Highlighted publications

The Role of Microbiota-Derived Metabolites in Colorectal Cancer

Duizer C, De Zoete MR

Int J Mol Sci. 2023 Apr 28;24(9):8024.  doi: 10.3390/ijms24098024.

The impact of bacterial members of the microbiota on the development of colorectal cancer (CRC) has become clear in recent years. However, exactly how bacteria contribute to the development of cancer is often still up for debate. The impact of bacteria-derived metabolites, which can influence the development of CRC either in a promoting or inhibiting manner, is undeniable. Here, we discuss the effects of the most well-studied bacteria-derived metabolites associated with CRC, including secondary bile acids, short-chain fatty acids, trimethylamine-N-oxide and indoles. We show that the effects of individual metabolites on CRC development are often nuanced and dose- and location-dependent. In the coming years, the array of metabolites involved in CRC development will undoubtedly increase further, which will emphasize the need to focus on causation and mechanisms and the clearly defined roles of bacterial species within the microbiota.

Identification of Allobaculum mucolyticum as a novel human intestinal mucin degrader

Van Muijlwijk GH, Van Mierlo G, Jansen PWTC, Vermeulen M, Bleumink-Pluym NMC, Palm NW, Van PuttenJPM, De Zoete MR

Gut Microbes. 2021 Jan-Dec;13(1):1966278.  doi: 10.1080/19490976.2021.1966278.

The human gut microbiota plays a central role in intestinal health and disease. Yet, many of its bacterial constituents are functionally still largely unexplored. A crucial prerequisite for bacterial survival and proliferation is the creation and/or exploitation of an own niche. For many bacterial species that are linked to human disease, the inner mucus layer was found to be an important niche. Allobaculum mucolyticum is a newly identified, IBD-associated species that is thought be closely associated with the host epithelium. To explore how this bacterium is able to effectively colonize this niche, we screened its genome for factors that may contribute to mucosal colonization. Up to 60 genes encoding putative Carbohydrate Active Enzymes (CAZymes) were identified in the genome of A. mucolyticum. Mass spectrometry revealed 49 CAZymes of which 26 were significantly enriched in its secretome. Functional assays demonstrated the presence of CAZyme activity in A. mucolyticum conditioned medium, degradation of human mucin O-glycans, and utilization of liberated non-terminal monosaccharides for bacterial growth. The results support a model in which sialidases and fucosidases remove terminal O-glycan sugars enabling subsequent degradation and utilization of carbohydrates for A. mucolyticum growth. A. mucolyticum CAZyme secretion may thus facilitate bacterial colonization and degradation of the mucus layer and may pose an interesting target for future therapeutic intervention.

The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells.

Cui J, Duizer C, Bouwman LI, van Rooijen KS, Voogdt CGP, van Putten JPM, de Zoete MR.

PLoS Pathog. 2021 Aug 2;17(8):e1009787. doi: 10.1371/journal.ppat.1009787.

Understanding the virulence mechanism of pathogenic bacteria is an important step in the development of targeted intervention or treatment strategies. Campylobacter jejuni is the most common cause of bacterial foodborne enteritis, but the underlying molecular cause of C. jejuni-mediated disease remains unresolved. In this study, Jiannan Cui and Coco Duizer identify the inflammatory metabolite ADP-heptose, released by C. jejuni into its environment during growth, as a novel potent C. jejuni activator of inflammation in intestinal epithelial cells. C. jejuni-derived heptose phosphates signals through the intracellular receptor ALPK1 and induces a wide range of pro-inflammatory genes. Revealing the importance of the ALPK1 signaling axis during C. jejuniinfection may pave the road for the development of new therapeutic strategies that target this inflammatory pathway or the production and release of ADP-heptose by Campylobacter


The Role of Microbiota-Derived Metabolites in Colorectal Cancer.

Duizer C, de Zoete MR. Int J Mol Sci. 2023 Apr 28;24(9):8024. doi: 10.3390/ijms24098024.


