microbes Infect. 2002;4:1259-1264.
Mortaz E, Alipoor SD, Adcock IM, Mumby S, Koenderman L. Update on neutrophil function in severe inflammation. Front Immunol. 2018;9:2171.
Biancheri P, Di Sabatino A, Corazza GR, MacDonald TT. Proteases and the gut barrier. Cell Tissue Res. 2013;351:269-280.
Clayburgh DR, Shen L, Turner JR. A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest. 2004;84:282-291.
Odenwald MA, Turner JR. The intestinal epithelial barrier: a therapeutic target? Nat Rev Gastroenterol Hepatol. 2017;14:9-21.
Madara JL. Intestinal absorptive cell tight junctions are linked to cytoskeleton. Am J Physiol. 1987;253:171-175.
Shen L. Tight junctions on the move: molecular mechanisms for epithelial barrier regulation. Ann N Y Acad. Sci. 2012;1258:9-18.
Xiong Y, Wang C, Shi L, et al. Myosin light chain kinase: a potential target for treatment of inflammatory diseases. Front Pharmacol. 2017;8:292.
He WQ, Wang J, Sheng JY, Zha JM, Graham WV, Turner JR. Contributions of myosin light chain kinase to regulation of epithelial paracellular permeability and mucosal homeostasis. Int J Mol Sci. 2020;21:pii: E993.
Dörfel MJ, Huber O. Modulation of tight junction structure and function by kinases and phosphatases targeting occludin. J Biomed Biotechnol. 2012;2012:1-14.
Lahey KA, Ronaghan NJ, Shang J, et al. Signaling pathways induced by serine proteases to increase intestinal epithelial barrier function. PLoS ONE. 2017;12:e0180259.
Swystun VA, Renaux B, Moreau F, et al. Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Czeta. Am J Physiol Gastrointest Liver Physiol. 2009;297:60-70.
List K, Kosa P, Szabo R, et al. Epithelial integrity is maintained by a matriptase-dependent proteolytic pathway. Am J Pathol. 2009;175:1453-1463.
Buzza MS, Netzel-Arnett S, Shea-Donohue T, et al. Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine. Proc Natl Acad Sci U S A. 2010;107:4200-4205.
Buzza MS, Martin EW, Driesbaugh KH, Désilets A, Leduc R, Antalis TM. Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. J Biol Chem. 2013;288:10328-10337.
Netzel-Arnett S, Buzza MS, Shea-Donohue T, et al. Matriptase protects against experimental colitis and promotes intestinal barrier recovery. Inflamm Bowel Dis. 2012;18:1303-1314.
Ronaghan NJ, Shang J, Iablokov V, et al. The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction. Am J Physiol Gastrointest Liver Physiol. 2016;311:466-479.
Motta JP, Denadai-Souza A, Sagnat D, et al. Active thrombin produced by the intestinal epithelium controls mucosal biofilms. Nat Commun. 2019;10:1-12.
Macfarlane GT, Cummings JH, Allison C. Protein degradation by human intestinal bacteria. J Gen Microbiol. 1986;132:1647-1656.
Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59-65.
Buhner S, Hahne H, Hartwig K, et al. Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients. PLoS ONE. 2018;13:e0193943.
Edogawa S, Edwinson AL, Peters SA, et al. Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS. Gut. 2020;69:62-73.
Heuberger DM, Schuepbach RA. Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb J. 2019;17:1-55.
Vergnolle N. Clinical relevance of proteinase activated receptors (pars) in the gut. Gut. 2005;54:867-874.
Kawabata A, Matsunami M, Sekiguchi F. Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol. 2008;153:230-240.
Cenac N. Protease-activated receptors as therapeutic targets in visceral pain. Curr Neuropharmacol. 2013;11:598-605.
Raithel M, Winterkamp S, Pacurar A, Ulrich P, Hochberger J, Hahn EG. Release of mast cell tryptase from human colorectal mucosa in inflammatory bowel disease. Scand J Gastroenterol. 2001;36:174-179.
Dabek M, Ferrier L, Roka R, et al. Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. Am J Pathol. 2009;175:207-214.
