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Cited by 20Inflammatory Bowel DiseaseIL-33, ST2, and ILC PathwaysGut microbiota and health

Gut Epithelial Inositol Polyphosphate Multikinase Alleviates Experimental Colitis via Governing Tuft Cell Homeostasis

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Park, Seung Eun, Lee, Dongeun, Jeong, Jae Woong, Lee, Su-Hyung, Park, Seung Ju, Ryu, Jaeseung, Oh, Se Kyu, Yang, Hanseul +2 more·2022·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2022.08.004PMC PMC9579329
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Abstract

Background & Aims Inositol polyphosphate multikinase (IPMK), an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. Recent studies have identified single-nucleotide polymorphisms in the IPMK gene associated with inflammatory bowel disease predisposition. Therefore, we aimed to investigate the functional significance of IPMK in gut epithelium. Methods We generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMK ΔIEC ) mice, and assessed their vulnerability against dextran sulfate sodium–induced experimental colitis. Both bulk and single-cell RNA sequencing were performed to analyze IPMK-deficient colonic epithelial cells and colonic tuft cells. Results Although IPMK ΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium–induced colitis, with higher clinical colitis scores, and increased epithelial barrier permeability. Surprisingly, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other IECs. Single-cell RNA sequencing of mouse colonic tuft cells showed 3 distinct populations of tuft cells, and further showed that a transcriptionally inactive population was expanded markedly in IPMK ΔIEC mice, while neuronal-related cells were relatively decreased. Conclusions Cholinergic output from tuft cells is known to be critical for the restoration of intestinal architecture upon damage, supporting that tuft cell–defective IPMK ΔIEC mice are more prone to colitis. Thus, intestinal epithelial IPMK is a critical regulator of colonic integrity and tissue regeneration by determining tuft cell homeostasis and affecting cholinergic output.

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  • IPMK is implicated in neurodegeneration, cancer, and inflammation.

    “Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [33]

    The Conclusions passage links an IPMK mutation to familial small-intestinal carcinoids, and the Discussion reports that epithelial IPMK depletion worsened experimental colitis. These support the cancer and inflammation examples. Our copy does not establish an implication of IPMK in neurodegeneration, so it does not support the full list. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • IPMK is involved in inflammatory disorders, obesity, Alzheimer's disease, inflammatory bowel disease, and intestinal neuroendocrine tumors.

    “Over the past two decades, research utilizing animal models and human mutation analyses has revealed IPMK’s involvement in a wide array of human diseases, including inflammatory disorders [28,29], obesity [30,31], Alzheimer’s disease [32], inflammatory bowel disease [33,34], and intestinal neuroendocrine tumors [35].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [33]