Cohort profile of PLUTO: a perioperative biobank focusing on prediction and early diagnosis of postoperative complications.

de Mul N, Verlaan D, Ruurda JP, van Grevenstein WMU, Hagendoorn J, de Borst GJ, Vriens MR, de Bree R, Zweemer RP, Vogely C, Haitsma Mulier JLG, Vernooij LM, Reitsma JB, de Zoete MR, Top J, Kluijtmans JAJ, Hoefer IE, Noordzij P, Rettig T, Marsman M, de Smet AMGA, Derde L, van Waes J, Rijsdijk M, Schellekens WJM, Bonten MJM, Slooter AJC, Cremer OL. BMJ Open. 2023 Apr 19;13(4):e068970. doi: 10.1136/bmjopen-2022-068970.


Allobaculum mucilyticum sp. nov. and Allobaculum fili sp. nov., isolated from the human intestinal tract.

 van Muijlwijk GH, Rice TA, Flavell RA, Palm NW, de Zoete MR. Int J Syst Evol Microbiol. 2023 Feb;73(1). doi: 10.1099/ijsem.0.005635.


Interspecies commensal interactions have nonlinear impacts on host immunity.

Rice TA, Bielecka AA, Nguyen MT, Rosen CE, Song D, Sonnert ND, Yang Y, Cao Y, Khetrapal V, Catanzaro JR, Martin AL, Rashed SA, Leopold SR, Hao L, Yu X, van Dijk D, Ring AM, Flavell RA, de Zoete MR, Palm NW. Cell Host Microbe. 2022 Jul 13;30(7):988-1002.e6. doi: 10.1016/j.chom.2022.05.004.


Ablation of liver Fxr results in an increased colonic mucus barrier in mice.

Ijssennagger N, van Rooijen KS, Magnúsdóttir S, Ramos Pittol JM, Willemsen ECL, de Zoete MR, Baars MJD, Stege PB, Colliva C, Pellicciari R, Youssef SA, de Bruin A, Vercoulen Y, Kuipers F, van Mil SWC.JHEP Rep. 2021 Aug 4;3(5):100344. doi: 10.1016/j.jhepr.2021.100344.


Identification of Allobaculum mucolyticum as a novel human intestinal mucin degrader.

van Muijlwijk GH, van Mierlo G, Jansen PWTC, Vermeulen M, Bleumink-Pluym NMC, Palm NW, van Putten JPM, de Zoete MR. Gut Microbes. 2021 Jan-Dec;13(1):1966278. doi: 10.1080/19490976.2021.1966278.


The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells.

Cui J, Duizer C, Bouwman LI, van Rooijen KS, Voogdt CGP, van Putten JPM, de Zoete MR. PLoS Pathog. 2021 Aug 2;17(8):e1009787. doi: 10.1371/journal.ppat.1009787.


Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients.

Brand EC, Klaassen MAY, Gacesa R, Vich Vila A, Ghosh H, de Zoete MR, Boomsma DI, Hoentjen F, Horjus Talabur Horje CS, van de Meeberg PC, Willemsen G, Fu J, Wijmenga C, van Wijk F, Zhernakova A, Oldenburg B, Weersma RK; Dutch TWIN-IBD consortium and the Dutch Initiative on Crohn and Colitis. Gastroenterology. 2021 May;160(6):1970-1985. doi: 10.1053/j.gastro.2021.01.030.


Immunoglobulin A Targets a Unique Subset of the Microbiota in Inflammatory Bowel Disease.

Shapiro JM, de Zoete MR, Palm NW, Laenen Y, Bright R, Mallette M, Bu K, Bielecka AA, Xu F, Hurtado-Lorenzo A, Shah SA, Cho JH, LeLeiko NS, Sands BE, Flavell RA, Clemente JC. Cell Host Microbe. 2021 Jan 13;29(1):83-93.e3. doi: 10.1016/j.chom.2020.12.003.


Behçet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behçet's Disease Patients.

van der Houwen TB, van Laar JAM, Kappen JH, van Hagen PM, de Zoete MR, van Muijlwijk GH, Berbers RM, Fluit AC, Rogers M, Groot J, Hazelbag CM, Consolandi C, Severgnini M, Peano C, D'Elios MM, Emmi G, Leavis HL. Front Immunol. 2020 Jun 12;11:1192. doi: 10.3389/fimmu.2020.01192.


Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity.