Yoon H, Schaubeck M, Lagkouvardos I, et al. Increased pancreatic protease activity in response to antibiotics impairs gut barrier and triggers colitis. Cell Mol Gastroenterol Hepatol. 2018;6:370-388.
Midtvedt T, Zabarovsky E, Norin E, et al. Increase of faecal tryptic activity relates to changes in the intestinal microbiome: analysis of Crohn's disease with a multidisciplinary platform. PLoS ONE. 2013;8:e66074.
van de Merwe JP, Mol GJ. Levels of trypsin and alpha-chymotrypsin in feces from patients with Crohn's disease. Digestion. 1982;24:1-4.
Benno P, Leijonmarck CE, Monsén U, Uribe A, Midtvedt T. Functional alterations of the microflora in patients with ulcerative colitis. Scand J Gastroenterol. 1993;28:839-844.
Marchbank T, Chinery R, Hanby AM, Poulsom R, Elia G, Playford RJ. Distribution and expression of pancreatic secretory trypsin inhibitor and its possible role in epithelial restitution. Am J Pathol. 1996;148:715-722.
Ramare F, Hautefort I, Verhe F, Raibaud P, Iovanna J. Inactivation of tryptic activity by a human-derived strain of Bacteroides distasonis in the large intestines of gnotobiotic rats and mice. Appl Environ Microbiol. 1996;62:1434-1436.
Qin X. Inactivation of digestive proteases: another aspect of gut bacteria that should be taken into more consideration. World J Gastroenterol. 2007;13:2390-2391.
Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012;18:1708-1722.
Pontarollo G, Mann A, Brandão I, Malinarich F, Schöpf M, Reinhardt C. Protease-activated receptor signaling in intestinal permeability regulation. FEBS J. 2019;2019:1-14.
Sébert M, Sola-Tapias N, Mas E, Barreau F, Ferrand A. Protease-activated receptors in the intestine: focus on inflammation and cancer. Front Endocrinol. 2019;10:717.
Graziani C, Talocco C, De Sire R, et al. Intestinal permeability in physiological and pathological conditions: major determinants and assessment modalities. Eur Rev Med Pharmacol Sci. 2019;23:795-810.
Koshikawa N, Nagashima Y, Miyagi Y, et al. Expression of trypsin in vascular endothelial cells. FEBS Lett. 1997;409:442-448.
Rolland-Fourcade C, Denadai-Souza A, Cirillo C, et al. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut. 2017;66:1767-1778.
Albert-Bayo M, Paracuellos I, González-Castro AM, et al. Intestinal Mucosal mast cells: key modulators of barrier function and homeostasis. Cells. 2019;8:pii: E135.
Jacob C, Yang PC, Darmoul D, et al. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem. 2005;280:31936-31948.
Cenac N, Coelho AM, Nguyen C, et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol. 2002;161:1903-1915.
Reed DE, Barajas-Lopez C, Cottrell G, et al. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J Physiol. 2003;547:531-542.
Mrozkova P, Palecek J, Spicarova D. The role of protease-activated receptor type 2 in nociceptive signaling and pain. Physiol Res. 2016;65:357-367.
Lieu T, Savage E, Zhao P, et al. Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2. Br J Pharmacol. 2016;73:2752-2765.
Steinhoff M, Vergnolle N, Young SH, et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000;6:151-158.
Stead RH, Tomioka M, Quinonez G, Simon GT, Felten SY, Bienenstock J. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc Natl Acad Sci U S A. 1987;84:2975-2979.
Kodani M, Fukui H, Tomita T, Oshima T, Watari J, Miwa H. Association between gastrointestinal motility and macrophage/mast cell distribution in mice during the healing stage after DSS-induced colitis. Mol Med Rep. 2018;17:8167-8172.
Fiorucci S, Mencarelli A, Palazzetti B, et al. Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis. Proc Natl Acad Sci U S A. 2001;98:13936-13941.
Wershil BK, Furuta GT, Wang ZS, Galli SJ. Mast cell-dependent neutrophil and mononuclear cell recruitment in immunoglobulin E-induced gastric reactions in mice. Gastroenterology. 1996;110:1482-1490.
Mazzucchelli L, Hauser C, Zgraggen K, et al. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol. 1994;144:997-1007.
