The aim of this study was to investigate the use of a standardized animal model subjected to antibiotic treatment, and the effects of this treatment on the course of dextran sodium sulphate (DSS)-induced colitis in mice. By decontamination with selective antibiotics and observation of pathogenesis of ulcerative colitis (UC) induced chemically by exposure of mice to various concentrations of DSS, we obtained an optimum animal PGF model of acute UC manifested by mucin depletion, epithelial degeneration and necrosis, leading to the disappearance of epithelial cells, infiltration of lamina propria and submucosa with neutrophils, cryptitis, and accompanied by decreased viability of intestinal microbiota, loss of body weight, dehydration, moderate rectal bleeding, and a decrease in the selected markers of cellular proliferation and apoptosis. The obtained PGF model did not exhibit changes that could contribute to inflammation by means of alteration of the metabolic status and the induced dysbiosis did not serve as a bearer of pathogenic microorganisms participating in development of ulcerative colitis. The inflammatory process was induced particularly by exposure to DSS and its toxic action on compactness and integrity of mucosal barrier in the large intestine. This offers new possibilities of the use of this animal model in studies with or without participation of pathogenic microbiota in IBD pathogenesis.

Department of Biology and Physiology University of Veterinary Medicine and Pharmacy in Kosice 041 81 Kosice Slovakia

Department of Epizootology Parasitology and Protection of One Health University of Veterinary Medicine and Pharmacy in Kosice 041 81 Kosice Slovakia

Department of Microbiology and Immunology University of Veterinary Medicine and Pharmacy in Kosice 041 81 Kosice Slovakia

Department of Stomatology and Maxilofacial Surgery Pavol Jozef Safarik University in Kosice 041 81 Kosice Slovakia

Institute of Experimental Medicine Faculty of Medicine Pavol Jozef Safarik University in Kosice 041 81 Kosice Slovakia

Institute of Microbiology Czech Academy of Sciences Centre Algatech 379 01 Trebon Czech Republic

Institute of Parasitology Slovak Academy of Sciences 041 81 Kosice Slovakia

Zobrazit více v PubMed

Ramos G.P., Papadakis K.A. Mechanisms of disease: Inflammatory bowel diseases. Mayo Clin. Proc. 2019;94:155–165. doi: 10.1016/j.mayocp.2018.09.013. PubMed DOI PMC

Yu L.C. Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: Exploring a common ground hypothesis. J. Biomed. Sci. 2018 doi: 10.1186/s12929-018-0483-8. PubMed DOI PMC

Nishida A., Inoue R., Inatomi O., Bamba S., Naito Y., Andoh A. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin. J. Gastroenterol. 2018;11:1–10. doi: 10.1007/s12328-017-0813-5. PubMed DOI

Enck P., Mazurak N. Dysbiosis in functional bowel disorders. Ann. Nutr. Metab. 2018;72:296–306. doi: 10.1159/000488773. PubMed DOI

Rinninella E., Raoul P., Cintoni M., Franceschi F., Miggiano G.A.D., Gasbarrini A., Mele M.C. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. 2019;7:14. doi: 10.3390/microorganisms7010014. PubMed DOI PMC

De Jong R.J., Ohnmacht C. Defining dysbiosis in inflammatory bowel disease. Immunity. 2019;50:8–10. doi: 10.1016/j.immuni.2018.12.028. PubMed DOI

Khan I., Ullah N., Zha L., Bai Y., Khan A., Zhao T., Che T., Zhang C. Alteration of gut microbiota in inflammatory bowel disease (IBD): Cause or consequence? IBD treatment targeting the gut microbiome. Pathogens. 2019;8:126. doi: 10.3390/pathogens8030126. PubMed DOI PMC

Fang X., Monk J.M., Mih N., Du B., Sastry A.V., Kavvas E., Seif Y., Smarr L., Palsson B.O. Escherichia coli B2 strains prevalent in inflammatory bowel disease patients have distinct metabolic capabilities that enable colonization of intestinal mucosa. BMC Syst. Biol. 2018;12:66. doi: 10.1186/s12918-018-0587-5. PubMed DOI PMC