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  1. [1]Beumer J. Clevers H. Cell fate specification and differentiation in the adult mammalian intestine Nat Rev Mol Cell Biol 22 2021 39 53 32958874
  2. [3]Grencis R.K. Worthington J.J. Tuft cells: a new flavor in innate epithelial immunity Trends Parasitol 32 2016 583 585 27161767
  3. [4]Gerbe F. Jay P. Intestinal tuft cells: epithelial sentinels linking luminal cues to the immune system Mucosal Immunol 9 2016 1353 1359 27554294
  4. [5]Banerjee A. McKinley E.T. Von Moltke J. Coffey R.J. Lau K.S. Interpreting heterogeneity in intestinal tuft cell structure and function J Clin Invest 128 2018 1711 1719 29714721 PMC5919882
  5. [6]Qu D. Weygant N. May R. Chandrakesan P. Madhoun M. Ali N. Sureban S.M. An G. Schlosser M.J. Houchen C.W. Ablation of doublecortin-like kinase 1 in the colonic epithelium exacerbates dextran sulfate sodium-induced colitis PLoS One 10 2015 1 14 PMC4540568 26285154
  6. [7]May R. Qu D. Weygant N. Chandrakesan P. Ali N. Lightfoot S.A. Li L. Sureban S.M. Houchen C.W. Brief report: Dclk1 deletion in tuft cells results in impaired epithelial repair after radiation injury Stem Cells 32 2014 822 827 24123696 PMC4603545
  7. [8]Baumgart D.C. Carding S.R. Inflammatory bowel disease: cause and immunobiology Lancet 369 2007 1627 1640 17499605
  8. [9]Graham D.B. Xavier R.J. Pathway paradigms revealed from the genetics of inflammatory bowel disease Nature 578 2020 527 539 32103191 PMC7871366
  9. [10]Ananthakrishnan A.N. Bernstein C.N. Iliopoulos D. Macpherson A. Neurath M.F. Ali R.A.R. Vavricka S.R. Fiocchi C. Environmental triggers in IBD: a review of progress and evidence Nat Rev Gastroenterol Hepatol 15 2018 39 49 29018271
  10. [11]Aardoom M.A. Joosse M.E. De Vries A.C.H. Levine A. De Ridder L. Malignancy and mortality in pediatric-onset inflammatory bowel disease: a systematic review Inflamm Bowel Dis 24 2018 732 741 29522170
  11. [12]Nadeem M.S. Kumar V. Al-Abbasi F.A. Kamal M.A. Anwar F. Risk of colorectal cancer in inflammatory bowel diseases Semin Cancer Biol 64 2020 51 60 31112753
  12. [14]Resnick A.C. Snowman A.M. Kang B.M. Hurt K.J. Snyder S.H. Saiardi A. Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity Proc Natl Acad Sci U S A 102 2005 12783 12788 16123124 PMC1200306
  13. [15]Lee B. Park S.J. Hong S. Kim K. Kim S. Inositol polyphosphate multikinase signaling: multifaceted functions in health and disease Mol Cells 44 2021 187 194 33935040 PMC8112168
  14. [16]Kim E. Ahn H. Kim M.G. Lee H. Kim S. The expanding significance of inositol polyphosphate multikinase as a signaling hub Mol Cells 40 2017 315 321 28554203 PMC5463039
  15. [18]O’Donnell S. Borowski K. Espin-Garcia O. Milgrom R. Kabakchiev B. Stempak J. Panikkath D. Eksteen B. Xu W. Steinhart A.H. Kaplan G.G. McGovern D.P.B. Silverberg M.S. The unsolved link of genetic markers and Crohn’s disease progression: a North American cohort experience Inflamm Bowel Dis 25 2019 1541 1549 30801121
  16. [19]Sei Y. Zhao X. Forbes J. Szymczak S. Li Q. Trivedi A. Voellinger M. Joy G. Feng J. Whatley M. Jones M.P.S. Harper U.L. Marx S.J. Venkatesan A.M. Chandrasekharappa S.C. Raffeld M. Quezado M.M. Louie A. Chen C.C. Lim R.M. Agarwala R. Schäffer A.A. Hughes M.S. Bailey-Wilson J.E. Wank S.A. A hereditary form of small intestinal carcinoid associated with a germline mutation in inositol polyphosphate multikinase Gastroenterology 149 2015 67 78 25865046 PMC4858647