Geraghty P, Rogan MP, Greene CM, et al. Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression. J Immunol. 2007;178:5871-5878.
Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133:2178-2185.
Mao J, Tang H, Tan X, Wang Y. Effect of Etiasa on the expression of matrix metalloproteinase-2 and tumor necrosis factor-α in a rat model of ulcerative colitis. Mol Med Rep. 2012;6:996-1000.
Ginzberg HH, Cherapanov V, Dong Q, et al. Neutrophil-mediated epithelial injury during transmigration: role of elastase. Am J Physiol Gastrointest Liver Physiol. 2001;281:705-717.
Gordon MH, Chauvin A, Boisvert FM, MacNaughton WK. Proteolytic processing of the epithelial adherens junction molecule E-cadherin by neutrophil elastase generates short peptides with novel wound-healing bioactivity. Cell Mol Gastroenterol Hepatol. 2019;7:483-486.
Barry R, Ruano-Gallego D, Radhakrishnan ST, et al. Faecal neutrophil elastase-antiprotease balance reflects colitis severity. Mucosal Immunol. 2019;2019:1-12.
Black R, Kronheim S, Sleath P, et al. The proteolytic activation of interleukin-1 beta. Agents Actions. 1991;35:85-89.
Lefrançais E, Roga S, Gautier V, et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A. 2012;109:1673-1678.
Xu WF, Andersen H, Whitmore TE, et al. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci U S A. 1998;95:6642-6646.
Denadai-Souza A, Bonnart C, Tapias NS, et al. Functional proteomic profiling of secreted serine proteases in health and inflammatory bowel disease. Sci Rep. 2018;8:7834.
Danese S, Papa A, Saibeni S, Repici A, Malesci A, Vecchi M. Inflammation and coagulation in inflammatory bowel disease: the clot thickens. Am J Gastroenterol. 2007;102:174-186.
Matowicka-Karna J. Markers of inflammation, activation of blood platelets and coagulation disorders in inflammatory bowel diseases. Postepy Hig Med Dosw. 2016;70:305-312.
Ando K, Fujiya M, Nomura Y, et al. The incidence and risk factors of venous thromboembolism in patients with inflammatory bowel disease: a prospective multicenter cohort study. Digestion. 2019;100:229-237.
Lagrange J, Lacolley P, Wahl D, Peyrin-Biroulet L, Regnault V. Shedding light on hemostasis in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2020;20:1-30.
Chen D, Dorling A. Critical roles for thrombin in acute and chronic inflammation. J Thromb Haemost. 2009;7:122-126.
De Candia E. Mechanisms of platelet activation by thrombin: a short history. Thromb Res. 2012;129:250-256.
Cenac N, Cellars L, Steinhoff M, et al. Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response. Inflamm Bowel Dis. 2005;11:792-798.
Rajakovich LJ, Balskus EP. Metabolic functions of the human gut microbiota: the role of metalloenzymes. Nat Prod Rep. 2019;36:593-625.
Tripathi LP, Sowdhamini R. Genome-wide survey of prokaryotic serine proteases: analysis of distribution and domain architectures of five serine protease families in prokaryotes. BMC Genom. 2008;9:549.
Lantz MS. Are bacterial proteases important virulence factors? J Periodontal Res. 1997;32:126-132.
Lantz MS, Allen RD, Vail TA, Switalski LM, Hook M. Specific cell components of Bacteroides gingivalis mediate binding and degradation of human fibrinogen. J Bacteriol. 1991;173:495-504.
Kilian M, Mestecky J, Russell MW. Defense mechanisms involving Fc-dependent functions of immunoglobulin A and their subversion by bacterial immunoglobulin A proteases. Microbiol Rev. 1988;52:296-303.
Macfarlane GT, Allison C, Gibson SA, Cummings JH. Contribution of the microflora to proteolysis in the human large intestine. J Appl Bacteriol. 1988;64:37-46.
Ruiz-Perez F, Nataro JP. Bacterial serine proteases secreted by the autotransporter pathway: classification, specificity, and role in virulence. Cell Mol Life Sci. 2014;71:745-770.
