An IBD-associated pathobiont synergises with NSAID to promote colitis which is blocked by NLRP3 inflammasome and Caspase-8 inhibitors

References

• Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–20. doi:10.1038/nri2515.
   PubMed Web of Science ®Google Scholar
• Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7(2):99–109. doi:10.1038/nrmicro2070.
   PubMed Web of Science ®Google Scholar
• Ananthakrishnan AN, Higuchi LM, Huang ES, Khalili H, Richter JM, Fuchs CS, Chan AT, Higuchi LM, Huang ES, Khalili H, et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann Intern Med. 2012;156(5):350–359. doi:10.7326/0003-4819-156-5-201203060-00007.
   PubMed Web of Science ®Google Scholar
• Klein A, Eliakim R. Non steroidal anti-inflammatory drugs and inflammatory bowel disease. Pharmaceuticals. 2010;3(4):1084–1092. doi:10.3390/ph3041084.
   Google Scholar
• Moninuola OO, Milligan W, Lochhead P, Khalili H. Systematic review with meta-analysis: association between Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of Crohn’s disease and ulcerative colitis exacerbation. Aliment Pharmacol Ther. 2018;47(11):1428–1439. doi:10.1111/apt.14606.
   PubMed Web of Science ®Google Scholar
• Wang X, Tang Q, Hou H, Zhang W, Li M, Chen D, Gu Y, Wang B, Hou J, Liu Y, et al. Gut microbiota in NSAID enteropathy: new insights from inside. Front Cell Infect Microbiol. 2021;11:679396. doi:10.3389/fcimb.2021.679396.
   PubMed Web of Science ®Google Scholar
• Robert A, Asano T. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins. 1977;14(2):333–341. doi:10.1016/0090-6980(77)90178-2.
   PubMedGoogle Scholar
• Rogers MAM, Aronoff DM. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect. 2016;22(2):178 e171–178 e179. doi:10.1016/j.cmi.2015.10.003.
   Web of Science ®Google Scholar
• Lázár B, B LS, Hutka B, S TA, Mohammadzadeh A, Berekméri E, Ágg B, Balogh M, Sajtos V, Király K. A comprehensive time course and correlation analysis of indomethacin-induced inflammation, bile acid alterations and dysbiosis in the rat small intestine. Biochem Pharmacol. 2021;190:114590. doi:10.1016/j.bcp.2021.114590.
   PubMed Web of Science ®Google Scholar
• Mortensen B, Murphy C, O’Grady J, Lucey M, Elsafi G, Barry L, Westphal V, Wellejus A, Lukjancenko O, C EA, et al. Bifidobacteriumbreve bif195 protects against small-intestinal damage caused by acetylsalicylic acid in healthy volunteers. Gastroenterology. 2019;157(3):637–646 e634. doi:10.1053/j.gastro.2019.05.008.
   PubMed Web of Science ®Google Scholar
• Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23(4):473–480. doi:10.1016/j.coi.2011.07.010.
   PubMed Web of Science ®Google Scholar
• Nadalian B, Yadegar A, Houri H, Olfatifar M, Shahrokh S, Asadzadeh Aghdaei H, Suzuki H, Zali MR. Prevalence of the pathobiont adherent-invasive Escherichia coli and inflammatory bowel disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2021;36(4):852–863. doi:10.1111/jgh.15260.
   PubMed Web of Science ®Google Scholar
• Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, Barnich N, Ng SC, Colombel JF. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut. 2018;67(3):574–587. doi:10.1136/gutjnl-2017-314903.
   PubMed Web of Science ®Google Scholar
• Small CL, Reid-Yu SA, McPhee JB, Coombes BK. Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis. Nat Commun. 2013;4(1):1957. doi:10.1038/ncomms2957.