  17. [20]Okabe A. Huang K.K. Matsusaka K. Fukuyo M. Xing M. Ong X. Hoshii T. Usui G. Seki M. Mano Y. Rahmutulla B. Kanda T. Suzuki T. Rha S.Y. Ushiku T. Fukayama M. Tan P. Kaneda A. Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma Nat Genet 52 2020 919 930 32719515
  18. [21]Yin S. Ray G. Kerschner J.L. Hao S. Perez A. Drumm M.L. Browne J.A. Leir S.H. Longworth M. Harris A. Functional genomics analysis of human colon organoids identifies key transcription factors Physiol Genomics 52 2020 234 244 32390556 PMC7311676
  19. [22]Indukuri R. Jafferali M.H. Song D. Damdimopoulos A. Hases L. Zhao C. Archer A. Williams C. Genome-wide estrogen receptor β chromatin binding in human colon cancer cells reveals its tumor suppressor activity Int J Cancer 149 2021 692 706 33754337
  20. [23]Sims R.J. Millhouse S. Chen C.F. Lewis B.A. Erdjument-Bromage H. Tempst P. Manley J.L. Reinberg D. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing Mol Cell 28 2007 665 676 18042460 PMC2276655
  21. [24]Uhlén M. Fagerberg L. Hallström B.M. Lindskog C. Oksvold P. Mardinoglu A. Sivertsson Å. Kampf C. Sjöstedt E. Asplund A. Olsson I.M. Edlund K. Lundberg E. Navani S. Szigyarto C.A.K. Odeberg J. Djureinovic D. Takanen J.O. Hober S. Alm T. Edqvist P.H. Berling H. Tegel H. Mulder J. Rockberg J. Nilsson P. Schwenk J.M. Hamsten M. Von Feilitzen K. Forsberg M. Persson L. Johansson F. Zwahlen M. Von Heijne G. Nielsen J. Pontén F. Tissue-based map of the human proteome Science 347 2015 1260419 25613900
  22. [25]Herring C.A. Banerjee A. McKinley E.T. Simmons A.J. Ping J. Roland J.T. Franklin J.L. Liu Q. Gerdes M.J. Coffey R.J. Lau K.S. Unsupervised trajectory analysis of single-cell RNA-Seq and imaging data reveals alternative tuft cell origins in the gut Cell Syst 6 2018 37 51.e9 29153838 PMC5799016
  23. [26]Andrews N. Serviss J.T. Geyer N. Andersson A.B. Dzwonkowska E. Šutevski I. Heijboer R. Baryawno N. Gerling M. Enge M. An unsupervised method for physical cell interaction profiling of complex tissues Nat Methods 18 2021 912 920 34253926
  24. [27]Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. Tirosh I. Beyaz S. Dionne D. Zhang M. Raychowdhury R. Garrett W.S. Rozenblatt-Rosen O. Shi H.N. Yilmaz O. Xavier R.J. Regev A. A single-cell survey of the small intestinal epithelium Nature 551 2017 333 339 29144463 PMC6022292
  25. [28]Maag D. Maxwell M.J. Hardesty D.A. Boucher K.L. Choudhari N. Hanno A.G. Ma J.F. Snowman A.S. Pietropaoli J.W. Xu R. Storm P.B. Saiardi A. Snyder S.H. Resnick A.C. Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB Proc Natl Acad Sci U S A 108 2011 1391 1396 21220345 PMC3029688
  26. [29]Nagahama Y. Shimoda M. Mao G. Singh S.K. Kozakai Y. Sun X. Motooka D. Nakamura S. Tanaka H. Satoh T. Maeda K. Akira S. Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism Proc Natl Acad Sci U S A 115 2018 11036 11041 30297433 PMC6205455
  27. [30]Tesfaigzi J. Carlson D.M. Expression, regulation, and function of the SPR family of proteins: a review Cell Biochem Biophys 30 1999 243 265 10356644
  28. [31]Fang K. Zhang S. Glawe J. Grisham M.B. Kevil C.G. Temporal genome expression profile analysis during t-cell-mediated colitis: Identification of novel targets and pathways Inflamm Bowel Dis 18 2012 1411 1423 22179924 PMC4413946
  29. [32]Ma G.W. Chu Y.K. Yang H. Yan X.H. Rong E.G. Li H. Wang N. Functional analysis of sheep POU2F3 isoforms Biochem Genet 58 2020 335 347 31893322 PMC7113193