Perna A, Hay E, Contieri M, De Luca A, Guerra G, Lucariello A. Adherent-invasive Escherichia coli (AIEC): cause or consequence of inflammation, dysbiosis, and rupture of cellular joints in patients with IBD? J Cell Physiol. 2020;2020:1-9.
da Silva Santos AC, Gomes Romeiro F, Yukie Sassaki L, Rodrigues J. Escherichia coli from Crohn's disease patient displays virulence features of enteroinvasive (EIEC), enterohemorragic (EHEC), and enteroaggregative (EAEC) pathotypes. Gut Pathog. 2015;7:1-10.
Darfeuille-Michaud A, Boudeau J, Bulois P, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127:412-421.
Glasser AL, Boudeau J, Barnich N, Perruchot MH, Colombel JF, Darfeuille-Michaud A. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infect Immun. 2001;69:5529-5537.
De la Fuente M, Franchi L, Araya D, et al. Escherichia coli isolates from inflammatory bowel diseases patients survive in macrophages and activate NLRP3 inflammasome. Int J Med Microbiol. 2014;304:384-392.
Shawki A, McCole DF. Mechanisms of intestinal epithelial barrier dysfunction by adherent-invasive Escherichia coli. Cell Mol Gastroenterol Hepatol. 2017;3:41-50.
Boisen N, Ruiz-Perez F, Scheutz F, Krogfelt KA, Nataro JP. Short report: high prevalence of serine protease autotransporter cytotoxins among strains of enteroaggregative Escherichia coli. Am J Trop Med Hyg. 2009;80:294-301.
Michielan A, D’Incà R. Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediat Inflamm. 2015;2015:628157.
Henderson IR, Czeczulin J, Eslava C, Noriega F, Nataro JP. Characterization of pic, a secreted protease of Shigellaflexneri and enteroaggregative Escherichia coli. Infect Immun. 1999;67:5587-5596.
Harrington SM, Sheikh J, Henderson IR, Ruiz-Perez F, Cohen PS, Nataro JP. The Pic protease of enteroaggregative Escherichia coli promotes intestinal colonization and growth in the presence of mucin. Infect Immun. 2009;77:2465-2473.
Cornick S, Tawiah A, Chadee K. Roles and regulation of the mucus barrier in the gut. Tissue Barriers. 2015;3:e982426.
Azghani AO, Gray LD, Johnson AR. A bacterial protease perturbs the paracellular barrier function of transporting epithelial monolayers in culture. Infect Immun. 1993;61:2681-2686.
Guignot J, Chaplais C, Coconnier-Polter MH, Servin AL. The secreted autotransporter toxin, Sat, functions as a virulence factor in Afa/Dr diffusely adhering Escherichia coli by promoting lesions in tight junction of polarized epithelial cells. Cell Microbiol. 2007;9:204-221.
Dutta PR, Cappello R, Navarro-García F, Nataro JP. Functional comparison of serine protease autotransporters of enterobacteriaceae. Infect Immun. 2002;70:7105-7113.
Van Spaendonk H, Ceuleers H, Witters L, et al. Regulation of intestinal permeability: the role of proteases. World J Gastroenterol. 2017;23:2106-2123.
Moustafa A, Li W, Anderson EL, et al. Genetic risk, dysbiosis, and treatment stratification using host genome and gut microbiome in inflammatory bowel disease. Clin Transl Gastroenterol. 2018;9:e132.
Kotlowski R, Bernstein CN, Sepehri S, Krause DO. High prevalence of Escherichia coli belonging to the B2�D phylogenetic group in inflammatory bowel disease. Gut. 2007;56:669-675.
Sepehri S, Khafipour E, Bernstein CN, et al. Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1451-1463.
Backert S, Bernegger S, Skórko-Glonek J, Wessler S. Extracellular HtrA serine proteases: an emerging new strategy in bacterial pathogenesis. Cell Microbiol. 2018;20:e12845.
Zarzecka U, Modrak-Wójcik A, Figaj D, et al. Properties of the htra protease from bacterium Helicobacter pylori whose activity is indispensable for growth under stress conditions. Front Microbiol. 2019;10:961.
Harrer A, Boehm M, Backert S, Tegtmeyer N. Overexpression of serine protease HtrA enhances disruption of adherens junctions, paracellular transmigration and type IV secretion of CagA by Helicobacter pylori. Gut Pathog. 2017;9:1-12.