Jarret A, Jackson R, Duizer C, Healy ME, Zhao J, Rone JM, Bielecki P, Sefik E, Roulis M, Rice T, Sivanathan KN, Zhou T, Solis AG, Honcharova-Biletska H, Vélez K, Hartner S, Low JS, Qu R, de Zoete MR, Palm NW, Ring AM, Weber A, Moor AE, Kluger Y, Nowarski R, Flavell RA. Cell. 2020 Jan 9;180(1):50-63.e12. doi: 10.1016/j.cell.2019.12.016.


Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity.

Solis AG, Bielecki P, Steach HR, Sharma L, Harman CCD, Yun S, de Zoete MR, Warnock JN, To SDF, York AG, Mack M, Schwartz MA, Dela Cruz CS, Palm NW, Jackson R, Flavell RA. Nature. 2019 Sep;573(7772):69-74. doi: 10.1038/s41586-019-1485-8.


Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.

Grootjans J, Krupka N, Hosomi S, Matute JD, Hanley T, Saveljeva S, Gensollen T, Heijmans J, Li H, Limenitakis JP, Ganal-Vonarburg SC, Suo S, Luoma AM, Shimodaira Y, Duan J, Shih DQ, Conner ME, Glickman JN, Fuhler GM, Palm NW, de Zoete MR, van der Woude CJ, Yuan GC, Wucherpfennig KW, Targan SR, Rosenstiel P, Flavell RA, McCoy KD, Macpherson AJ, Kaser A, Blumberg RS. Science. 2019 Mar 1;363(6430):993-998. doi: 10.1126/science.aat7186.


Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model.

Pérez MM, Martins LMS, Dias MS, Pereira CA, Leite JA, Gonçalves ECS, de Almeida PZ, de Freitas EN, Tostes RC, Ramos SG, de Zoete MR, Ryffel B, Silva JS, Carlos D. Immunology. 2019 Apr;156(4):339-355. doi: 10.1111/imm.13028.


NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease.

Tye H, Yu CH, Simms LA, de Zoete MR, Kim ML, Zakrzewski M, Penington JS, Harapas CR, Souza-Fonseca-Guimaraes F, Wockner LF, Preaudet A, Mielke LA, Wilcox SA, Ogura Y, Corr SC, Kanojia K, Kouremenos KA, De Souza DP, McConville MJ, Flavell RA, Gerlic M, Kile BT, Papenfuss AT, Putoczki TL, Radford-Smith GL, Masters SL. Nat Commun. 2018 Sep 13;9(1):3728. doi: 10.1038/s41467-018-06125-0.


Interleukin-23 promotes intestinal T helper type17 immunity and ameliorates obesity-associated metabolic syndrome in a murine high-fat diet model.

Martins LMS, Perez MM, Pereira CA, Costa FRC, Dias MS, Tostes RC, Ramos SG, de Zoete MR, Ryffel B, Silva JS, Carlos D. Immunology. 2018 May 2;154(4):624-36. doi: 10.1111/imm.12946. Online ahead of print.


Humanized mouse model supports development, function, and tissue residency of human natural killer cells.

Herndler-Brandstetter D, Shan L, Yao Y, Stecher C, Plajer V, Lietzenmayer M, Strowig T, de Zoete MR, Palm NW, Chen J, Blish CA, Frleta D, Gurer C, Macdonald LE, Murphy AJ, Yancopoulos GD, Montgomery RR, Flavell RA. Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9626-E9634. doi: 10.1073/pnas.1705301114.


Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells.

Zhu S, Ding S, Wang P, Wei Z, Pan W, Palm NW, Yang Y, Yu H, Li HB, Wang G, Lei X, de Zoete MR, Zhao J, Zheng Y, Chen H, Zhao Y, Jurado KA, Feng N, Shan L, Kluger Y, Lu J, Abraham C, Fikrig E, Greenberg HB, Flavell RA. Nature. 2017 Jun 29;546(7660):667-670. doi: 10.1038/nature22967. Epub 2017 Jun 21.


Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.

Błażejewski AJ, Thiemann S, Schenk A, Pils MC, Gálvez EJC, Roy U, Heise U, de Zoete MR, Flavell RA, Strowig T.Cell Rep. 2017 Jun 13;19(11):2319-2330. doi: 10.1016/j.celrep.2017.05.058.


Invasive behavior of Campylobacter jejuni in immunosuppressed chicken.