   PubMedGoogle Scholar
• Buisson A, Sokol H, Hammoudi N, Nancey S, Treton X, Nachury M, Fumery M, Hebuterne X, Rodrigues M, P HJ, et al. Role of adherent and invasive Escherichia coli in Crohn’s disease: lessons from the postoperative recurrence model. Gut. 2022;gutjnl-2021–325971. doi:10.1136/gutjnl-2021-325971.
   Web of Science ®Google Scholar
• Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–420. doi:10.1038/nri.2016.58.
   PubMed Web of Science ®Google Scholar
• Aguilera M, Darby T, Melgar S. The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases - lessons learned from experimental models. Cytokine Growth Factor Rev. 2014;25(6):715–730. doi:10.1016/j.cytogfr.2014.04.003.
   PubMed Web of Science ®Google Scholar
• De la Fuente M, Franchi L, Araya D, Diaz-Jimenez D, Olivares M, Alvarez-Lobos M, Golenbock D, J GM, Lopez-Kostner F, Quera R, et al. Escherichia coli isolates from inflammatory bowel diseases patients survive in macrophages and activate NLRP3 inflammasome. Int J Med Microbiol. 2014;304(3–4):384–392. doi:10.1016/j.ijmm.2014.01.002.
   PubMed Web of Science ®Google Scholar
• Mao L, Kitani A, Similuk M, J OA, Albenberg L, Kelsen J, Aktay A, Quezado M, Yao M, Montgomery-Recht K, et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease. J Clin Invest. 2018;128(5):1793–1806. doi:10.1172/JCI98642.
   PubMed Web of Science ®Google Scholar
• Higashimori A, Watanabe T, Nadatani Y, Takeda S, Otani K, Tanigawa T, Yamagami H, Shiba M, Tominaga K, Fujiwara Y, et al. Mechanisms of NLRP3 inflammasome activation and its role in NSAID-induced enteropathy. Mucosal Immunol. 2016;9(3):659–668. doi:10.1038/mi.2015.89.
   PubMed Web of Science ®Google Scholar
• Di Sabatino A, Ciccocioppo R, Luinetti O, Ricevuti L, Morera R, Cifone MG, Solcia E, Corazza GR. Increased enterocyte apoptosis in inflamed areas of Crohn’s disease. Dis Colon Rectum. 2003;46(11):1498–1507. doi:10.1007/s10350-004-6802-z.
   PubMed Web of Science ®Google Scholar
• Newton K, Dixit VM, Kayagaki N. Dying cells fan the flames of inflammation. Science. 2021;374(6571):1076–1080. doi:10.1126/science.abi5934.
   PubMed Web of Science ®Google Scholar
• S LA, F FH, Marquardt B, E MB, Magg T, Li Y, Liu Y, Ghalandary M, Lammens K, Hollizeck S, et al. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology. 2019;156(1):275–278. doi:10.1053/j.gastro.2018.09.041.
   PubMed Web of Science ®Google Scholar
• Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, J WM, M HS, Tenzer S, F NM, et al. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature. 2011;477(7364):335–339. doi:10.1038/nature10400.
   PubMed Web of Science ®Google Scholar
• Mashimo M, Onishi M, Uno A, Tanimichi A, Nobeyama A, Mori M, Yamada S, Negi S, N BX, R KJ, et al. The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis. J Biol Chem. 2021;296. doi:10.1074/jbc.RA120.014479.
   PubMed Web of Science ®Google Scholar
• Gram AM, Booty LM, Bryant CE. Chopping GSDMD: caspase-8 has joined the team of pyroptosis-mediating caspases. Embo J. 2019;38(10):e102065. doi:10.15252/embj.2019102065.
   PubMed Web of Science ®Google Scholar
• Sarhan J, C LB, I MH, Li P, Nilson R, Y TA, Rongvaux A, C BS, Shao F, R GD, et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc Natl Acad Sci USA. 2018;115(46):E10888–E10897. doi:10.1073/pnas.1809548115.