  30. [33]Yamashita J. Ohmoto M. Yamaguchi T. Matsumoto I. Hirota J. Skn-1a/Pou2f3 functions as a master regulator to generate Trpm5-expressing chemosensory cells in mice PLoS One 12 2017 1 14 PMC5720759 29216297
  31. [34]Howitt M.R. Lavoie S. Michaud M. Blum A.M. Tran S.V. Weinstock J.V. Gallini C.A. Redding K. Margolskee R.F. Osborne L.C. Artis D. Garrett W.S. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut Science 351 2016 1329 1333 26847546 PMC5528851
  32. [35]Gerbe F. Sidot E. Smyth D.J. Ohmoto M. Matsumoto I. Dardalhon V. Cesses P. Garnier L. Pouzolles M. Brulin B. Bruschi M. Harcus Y. Zimmermann V.S. Taylor N. Maizels R.M. Jay P. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites Nature 529 2016 226 230 26762460 PMC7614903
  33. [36]Middelhoff M. Westphalen C.B. Hayakawa Y. Yan K.S. Gershon M.D. Wang T.C. Quante M. Dclk1-expressing tuft cells: critical modulators of the intestinal niche? Am J Physiol Gastrointest Liver Physiol 313 2017 G285 G299 28684459 PMC5668570
  34. [37]Saiardi A. Erdjument-Bromage H. Snowman A.M. Tempst P. Snyder S.H. Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases Curr Biol 9 1999 1323 1326 10574768
  35. [38]Anutosh Chakraborty Kim S. Snyder S.H. Inositol pyrophosphates as mammalian cell signals Sci Signal 4 2011 re1 21878680 PMC3667551
  36. [39]Kim E. Beon J. Lee S. Park S.J. Ahn H. Kim M.G. Park J.E. Kim W. Yuk J.-M. Kang S.-J. Lee S.-H. Jo E.-K. Seong R.H. Kim S. Inositol polyphosphate multikinase promotes Toll-like receptor–induced inflammation by stabilizing TRAF6 Sci Adv 3 2017 e1602296 PMC5400429 28439546
  37. [40]Nadjsombati M.S. McGinty J.W. Lyons-Cohen M.R. Jaffe J.B. DiPeso L. Schneider C. Miller C.N. Pollack J.L. Nagana Gowda G.A. Fontana M.F. Erle D.J. Anderson M.S. Locksley R.M. Raftery D. von Moltke J. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit Immunity 49 2018 33 41.e7 30021144 PMC6084797
  38. [41]Lei W. Ren W. Ohmoto M. Urban J.F. Matsumoto I. Margolskee R.F. Jiang P. Activation of intestinal tuft cell-expressed sucnr1 triggers type 2 immunity in the mouse small intestine Proc Natl Acad Sci U S A 115 2018 5552 5557 29735652 PMC6003470
  39. [42]Westphalen C.B. Asfaha S. Hayakawa Y. Takemoto Y. Lukin D. Nuber A. Brandtner A. Setlik W. Remotti H. Muley A. Chen X. May R. Houchen C. Fox J. Gershon M. Quante M. Wang T. Long-lived intestinal tuft cells serve as colon cancer–initiating cells J Clin Invest 124 2014 1283 1295 24487592 PMC3934168
  40. [43]Hayakawa Y. Sakitani K. Konishi M. Asfaha S. Niikura R. Tomita H. Renz B.W. Tailor Y. Macchini M. Middelhoff M. Jiang Z. Tanaka T. Dubeykovskaya Z.A. Kim W. Chen X. Urbanska A.M. Nagar K. Westphalen C.B. Quante M. Lin C.S. Gershon M.D. Hara A. Zhao C.M. Chen D. Worthley D.L. Koike K. Wang T.C. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling Cancer Cell 31 2017 21 34 27989802 PMC5225031
  41. [44]Fernandez Vallone V. Leprovots M. Ribatallada-Soriano D. Gerbier R. Lefort A. Libert F. Vassart G. Garcia M. LGR5 controls extracellular matrix production by stem cells in the developing intestine EMBO 21 2020 e49224 PMC7332981 32468660
  42. [45]Gerbe F. Van Es J.H. Makrini L. Brulin B. Mellitzer G. Robine S. Romagnolo B. Shroyer N.F. Bourgaux J.F. Pignodel C. Clevers H. Jay P. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium J Cell Biol 192 2011 767 780 21383077 PMC3051826