Vaezirad MM, Keestra-Gounder AM, de Zoete MR, Koene MG, Wagenaar JA, van Putten JPM. Virulence. 2017 Apr 3;8(3):248-260. doi: 10.1080/21505594.2016.1221559.


Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset.

Costa FR, Françozo MC, de Oliveira GG, Ignacio A, Castoldi A, Zamboni DS, Ramos SG, Câmara NO, de Zoete MR, Palm NW, Flavell RA, Silva JS, Carlos D. J Exp Med. 2016 Jun 27;213(7):1223-39. doi: 10.1084/jem.20150744. Epub 2016 Jun 20.


Immunomodulatory and Anti-Inflammatory Activities of Chicken Cathelicidin-2 Derived Peptides.

van Dijk A, van Eldik M, Veldhuizen EJ, Tjeerdsma-van Bokhoven HL, de Zoete MR, Bikker FJ, Haagsman HP. PLoS One. 2016 Feb 5;11(2):e0147919. doi: 10.1371/journal.pone.0147919.


Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis.

Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, Low JS, Harman CC, Graham M, Elinav E, Flavell RA. Cell. 2015 Dec 3;163(6):1444-56. doi: 10.1016/j.cell.2015.10.072.


Redirection of Epithelial Immune Responses by Short-Chain Fatty Acids through Inhibition of Histone Deacetylases.

Lin MY, de Zoete MR, van Putten JP, Strijbis K. Front Immunol. 2015 Nov 3;6:554. doi: 10.3389/fimmu.2015.00554.


Guanylate binding proteins enable rapid activation of canonical and noncanonical inflammasomes in Chlamydia-infected macrophages.

Finethy R, Jorgensen I, Haldar AK, de Zoete MR, Strowig T, Flavell RA, Yamamoto M, Nagarajan UM, Miao EA, Coers J. Infect Immun. 2015 Dec;83(12):4740-9. doi: 10.1128/IAI.00856-15.


Immune-microbiota interactions in health and disease.

Palm NW, de Zoete MR, Flavell RA. Clin Immunol. 2015 Aug;159(2):122-127. doi: 10.1016/j.clim.2015.05.014. Epub 2015 Jun 30.


Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.

Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. Nature. 2015 Jul 9;523(7559):221-5. doi: 10.1038/nature14452.


Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA.

Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ, Iwasaki A, Flavell RA. Cell. 2014 Dec 18;159(7):1563-77. doi: 10.1016/j.cell.2014.11.037.



de Zoete MR, Palm NW, Zhu S, Flavell RA. Cold Spring Harb Perspect Biol. 2014 Oct 16;6(12):a016287. doi: 10.1101/cshperspect.a016287.


Inflammasome activation by Campylobacter jejuni.

Bouwman LI, de Zoete MR, Bleumink-Pluym NM, Flavell RA, van Putten JP. J Immunol. 2014 Nov 1;193(9):4548-57. doi: 10.4049/jimmunol.1400648.


Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.

Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J, Hao L, Degnan PH, Hu J, Peter I, Zhang W, Ruggiero E, Cho JH, Goodman AL, Flavell RA. Cell. 2014 Aug 28;158(5):1000-1010. doi: 10.1016/j.cell.2014.08.006.


Detecting "different": Pyrin senses modified GTPases.

de Zoete MR, Flavell RA. Cell Res. 2014 Nov;24(11):1286-7. doi: 10.1038/cr.2014.101. Epub 2014 Aug 5.


Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota.

Gagliani N, Palm NW, de Zoete MR, Flavell RA. Int Immunol. 2014 Sep;26(9):495-9. doi: 10.1093/intimm/dxu066. Epub 2014 Jun 19.


Interactions between Nod-Like Receptors and Intestinal Bacteria.

de Zoete MR, Flavell RA. Front Immunol. 2013 Dec 17;4:462. doi: 10.3389/fimmu.2013.00462.


Unique features of chicken Toll-like receptors.

Keestra AM, de Zoete MR, Bouwman LI, Vaezirad MM, van Putten JP. Dev Comp Immunol. 2013 Nov;41(3):316-23. doi: 10.1016/j.dci.2013.04.009.


Rabies virus is recognized by the NLRP3 inflammasome and activates interleukin-1β release in murine dendritic cells.