Ribaldone D.G., Caviglia G.P., Abdulle A., Pellicano R., Ditto M.C., Morino M., Fusaro E., Saracco G.M., Bugianesi E., Astegiano M. Adalimumab Therapy Improves Intestinal Dysbiosis in Crohn’s Disease. J. Clin. Med. 2019;8:1646. doi: 10.3390/jcm8101646. PubMed DOI PMC

Wei S.C., Chang T.A., Chao T.H., Chen J.S., Chou Y.H., Chuang C.H., Hsu W.H., Huang T.Y., Hsu T.C., Lin C.C., et al. Management of Crohn’s disease in Taiwan: Consensus guideline of the Taiwan society of inflammatory bowel disease. Intest. Res. 2017;15:285–310. doi: 10.5217/ir.2017.15.3.285. PubMed DOI PMC

Celik S.U., Nazarzade N., Turhan M.A., Cetinkaya H., Cakmak A., Tuzuner A. Gastroduodenal Crohn’s disease: A clinical case report. HPB. 2018;20:768. doi: 10.1016/j.hpb.2018.06.2491. PubMed DOI

Jiminez J.A., Uwiera T.C., Douglas Inglis G., Uwiera R.R. Animal models to study acute and chronic intestinal inflammation in mammals. Gut Pathog. 2015;7:29. doi: 10.1186/s13099-015-0076-y. PubMed DOI PMC

Nicklas W., Keubler L., Bleich A. Maintaining and monitoring the defined microbiota status of gnotobiotic rodents. ILAR J. 2015;56:241–249. doi: 10.1093/ilar/ilv029. PubMed DOI

Bylund-Fellenius A.C., Landström E., Axelsson L.G., Midtvedt T. Experimental colitis induced by dextran sulphate in normal and germfree mice. Microb. Ecol. Health Dis. 1994;7:207–215.

Kitajima S., Morimoto M., Sagara E., Shimizu C., Ikeda Y. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp. Anim. 2001;50:387–395. doi: 10.1538/expanim.50.387. PubMed DOI

Hudcovic T., Stěpánková R., Cebra J., Tlaskalová-Hoggenová H. The role of microflora in the development of intestinal inflammation: Acute and chronic colitis induced by dextran sulfate in germ-free and conventionally reared immunocompetent and immunodeficient mice. Folia Microbiol. 2001;46:565–572. doi: 10.1007/BF02818004. PubMed DOI

Maslowski K.M., Vieira A.T., Ng A., Kranich J., Sierro F., Yu D., Schilter H.C., Rolph M.S., Mackay F., Artis D., et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–1286. doi: 10.1038/nature08530. PubMed DOI PMC

Hernández-Chirlaque C., Aranda C.J., Ocón B., Capitán-Cañadas F., Ortega-González M., Carrero J.J., Suárez M.D., Zarzuelo A., Sánchez de Medina F., Martínez-Augustin O. Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J. Crohns Colitis. 2016;10:1324–1335. doi: 10.1093/ecco-jcc/jjw096. PubMed DOI

Popper M., Gancarčíková S., Maďar M., Mudroňová D., Hrčková G., Nemcová R. Amoxicillin-clavulanic acid and ciprofloxacin-treated SPF mice as gnotobiotic model. Appl. Microbiol. Biotechnol. 2016;100:9671–9682. doi: 10.1007/s00253-016-7855-3. PubMed DOI

Gancarčíková S., Popper M., Hrčková G., Ma’ar M., Mudroňová D., Sopková D., Nemcová R. In: Antibiotic-treated SPF Mice as a Gnotobiotic Model. Savic S., editor. InTech; Rijeka, Croatia: 2018. pp. 45–83. Use in Animals.