  43. [46]Banerjee A. Herring C.A. Chen B. Kim H. Simmons A.J. Southard-Smith A.N. Allaman M.M. White J.R. Macedonia M.C. Mckinley E.T. Ramirez-Solano M.A. Scoville E.A. Liu Q. Wilson K.T. Coffey R.J. Washington M.K. Goettel J.A. Lau K.S. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation Gastroenterology 159 2020 2101 2115.e5 32828819 PMC7725941
  44. [47]Kjærgaard S. Jensen T.S.R. Feddersen U.R. Bindslev N. Grunddal K.V. Poulsen S.S. Rasmussen H.B. Budtz-Jørgensen E. Berner-Hansen M. Decreased number of colonic tuft cells in quiescent ulcerative colitis patients Eur J Gastroenterol Hepatol 25 2021 817 824 PMC8083166 33079783
  45. [48]Shao L. Oshima S. Duong B. Advincula R. Barrera J. Malynn B.A. Ma A. A20 restricts Wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis PLoS One 8 2013 1 7 PMC3645994 23671587
  46. [49]Jiang H. Lei R. Ding S.W. Zhu S. Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads BMC Bioinformatics 15 2014 1 12 24925680 PMC4074385
  47. [50]Dobin A. Davis C.A. Schlesinger F. Drenkow J. Zaleski C. Jha S. Batut P. Chaisson M. Gingeras T.R. STAR: ultrafast universal RNA-seq aligner Bioinformatics 29 2013 15 21 23104886 PMC3530905
  48. [51]Li B. Dewey C.N. RSEM: accurate transcript quantification from RNA-seq data with or without a reference genome BMC Bioinformatics 12 2011 323 21816040 PMC3163565
  49. [52]Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol 15 2014 1 21 PMC4302049 25516281
  50. [53]Picelli S. Björklund Å.K. Faridani O.R. Sagasser S. Winberg G. Sandberg R. Smart-seq2 for sensitive full-length transcriptome profiling in single cells Nat Methods 10 2013 1096 1100 24056875
  51. [54]Langmead B. Salzberg S.L. Fast gapped-read alignment with Bowtie 2 Nat Methods 9 2012 357 359 22388286 PMC3322381
  52. [57]Hao Y. Hao S. Andersen-Nissen E. Mauck W.M. Zheng S. Butler A. Lee M.J. Wilk A.J. Darby C. Zager M. Hoffman P. Stoeckius M. Papalexi E. Mimitou E.P. Jain J. Srivastava A. Stuart T. Fleming L.M. Yeung B. Rogers A.J. McElrath J.M. Blish C.A. Gottardo R. Smibert P. Satija R. Integrated analysis of multimodal single-cell data Cell 184 2021 3573 3587.e29 34062119 PMC8238499

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Authors
Park, S. E., Lee, D., Jeong, J. W., Lee, S.-H., Park, S. J., Ryu, J., Oh, S. K., Yang, H., Fang, S., & Kim, S.
Affiliations
  • Korea Advanced Institute of Science and Technology (KR)
  • Yonsei University (KR)
  • Vanderbilt University Medical Center (US)
Corresponding author
Kim, Seyun
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2022
Volume
14
Issue
6
Pages
1235-1256
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2022.08.004
PMC
PMC9579329
OpenAlex
W4292681846
Cited by
20
References
3
Citations by year
2026: 2 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 1
FWCI
3.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
  • POSCO TJ Park Foundation
  • National Research Foundation of Korea (NRF-2021R1C1C100791612, 2019R1A6A1A10073887, 2021R1A2C2009749, 2018R1A5A102426121, 2020R1A2C3005765)
  • Korea Advanced Institute of Science and Technology (N11210197)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
inositol polyphosphate multikinase, tuft cells, experimental colitis, DSS-induced colitis, intestinal epithelium, epithelial permeability, intestinal regeneration, inflammatory bowel disease
MeSH terms
Animals, Colitis, Homeostasis, Dextran Sulfate, Phosphotransferases (Alcohol Group Acceptor), Mice

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