   PubMed Web of Science ®Google Scholar
• Kang S, Fernandes-Alnemri T, Rogers C, Mayes L, Wang Y, Dillon C, Roback L, Kaiser W, Oberst A, Sagara J, et al. Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat Commun. 2015;6(1):7515. doi:10.1038/ncomms8515.
   PubMedGoogle Scholar
• Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, Zhu J, Wu F, Ouyang H, Ge J, et al. Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma. Proc Natl Acad Sci USA. 2014;111(30):11181–11186. doi:10.1073/pnas.1402819111.
   PubMed Web of Science ®Google Scholar
• Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X, Kaiser WJ, Mocarski ES, Dubyak GR. Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J Biol Chem. 2015;290(33):20167–20184. doi:10.1074/jbc.M115.652321.
   PubMed Web of Science ®Google Scholar
• Chung H, Vilaysane A, Lau A, Stahl M, Morampudi V, Bondzi-Simpson A, M PJ, A BN, C FM, L BP, et al. NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis. Cell Death Differ. 2016;23(8):1331–1346. doi:10.1038/cdd.2016.14.
   PubMed Web of Science ®Google Scholar
• Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R, Englyst H, Williams HF, Rhodes JM. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology. 2004;127:80–93. doi:10.1053/j.gastro.2004.03.054.
   PubMed Web of Science ®Google Scholar
• Barthel M, Hapfelmeier S, Quintanilla-Martinez L, Kremer M, Rohde M, Hogardt M, Pfeffer K, Russmann H, Hardt WD. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun. 2003;71(5):2839–2858. doi:10.1128/IAI.71.5.2839-2858.2003.
   PubMed Web of Science ®Google Scholar
• Melgar S, Karlsson A, Michaëlsson E, Di Sabatino A, Ciccocioppo R, Luinetti O, Ricevuti L, Morera R, Cifone MG, Solcia 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(6):G1328–G1338. doi:10.1152/ajpgi.00467.2004.
   PubMed Web of Science ®Google Scholar
• D GA, Heger K, F SA, Reja R, Yan D, C PV, Suto E, Zhang J, C KY, C FE, et al. Integration of innate immune signalling by caspase-8 cleavage of N4BP1. Nature. 2020;587(7833):275–280. doi:10.1038/s41586-020-2796-5.
   PubMed Web of Science ®Google Scholar
• Kim SY, Hwangbo H, Lee H, Park C, Kim GY, Moon SK, Yun SJ, Kim WJ, Cheong J, Choi YH. Induction of apoptosis by coptisine in Hep3B hepatocellular carcinoma cells through activation of the ROS-mediated JNK signaling pathway. Int J Mol Sci. 2020;21(5502). doi:10.3390/ijms21155502.
   Google Scholar
• Gkouskou KK, Deligianni C, Tsatsanis C, Eliopoulos AG. The gut microbiota in mouse models of inflammatory bowel disease. Front Cell Infect Microbiol. 2014;4:28. doi:10.3389/fcimb.2014.00028.
   PubMed Web of Science ®Google Scholar
• Xiao L, Zheng H, Li J, Zeng M, He D, Liang J, Sun K, Luo Y, Li F, Ping B, et al. Targeting NLRP3 inflammasome modulates gut microbiota, attenuates corticospinal tract injury and ameliorates neurobehavioral deficits after intracerebral hemorrhage in mice. Biomed Pharmacother. 2022;149:112797. doi:10.1016/j.biopha.2022.112797.
   PubMed Web of Science ®Google Scholar
• M SE, V GL, L R-GF, De Meis J, M PR, Wu Z, C C-ST, H SS, G LU, M SR, et al. Caspase-8 activity prevents type 2 cytokine responses and is required for protective T cell-mediated immunity against Trypanosoma cruzi infection. J Immunol. 2005;174(10):6314–6321. doi:10.4049/jimmunol.174.10.6314.