Klindworth A., Pruesse E., Schweer T., Peplies J., Quast C., Horn M., Glöckner F.O. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res. 2013;41:e1. doi: 10.1093/nar/gks808. PubMed DOI PMC

Vetrovský T., Baldrian P., Morais D. SEED 2: A user-friendly platform for amplicon high-throughput sequencing data analyses. Bioinformatics. 2018;34:2292–2294. doi: 10.1093/bioinformatics/bty071. PubMed DOI PMC

Edgar R.C. UPARSE: Highly accurate OTU sequences from microbial amplicon reads. Nat. Methods. 2013;10:996–998. doi: 10.1038/nmeth.2604. PubMed DOI

Smolen A.J. In: Image Analytic Techniques for Quantification of Immunocytochemical Staining in the Nervous System. Conn P.M., editor. Academic Press; New York, NY, USA: 1990. pp. 208–229. Methods in Neurosciences.

Erben U., Loddenkemper C., Doerfel K., Spieckermann S., Haller D., Heimesaat M.M., Zeitz M., Siegmund B., Kühl A.A. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int. J. Clin. Exp. Pathol. 2014;7:4557–4576. PubMed PMC

Gaudio E., Taddei G., Vetuschi A., Sferra R., Frieri G., Ricciardi G., Caprilli R. Dextran sulfate sodium (DSS) colitis in rats (clinical, structural, and ultrastructural aspects) Dig. Dis. Sci. 1999;44:1458–1475. doi: 10.1023/A:1026620322859. PubMed DOI

Abdelmegid A.M., Abdo F.K., Ahmed F.E., Kattaia A.A.A. Therapeutic effect of gold nanoparticles on DSS-induced ulcerative colitis in mice with reference to interleukin-17 expression. Sci. Rep. 2019;9:10176. doi: 10.1038/s41598-019-46671-1. PubMed DOI PMC

Kiesler P., Fuss I.J., Strober W. Experimental models of inflammatory bowel diseases. Cell. Mol. Gastroenterol. Hepatol. 2015;1:154–170. doi: 10.1016/j.jcmgh.2015.01.006. PubMed DOI PMC

Gardlik R., Wagnerova A., Celec P. Effects of bacteria-mediated reprogramming and antibiotic pretreatment on the course of colitis in mice. Mol. Med. Rep. 2014;10:983–988. doi: 10.3892/mmr.2014.2244. PubMed DOI

Caputi V., Marsilio I., Filpa V., Cerantola S., Orso G., Bistoletti M., Paccagnella N., De Martin S., Montopoli M., Dall’Acqua S., et al. Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice. Br. J. Pharmacol. 2017;174:3623–3639. doi: 10.1111/bph.13965. PubMed DOI PMC

Kennedy E.A., King K.Y., Baldridge M.T. Mouse microbiota models: Comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front. Physiol. 2018;9:1534. doi: 10.3389/fphys.2018.01534. PubMed DOI PMC

Johnson S.A., Nicolson S.W., Jackson S. The effect of different oral antibiotics on the gastrointestinal microflora of a wild rodent (Aethomys namaquensis) Comp. Biochem. Physiol. A Mol. Integr. Physiol. 2004;138:475–483. doi: 10.1016/j.cbpb.2004.06.010. PubMed DOI

Gonzalez-Perez G., Hicks A.L., Tekieli T.M., Radens C.M., Williams B.L., Lamousé-Smith E.S. Maternal antibiotic treatment impacts development of the neonatal intestinal microbiome and antiviral immunity. J. Immunol. 2016;196:3768–3779. doi: 10.4049/jimmunol.1502322. PubMed DOI

Brown R.L., Sequeira R.P., Clarke T.B. The microbiota protects against respiratory infection via GM-CSF signaling. Nat. Commun. 2017;8:1512. doi: 10.1038/s41467-017-01803-x. PubMed DOI PMC

Hansen A.K. Antibiotic treatment of nude rats and its impact on the aerobic bacterial flora. Lab. Anim. 1995;29:37–44. doi: 10.1258/002367795780740410. PubMed DOI