Elmi A, Nasher F, Jagatia H, et al. Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin. Cell Microbiol. 2016;18:561-572.
Abfalter CM, Schubert M, Götz C, Schmidt TP, Posselt G, Wessler S. HtrA-mediated E-cadherin cleavage is limited to DegP and DegQ homologs expressed by gram-negative pathogens. Cell Commun Signal. 2016;14:1-18.
Boehm M, Simson D, Escher U, et al. Function of serine protease HtrA in the lifecycle of the foodborne pathogen Campylobacter jejuni. Eur J Microbiol Immunol. 2018;8:70-77.
Kajikawa H, Yoshida N, Katada K, et al. Helicobacter pylori activates gastric epithelial cells to produce interleukin-8 via protease-activated receptor 2. Digestion. 2007;76:248-255.
Caminero A, McCarville JL, Galipeau HJ, et al. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat Commun. 2019;10:1-14.
Dulon S, Leduc D, Cottrell GS, et al. Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells. Am J Respir Cell Mol Biol. 2005;32:411-419.
Maharshak N, Huh EY, Paiboonrungruang C, et al. Enterococcus faecalis gelatinase mediates intestinal permeability via protease-activated receptor 2. Infect Immun. 2015;83:2762-2770.
Holzhausen M, Spolidorio LC, Ellen RP, et al. Protease-activated receptor-2 activation: a major role in the pathogenesis of Porphyromonas gingivalis infection. Am J Pathol. 2006;168:1189-1199.
Cottrell GS, Amadesi S, Pikios S, et al. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis. Gastroenterology. 2007;132:2422-2437.
Pontarollo G, Acquasaliente L, Peterle D, Frasson R, Artusi I, De Filippis V. Non-canonical proteolytic activation of human prothrombin by subtilisin from Bacillus subtilis may shift the procoagulant-anticoagulant equilibrium toward thrombosis. J Biol Chem. 2017;292:15161-15179.
Giannotta M, Tapete G, Emmi G, Silvestri E, Milla M. Thrombosis in inflammatory bowel diseases: what's the link? Thromb J. 2015;13:1-9.
Zou Y, Xue W, Luo G, et al. 1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses. Nat Biotechnol. 2019;37:179-185.
Nayfach S, Shi ZJ, Seshadri R, Pollard KS, Kyrpides NC. New insights from uncultivated genomes of the global human gut microbiome. Nature. 2019;568:505-510.
Forster SC, Kumar N, Anonye BO, et al. A human gut bacterial genome and culture collection for improved metagenomic analyses. Nat Biotechnol. 2019;37:186-192.
Carroll IM, Ringel-Kulka T, Ferrier L, et al. Fecal protease activity is associated with compositional alterations in the intestinal microbiota. PLoS ONE. 2013;8:e78017.
Fava F, Danese S. Intestinal microbiota in inflammatory bowel disease: friend of foe? World J Gastroenterol. 2011;17:557-566.
Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. Gut. 2003;52:237-242.
Chen L, Wang W, Zhou R, et al. Characteristics of fecal and mucosa-associated microbiota in Chinese patients with inflammatory bowel disease. Medicine. 2014;93:e51.
Zhou Y, Chen H, He H, et al. Increased Enterococcus faecalis infection is associated with clinically active Crohn disease. Medicine. 2016;95:e5019.
Maukonen J, Kolho KL, Paasela M, et al. Altered fecal microbiota in paediatric inflammatory bowel disease. J Crohns Colitis. 2015;9:1088-1095.
Prosberg M, Bendtsen F, Vind I, Petersen AM, Gluud LL. The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis. Scand J Gastroenterol. 2016;2016:1-9.
Ehrhardt K, Steck N, Kappelhoff R, et al. Persistent Salmonella enterica Serovar Typhimurium infection induces protease expression during intestinal fibrosis. Inflamm Bowel Dis. 2019;25:1629-1643.
Kasperkiewicz P, Poreba M, Snipas SJ, et al. Design of ultrasensitive probes for human neutrophil elastase through hybrid combinatorial substrate library profiling. Proc Natl Acad Sci USA. 2014;111:2518-2523.