   PubMed Web of Science ®Google Scholar
• Shawki A, McCole DF. Mechanisms of intestinal epithelial barrier dysfunction by adherent-invasive Escherichia coli. Cell Mol Gastroenterol Hepatol. 2017;3(1):41–50. doi:10.1016/j.jcmgh.2016.10.004.
   PubMed Web of Science ®Google Scholar
• Holgersen K, Kvist PH, Markholst H, Hansen AK, Holm TL. Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse–a model mimicking inflammatory bowel disease. J Crohns Colitis. 2014;8(2):147–160. doi:10.1016/j.crohns.2013.08.002.
   PubMed Web of Science ®Google Scholar
• Itani S, Watanabe T, Nadatani Y, Sugimura N, Shimada S, Takeda S, Otani K, Hosomi S, Nagami Y, Tanaka F, et al. NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis. Sci Rep. 2016;6:39075. doi:10.1038/srep39075.
   PubMed Web of Science ®Google Scholar
• Perera AP, Fernando R, Shinde T, Gundamaraju R, Southam B, Sohal SS, Robertson AAB, Schroder K, Kunde D, Eri R. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci Rep. 2018;8(1):8618. doi:10.1038/s41598-018-26775-w.
   PubMed Web of Science ®Google Scholar
• Zhang J, Fu S, Sun S, Li Z, Guo B. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol. 2014;7(5):1139–1150. doi:10.1038/mi.2014.1.
   PubMed Web of Science ®Google Scholar
• Lu J, Xie S, Deng Y, Xie X, Liu Y. Blocking the NLRP3 inflammasome reduces osteogenic calcification and M1 macrophage polarization in a mouse model of calcified aortic valve stenosis. Atherosclerosis. 2022;347:28–38. doi:10.1016/j.atherosclerosis.2022.03.005.
   PubMed Web of Science ®Google Scholar
• Kim CH, Park J, Kim M. Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immune Netw. 2014;14(6):277–288. doi:10.4110/in.2014.14.6.277.
   PubMedGoogle Scholar
• Takeshita K, Mizuno S, Mikami Y, Sujino T, Saigusa K, Matsuoka K, Naganuma M, Sato T, Takada T, Tsuji H, et al. A single species of clostridium subcluster xiva decreased in ulcerative colitis patients. Inflamm Bowel Dis. 2016;22(12):2802–2810. doi:10.1097/MIB.0000000000000972.
   PubMed Web of Science ®Google Scholar
• Xu L, Zhang C, He D, Jiang N, Bai Y, Xin Y. Rapamycin and MCC950 modified gut microbiota in experimental autoimmune encephalomyelitis mouse by brain gut axis. Life Sci. 2020;253:117747. doi:10.1016/j.lfs.2020.117747.
   PubMed Web of Science ®Google Scholar
• Somchit M, Faizah S, Zuraini A, Khairi H, Hasiah A, Zakaria Z. Selective in vitro cytotoxic effects of piroxicam and mefenamic acid on several cancer cells lines. Res J Pharmacol. 2009;3:15–18.
   Google Scholar
• Wadolkowski EA, Laux DC, Cohen PS. Colonization of the streptomycin-treated mouse large intestine by a human fecal Escherichia coli strain: role of growth in mucus. Infect Immun. 1988;56(5):1030–1035. doi:10.1128/iai.56.5.1030-1035.1988.
   PubMed Web of Science ®Google Scholar
• Spees AM, Wangdi T, Lopez CA, Kingsbury DD, Xavier MN, Winter SE, Tsolis RM, J BA. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. MBio. 2013;4(4):e00430–00413. doi:10.1128/mBio.00430-13.
   PubMed Web of Science ®Google Scholar
• Hall LJ, Murphy CT, Hurley G, Quinlan A, Shanahan F, Nally K, Melgar S. Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium. Infect Immun. 2013;81(2):460–469. doi:10.1128/IAI.00953-12.