Hoentjen F., Harmsen H.J., Braat H., Torrice C.D., Mann B.A., Sartor R.B., Dieleman L.A. Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice. Gut. 2003;52:1721–1727. doi: 10.1136/gut.52.12.1721. PubMed DOI PMC

Atarashi K., Tanoue T., Shima T., Imaoka A., Kuwahara T., Momose Y., Cheng G., Yamasaki S., Saito T., Ohba Y., et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–341. doi: 10.1126/science.1198469. PubMed DOI PMC

Schubert A.M., Sinani H., Schloss P.D. Antibiotic-induced alterations of the murine gut microbiota and subsequent effects on colonization resistance against Clostridium difficile. mBio. 2015;6:e00974. doi: 10.1128/mBio.00974-15. PubMed DOI PMC

Sun L., Zhang X., Zhang Y., Zheng K., Xiang Q., Chen N., Chen Z., Zhang N., Zhu J., He Q. Antibiotic-induced disruption of gut microbiota alters local metabolomes and immune responses. Front. Cell. Infect. Microbiol. 2019;9:99. doi: 10.3389/fcimb.2019.00099. PubMed DOI PMC

Hashiguchi M., Kashiwakura Y., Kojima H., Kobayashi A., Kanno Y., Kobata T. Peyer’s patch innate lymphoid cells regulate commensal bacteria expansion. Immunol. Lett. 2015;165:1–9. doi: 10.1016/j.imlet.2015.03.002. PubMed DOI

Johansson M.E., Jakobsson H.E., Holmén-Larsson J., Schütte A., Ermund A., Rodríguez-Piñeiro A.M., Arike L., Wising C., Svensson F., Bäckhed F., et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. 2015;18:582–592. doi: 10.1016/j.chom.2015.10.007. PubMed DOI PMC

Thackray L.B., Handley S.A., Gorman M.J., Poddar S., Bagadia P., Briseño C.G., Theisen D.J., Tan Q., Hykes B.L., Jr., Lin H., et al. Oral antibiotic treatment of mice exacerbates the disease severity of multiple flavivirus infections. Cell Rep. 2018;22:3440–3453.e6. doi: 10.1016/j.celrep.2018.03.001. PubMed DOI PMC

Zarrinpar A., Chaix A., Xu Z.Z., Chang M.W., Marotz C.A., Saghatelian A., Knight R., Panda S. Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat. Commun. 2018;9:2872. doi: 10.1038/s41467-018-05336-9. PubMed DOI PMC

Tamanai-Shacoori Z., Smida I., Bousarghin L., Loreal O., Meuric V., Fong S.B., Bonnaure-Mallet M., Jolivet-Gougeon A. Roseburia spp.: A marker of health? Future Microbiol. 2017;12:157–170. doi: 10.2217/fmb-2016-0130. PubMed DOI

Vermeiren J., Van den Abbeele P., Laukens D., Vigsnaes L.K., De Vos M., Boon N., Van de Wiele T. Decreased colonization of fecal Clostridium coccoides/Eubacterium rectale species from ulcerative colitis patients in an in vitro dynamic gut model with mucin environment. FEMS Microbiol. Ecol. 2012;79:685–696. doi: 10.1111/j.1574-6941.2011.01252.x. PubMed DOI

Chen L., Wang W., Zhou R., Ng S.C., Li J., Huang M., Zhou F., Wang X., Shen B., AKamm M., et al. Characteristics of fecal and mucosa-associated microbiota in Chinese patients with inflammatory bowel disease. Medicine. 2014;93:e51. doi: 10.1097/MD.0000000000000051. PubMed DOI PMC

Markowiak-Kopeć P., Śliżewska K. The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intestinal Microbiome. Nutrients. 2020;12:1107. doi: 10.3390/nu12041107. PubMed DOI PMC

Chaia A., Olivier G. Gut Flora, Nutrition, Immunity and Health. Wiley-Blackwell; Hoboken, NJ, USA: 2003. Intestinal Microflora and Metabolic Activity; pp. 77–98.