Lawrence TM, Hudacek AW, de Zoete MR, Flavell RA, Schnell MJ. J Virol. 2013 May;87(10):5848-57. doi: 10.1128/JVI.00203-13.


Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila.

Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR. Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1851-6. doi: 10.1073/pnas.1211521110.


NLRP1 joins the dark side?

de Zoete MR, Flavell RA. Immunity. 2012 Dec 14;37(6):950-2. doi: 10.1016/j.immuni.2012.11.008.


Cleavage and activation of a Toll-like receptor by microbial proteases.

de Zoete MR, Bouwman LI, Keestra AM, van Putten JP. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4968-73. doi: 10.1073/pnas.1018135108.


Chicken TLR21 is an innate CpG DNA receptor distinct from mammalian TLR9.

Keestra AM, de Zoete MR, Bouwman LI, van Putten JP. J Immunol. 2010 Jul 1;185(1):460-7. doi: 10.4049/jimmunol.0901921. Epub 2010 May 24.


Temperature-dependent FlgM/FliA complex formation regulates Campylobacter jejuni flagella length.

Wösten MM, van Dijk L, Veenendaal AK, de Zoete MR, Bleumink-Pluijm NM, van Putten JP. Mol Microbiol. 2010 Mar;75(6):1577-91. doi: 10.1111/j.1365-2958.2010.07079.x.


Reconstitution of a functional Toll-like receptor 5 binding site in Campylobacter jejuni flagellin.

de Zoete MR, Keestra AM, Wagenaar JA, van Putten JP. J Biol Chem. 2010 Apr 16;285(16):12149-58. doi: 10.1074/jbc.M109.070227.


Activation of human and chicken toll-like receptors by Campylobacter spp.

de Zoete MR, Keestra AM, Roszczenko P, van Putten JP. Infect Immun. 2010 Mar;78(3):1229-38. doi: 10.1128/IAI.00897-09.


Molecular mechanisms of campylobacter infection.

van Putten JP, van Alphen LB, Wösten MM, de Zoete MR. Curr Top Microbiol Immunol. 2009;337:197-229. doi: 10.1007/978-3-642-01846-6_7.


Unraveling bacterial interactions with toll-like receptors.

van Putten JP, Bouwman LI, de Zoete MR. Immunol Lett. 2010 Jan 18;128(1):8-11. doi: 10.1016/j.imlet.2009.09.007.


Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin.

Keestra AM, de Zoete MR, van Aubel RA, van Putten JP. Mol Immunol. 2008 Mar;45(5):1298-307. doi: 10.1016/j.molimm.2007.09.013.


The central leucine-rich repeat region of chicken TLR16 dictates unique ligand specificity and species-specific interaction with TLR2.

Keestra AM, de Zoete MR, van Aubel RA, van Putten JP. J Immunol. 2007 Jun 1;178(11):7110-9. doi: 10.4049/jimmunol.178.11.7110.


Vaccination of chickens against Campylobacter.

de Zoete MR, van Putten JP, Wagenaar JA. Vaccine. 2007 Jul 26;25(30):5548-57. doi: 10.1016/j.vaccine.2006.12.002. Epub 2006 Dec 15.


The ShdA adhesin binds to the cationic cradle of the fibronectin 13FnIII repeat module: evidence for molecular mimicry of heparin binding.

Kingsley RA, Keestra AM, de Zoete MR, Bäumler AJ. Mol Microbiol. 2004 Apr;52(2):345-55. doi: 10.1111/j.1365-2958.2004.03995.x.


Molecular and phenotypic analysis of the CS54 island of Salmonella enterica serotype typhimurium: identification of intestinal colonization and persistence determinants.

Kingsley RA, Humphries AD, Weening EH, De Zoete MR, Winter S, Papaconstantinopoulou A, Dougan G, Bäumler AJ.Infect Immun. 2003 Feb;71(2):629-40. doi: 10.1128/IAI.71.2.629-640.2003.


16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori.

Gerrits MM, de Zoete MR, Arents NL, Kuipers EJ, Kusters JG. Antimicrob Agents Chemother. 2002 Sep;46(9):2996-3000. doi: 10.1128/AAC.46.9.2996-3000.2002.