   PubMed Web of Science ®Google Scholar
• Las Heras V, G CA, J RF, Cabrera-Rubio R, G CP, M HC, Pinheiro J, K RJ, Melgar S, D CP, et al. Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection. Microbiome. 2019;7(1):7. doi:10.1186/s40168-019-0621-x.
   PubMedGoogle Scholar
• Saiz-Gonzalo G, Hanrahan N, Rossini V, Singh R, Ahern M, Kelleher M, Hill S, O’Sullivan R, Fanning A, T WP, et al. Regulation of CEACAM family members by IBD-associated triggers in intestinal epithelial cells, their correlation to inflammation and relevance to IBD pathogenesis. Front Immunol. 2021;12:655960. doi:10.3389/fimmu.2021.655960.
   PubMed Web of Science ®Google Scholar
• Hall LJ, Faivre E, Quinlan A, Shanahan F, Nally K, Melgar S. Induction and activation of adaptive immune populations during acute and chronic phases of a murine model of experimental colitis. Dig Dis Sci. 2011;56(1):79–89. doi:10.1007/s10620-010-1240-3.
   PubMed Web of Science ®Google Scholar
• J RF, M AA, S FR, J L-ME, M PE, G CA, W OK, J MP, Iwai S, Crits-Christoph A, et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat Commun. 2020;11(1):1512. doi:10.1038/s41467-020-15342-5.
   PubMed Web of Science ®Google Scholar
• Grenié M, Denelle P, Tucker CM, Munoz F, Violle C. Funrar: an R package to characterize functional rarity. Divers Distrib. 2017;23(12):1365–1371. doi:10.1111/ddi.12629.
   Web of Science ®Google Scholar
• Wickham H. Reshaping data with the reshape package. J Stat Softw. 2007;21(12):1–20. doi:10.18637/jss.v021.i12.
   Web of Science ®Google Scholar
• Wickham H. ggplot2: elegant graphics for data analysis. New York: springer; 2016.
   Google Scholar
• Kassambara A. Package ‘ggpubr’. R Package Version. 2019. https://cran.r-project.org/web/packages/ggpubr/index.html.
   Google Scholar
• Oksanen J, Blanchet FG, Kindt R, Legendre P, Minchin P, O’hara R, Simpson G, Solymos P, Stevens MHH, Wagner H. Community ecology package. R Package Version. 2013;2:321–326.
   Google Scholar
• McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One. 2013;8(4):e61217. doi:10.1371/journal.pone.0061217.
   PubMed Web of Science ®Google Scholar
• Wright K. pals: color palettes, colormaps, and tools to evaluate them. R Package Version. 2019;1. https://cran.r-project.org/web/packages/pals/index.html.
   Google Scholar
• Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi:10.1186/s13059-014-0550-8.
   PubMed Web of Science ®Google Scholar
• Team R C. R: a language and environment for statistical computing (version 3.5.2. Vienna (Austria): R Foundation for Statistical Computing; 2018.
   Google Scholar
• Wei T, Simko V, Levy M, Xie Y, Jin Y, Zemla J. Package ‘corrplot’. Statistician. 2017;56:e24.
   Google Scholar
• Aguilera M, Rossini V, Hickey A, Simnica D, Grady F, D FV, Moloney A, Pawley L, Fanning A, McCarthy L, et al. Inflammasome signaling regulates the microbial-neuroimmune axis and visceral pain in mice. Int J Mol Sci. 2021;22(15):8336. doi:10.3390/ijms22158336.
   PubMed Web of Science ®Google Scholar
• Singh R, Rossini V, Stockdale SR, Saiz-Gonzalo G, Hanrahan N, D’Souza T, Clooney A, Draper LA, Hill C, Nally K. An IBD-associated pathobiont synergises with NSAID to promote colitis which is blocked by NLRP3 inflammasome and Caspase-8 inhibitors. 2022. doi:10.1101/2022.08.18.504384.
   Google Scholar