Wong J.M., Jenkins D.J. Carbohydrate digestibility and metabolic effects. J. Nutr. 2007;137(Suppl. S11):2539S–2546S. doi: 10.1093/jn/137.11.2539S. PubMed DOI

Dobišová M. Využitie Germ-Free Animálnych Modelov v Biomedicínskom Výskume. [(accessed on 23 May 2019)];2019 Available online: http://opac.crzp.sk/?fn=detailBiblioForm&sid=AE9ECE62FB99CFC2CFD4E49C925D&seo=CRZP-detail-kniha.

Smith P.M., Howitt M.R., Panikov N., Michaud M., Gallini C.A., Bohlooly Y.M., Glickman J.N., Garrett W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–573. doi: 10.1126/science.1241165. PubMed DOI PMC

Arpaia N., Campbell C., Fan X., Dikiy S., Van der Veeken J., DeRoos P., Liu H., Cross J.R., Pfeffer K., Coffer P.J., et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–455. doi: 10.1038/nature12726. PubMed DOI PMC

Yan J., Herzog J.W., Tsang K., Brennan C.A., Bower M.A., Garrett W.S., Sartor B.R., Aliprantis A.O., Charles J.F. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc. Natl. Acad. Sci. USA. 2016;113:E7554–E7563. doi: 10.1073/pnas.1607235113. PubMed DOI PMC

Koh A., De Vadder F., Kovatcheva-Datchary P., Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016;165:1332–1345. doi: 10.1016/j.cell.2016.05.041. PubMed DOI

Reichardt N., Duncan S.H., Young P., Belenguer A., McWilliam Leitch C., Scott KPLouis P. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 2014;8:1323–1335. doi: 10.1038/ismej.2014.14. PubMed DOI PMC

Louis P., Hold G.L., Flint H.J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 2014;12:661–672. doi: 10.1038/nrmicro3344. PubMed DOI

Vital M., Howe A.C., Tiedje J.M. Revealing the bacterial butyrate synthesis pathways by analyzing (meta) genomic data. mBio. 2014;5:e00889. doi: 10.1128/mBio.00889-14. PubMed DOI PMC

Serpa J., Caiado F., Carvalho T., Torre C., Gonçalves L.G., Casalou C., Lamosa P., Rodrigues M., Zhu Z., Lam E.W., et al. Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells. J. Biol. Chem. 2010;285:39211–39223. doi: 10.1074/jbc.M110.156026. PubMed DOI PMC

Macfarlane S., Bahrami B., Macfarlane G.T. Mucosal biofilm communities in the human intestinal tract. Adv. Appl. Microbiol. 2011;75:111–143. PubMed

Kitajima S., Takuma S., Morimoto M. Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights. Exp. Anim. 2000;49:9–15. doi: 10.1538/expanim.49.9. PubMed DOI

Hirono I., Kuhara K., Yamaji T., Hosaka S., Golberg L. Carcinogenicity of dextran sulfate sodium in relation to its molecular weight. Cancer Lett. 1983;18:29–34. doi: 10.1016/0304-3835(83)90114-3. PubMed DOI

Melgar S., Karlsson A., Michaëlsson E. Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: Correlation between symptoms and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 2005;288:1328–1338. doi: 10.1152/ajpgi.00467.2004. PubMed DOI

Nunes N.S., Chandran P., Sundby M., Visioli F., Da Costa Gonçalves F., Burks S.R., Paz A.H., Frank J.A. Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway. EBioMedicine. 2019;45:495–510. doi: 10.1016/j.ebiom.2019.06.033. PubMed DOI PMC

Zhou H., Zhang H., Guan L., Zhang Y., Li Y., Sun M. Mechanism and therapeutic effects of Saccharomyces boulardii on experimental colitis in mice. Mol. Med. Rep. 2018;6:5652–5662. doi: 10.3892/mmr.2018.9612. PubMed DOI PMC