Gecse K, Róka R, Ferrier L, et al. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut. 2008;57:591-599.
Poulsen NA, Andersen V, Møller JC, et al. Comparative analysis of inflamed and non-inflamed colon biopsies reveals strong proteomic inflammation profile in patients with ulcerative colitis. BMC Gastroenterol. 2012;12:1-11.
Starr AE, Deeke SA, Ning Z, et al. Proteomic analysis of ascending colon biopsies from a paediatric inflammatory bowel disease inception cohort identifies protein biomarkers that differentiate Crohn's disease from UC. Gut. 2017;66:1573-1583.
Poreba M, Drag M. Current strategies for probing substrate specificity of proteases. Curr Med Chem. 2010;17:3968-3995.
Rut W, Kasperkiewicz P, Byzia A, Poreba M, Groborz K, Drag M. Recent advances and concepts in substrate specificity determination of proteases using tailored libraries of fluorogenic substrates with unnatural amino acids. BiolChem. 2015;396:329-337.
Ostresh JM, Winkle JH, Hamashin VT, Houghten RA. Peptide libraries: determination of relative reaction rates of protected amino acids in competitive couplings. Biopolymers. 1994;34:1681-1689.
Wysocka M, Lesner A, Guzow K, et al. Design of selective substrates of proteinase 3 using combinatorial chemistry methods. Anal Biochem. 2008;378:208-215.
Popow-Stellmaszyk J, Wysocka M, Lesner A, Korkmaz B, Rolka K. A new proteinase 3substrate with improved selectivity over human neutrophil elastase. Anal Biochem. 2013;442:75-82.
Mayers MD, Moon C, Stupp GS, Su AI, Wolan DW. Quantitative metaproteomics and activity-based probe enrichment reveals significant alterations in protein expression from a mouse model of inflammatory bowel disease. J Proteome Res. 2017;16:1014-1026.
Jablaoui A, Kriaa A, Mkaouar H, et al. Fecal serine protease profiling in inflammatory bowel diseases. Front Cell Infect Microbiol. 2020;10:1-7.
Pan Z, Jeffery DA, Chehade K, et al. Development of activity-based probes for trypsin-family serine proteases. Bioorg Med Chem Lett. 2006;16:2882-2885.
Irving JA, Steenbakkers PJM, Lesk AM, Op den Camp HJM, Pike RN, Whisstock JC. Serpins in prokaryotes. Mol Biol Evol. 2002;19:1881-1890.
Isozaki Y, Yoshida N, Kuroda M, et al. Anti-tryptase treatment using nafamostatmesilate has a therapeutic effect on experimental colitis. Scand J Gastroenterol. 2006;41:944-953.
Laskowski M, Quasim MA Jr. What can the structures of enzyme inhibitor complexes tell us about the structures of enzyme substrate complexes? Biochem Biophys. Acta. 2000;1477:324-337.
Tremaine WJ, Brzezinski A, Katz JA, et al. Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study. Aliment PharmacolTher. 2002;16:407-413.
Uchiyama K, Naito Y, Takagi T, et al. Serpin B1 protects colonic epithelial cell via blockage of neutrophil elastase activity and its expression is enhanced in patients with ulcerative colitis. Am J Physiol Gastrointest Liver Physiol. 2012;302:1163-1170.
Mkaouar H, Akermi N, Kriaa A, et al. Serine protease inhibitors and human wellbeing interplay: new insights for old friends. PeerJ. 2019;7:e7224.
Mkaouar H, Akermi N, Mariaule V, et al. Siropins, novel serine protease inhibitors from gut microbiota acting on human proteases involved in inflammatory bowel diseases. Microb Cell Fact. 2016;15:1-13.
Guarino C, Gruba N, Grzywa R, et al. Exploiting the S4-S5 specificity of human neutrophil proteinase 3 to improve the potency of peptidyl Di(chlorophenyl)-phosphonate ester inhibitors: a kinetic and molecular modeling analysis. J Med Chem. 2018;61:1858-1870.
Grzywa R, Lesner A, Korkmaz B, Sieńczyk M. Proteinase 3 phosphonic inhibitors. Biochimie. 2019;166:142-149.