Jenkins D., Goodall A., Scott B.B. Simple objective criteria for diagnosis of causes of acute diarrhoea on rectal biopsy. J. Clin. Pathol. 1997;50:580–585. doi: 10.1136/jcp.50.7.580. PubMed DOI PMC

Matos I., Bento A.F., Marcon R., Claudino R.F., Calixto J.B. Preventive and therapeutic oral administration of the pentacyclic triterpene α,β-amyrin ameliorates dextran sulfate sodium-induced colitis in mice: The relevance of cannabinoid system. Mol. Immunol. 2013;54:482–492. doi: 10.1016/j.molimm.2013.01.018. PubMed DOI

Song J.L., Qian Y., Li G.J., Zhao X. Anti-inflammatory effects of kudingcha methanol extract (Ilex kudingcha C.J. Tseng) in dextran sulfate sodium-induced ulcerative colitis. Mol. Med. Rep. 2013;8:1256–1262. doi: 10.3892/mmr.2013.1635. PubMed DOI

Zhao J., Hong T., Dong M., Meng Y., Mu J. Protective effect of myricetin in dextran sulphate sodium-induced murine ulcerative colitis. Mol. Med. Rep. 2013;7:565–570. doi: 10.3892/mmr.2012.1225. PubMed DOI

Perše M., Cerar A. Dextran sodium sulphate colitis mouse model: Traps and tricks. J. Biomed. Biotechnol. 2012;2012:718617. doi: 10.1155/2012/718617. PubMed DOI PMC

Rausch S., Huehn J., Loddenkemper C., Hepworth M.R., Klotz C., Sparwasser T., Hamann A., Lucius R., Hartmann S. Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells. Eur. J. Immunol. 2009;39:3066–3077. doi: 10.1002/eji.200939644. PubMed DOI

Asseman C., Mauze S., Leach M.W., Coffman R.L., Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 1999;190:995–1004. doi: 10.1084/jem.190.7.995. PubMed DOI PMC

Arda-Pirincci P., Aykol-Celik G. Galectin-1 reduces the severity of dextran sulfate sodium (DSS)-induced ulcerative colitis by suppressing inflammatory and oxidative stress response. Bosn. J. Basic Med. Sci. 2020 doi: 10.17305/bjbms.2019.4539. PubMed DOI PMC

Brown D.C., Gatter K.C. Monoclonal antibody Ki-67: Its use in histopathology. Histopathology. 1990;17:489–503. doi: 10.1111/j.1365-2559.1990.tb00788.x. PubMed DOI

Yamada K., Yoshitake K., Sato M., Ahnen D.J. Proliferating cell nuclear antigen expression in normal, preneoplastic, and neoplastic colonic epithelium of the rat. Gastroenterology. 1992;103:160–167. doi: 10.1016/0016-5085(92)91109-H. PubMed DOI

Kang J., Zhang Z., Wang J., Wang G., Yan Y., Qian H., Zhang X., Xu W., Mao F. hucMSCs attenuate IBD through releasing miR148b-5p to inhibit the expression of 15-lox-1 in macrophages. Mediat. Inflamm. 2019 doi: 10.1155/2019/6953963. PubMed DOI PMC

Adachi T., Sakurai T., Kashida H., Mine H., Hagiwara S., Matsui S., Yoshida K., Nishida N., Watanabe T., Itoh K., et al. Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease. Inflamm. Bowel. Dis. 2015;21:31–39. doi: 10.1097/MIB.0000000000000244. PubMed DOI PMC

Weder B., Mozaffari M., Biedermann L., Mamie C., Moncsek A., Wang L., Clarke S.H., Rogler G., McRae B.L., Graff C.L., et al. BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice. Clin. Exp. Immunol. 2018;193:346–360. doi: 10.1111/cei.13151. PubMed DOI PMC

Bäumler A., Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. 2016;535:85–93. doi: 10.1038/nature18849. PubMed DOI PMC