{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:31:12Z","timestamp":1791894672802,"version":"4.3.4"},"reference-count":116,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined.<\/jats:p>","DOI":"10.3390\/medsci14020202","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:24:51Z","timestamp":1776435891000},"page":"202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["From Chronic Inflammation to Cancer: The Role of Trained Immunity in IBD-Associated Colorectal Carcinogenesis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-7746","authenticated-orcid":false,"given":"Ferenc","family":"Sipos","sequence":"first","affiliation":[{"name":"Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, Szentkir\u00e1lyi Street 46, H-1088 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9099-0372","authenticated-orcid":false,"given":"Gy\u00f6rgyi","family":"M\u0171zes","sequence":"additional","affiliation":[{"name":"Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, Szentkir\u00e1lyi Street 46, H-1088 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Diez-Martin, E., Hernandez-Suarez, L., Mu\u00f1oz-Villafranca, C., Martin-Souto, L., Astigarraga, E., Ramirez-Garcia, A., and Barreda-G\u00f3mez, G. (2024). Inflammatory Bowel Disease: A Comprehensive Analysis of Molecular Bases, Predictive Biomarkers, Diagnostic Methods, and Therapeutic Options. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137062"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hisamatsu, T., Miyoshi, J., Oguri, N., Morikubo, H., Saito, D., Hayashi, A., Omori, T., and Matsuura, M. (2025). Inflammation-Associated Carcinogenesis in Inflammatory Bowel Disease: Clinical Features and Molecular Mechanisms. Cells, 14.","DOI":"10.3390\/cells14080567"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Qu, J., Guo, X., Wang, X., Meng, H., Li, P., and Sun, Z. (2025). The significance of trained immunity in cancer. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1665099"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yang, B., Wu, J., Hou, X., Bai, T., and Liu, S. (2025). Memory in Misfire: The Gut Microbiome-Trained Immunity Circuit in Inflammatory Bowel Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199663"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained immunity: A memory for innate host defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: A program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1042\/CS20171110","article-title":"The intestinal microbiota in the pathogenesis of inflammatory bowel diseases: New insights into complex disease","volume":"132","author":"Harris","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cohen, R.H., Colgan, S.P., and Cartwright, I.M. (2025). Pleiotropic Mucosal Innate Immune Memory in the Gastrointestinal Tract. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262010093"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41422-025-01171-y","article-title":"Trained immunity: Induction of an inflammatory memory in disease","volume":"35","author":"Priem","year":"2025","journal-title":"Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xu, W., Guo, Z., Xu, T., Chen, J., Chen, L., and Xu, W. (2025). Reversing inflammatory diseases via trained immunity: Mechanisms, challenges, and prospects. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1666233"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mousa, R.S., Invernizzi, P., and Mousa, H.S. (2024). Innate immune cells in the pathogenesis of inflammatory bowel disease\u2014From microbial metabolites to immune modulation. Front. Gastroenterol., 3.","DOI":"10.3389\/fgstr.2024.1452430"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alcaraz, J., Keyse, C., Hall, C., Walker, D.W., Doup\u00e9, D.P., and Clark, R.I. (2026). Chronic intestinal immune activation reveals separable impacts of inflammation and barrier loss on hallmarks of ageing. PLoS ONE, 21.","DOI":"10.1371\/journal.pone.0342910"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pavel, C.D., Gales, C., Pavel, I.A., and Zamfir, C.L. (2025). The Relevance of Experimental Models in Assessing the Impact of Oxidative Stress on Intestinal Pathology. J. Clin. Med., 14.","DOI":"10.3390\/jcm14186569"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.neo.2018.05.002","article-title":"Carcinogenesis as a Result of Multiple Inflammatory and Oxidative Hits: A Comprehensive Review from Tumor Microenvironment to Gut Microbiota","volume":"20","author":"Morgillo","year":"2018","journal-title":"Neoplasia"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nishida, A., and Andoh, A. (2025). The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis. Cells, 14.","DOI":"10.3390\/cells14070488"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lu, C., Liu, Y., Ali, N.M., Zhang, B., and Cui, X. (2023). The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1039260"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41392-021-00658-5","article-title":"Inflammation and tumor progression: Signaling pathways and targeted intervention","volume":"6","author":"Zhao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e104920","DOI":"10.7554\/eLife.104920","article-title":"Trained immunity: A new player in cancer immunotherapy","volume":"14","author":"Li","year":"2025","journal-title":"eLife"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Deng, J., and Fleming, J.B. (2022). Inflammation and Myeloid Cells in Cancer Progression and Metastasis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.759691"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1034\/j.1600-065X.2000.917309.x","article-title":"Innate immune recognition: Mechanisms and pathways","volume":"173","author":"Medzhitov","year":"2000","journal-title":"Immunol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev.immunol.23.021704.115526","article-title":"NK cell recognition","volume":"23","author":"Lanier","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1016\/j.jaci.2009.09.017","article-title":"Adaptive immunity","volume":"125","author":"Bonilla","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.cell.2016.09.034","article-title":"\u03b2-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance","volume":"167","author":"Novakovic","year":"2016","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nankabirwa, V., Tumwine, J.K., Mugaba, P.M., Tyllesk\u00e4r, T., and Sommerfelt, H. (2015). PROMISE-EBF Study Group Child survival and BCG vaccination: A community based prospective cohort study in Uganda. BMC Public Health, 15.","DOI":"10.1186\/s12889-015-1497-8"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/jpids\/piy142","article-title":"Maternal Priming: Bacillus Calmette-Gu\u00e9rin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar","volume":"9","author":"Berendsen","year":"2020","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/j.cell.2019.05.024","article-title":"Piwi\/PRG-1 Argonaute and TGF-\u03b2 Mediate Transgenerational Learned Pathogenic Avoidance","volume":"177","author":"Moore","year":"2019","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jurczak, M., and Druszczynska, M. (2025). Beyond Tuberculosis: The Surprising Immunological Benefits of the Bacillus Calmette-Gu\u00e9rin (BCG) Vaccine in Infectious, Auto-Immune, and Inflammatory Diseases. Pathogens, 14.","DOI":"10.3390\/pathogens14020196"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.coi.2020.02.002","article-title":"The epigenetically-encoded memory of the innate immune system","volume":"65","author":"Sun","year":"2020","journal-title":"Curr. Opin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8216","DOI":"10.1038\/s41598-026-39580-7","article-title":"Integrative profiling of transcriptome and H3K27ac modification reveals changes associated with BCG-induced trained immunity in bovine immune cells","volume":"16","author":"Samuel","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"W\u0142odarczyk, M., Druszczy\u0144ska, M., and Fol, M. (2019). Trained Innate Immunity Not Always Amicable. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102565"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100897","DOI":"10.1016\/j.mam.2020.100897","article-title":"Immunometabolic control of trained immunity","volume":"77","author":"Riksen","year":"2021","journal-title":"Mol. Asp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/cr.2015.68","article-title":"Metabolic reprogramming in macrophages and dendritic cells in innate immunity","volume":"25","author":"Kelly","year":"2015","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Darweesh, M., Mohammadi, S., Rahmati, M., Al-Hamadani, M., and Al-Harrasi, A. (2025). Metabolic reprogramming in viral infections: The interplay of glucose metabolism and immune responses. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1578202"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3390\/gastroent15030048","article-title":"Mucosal Immunity and Trained Innate Immunity of the Gut","volume":"15","author":"Velikova","year":"2024","journal-title":"Gastroenterol. Insights"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"McCuaig, B., and Goto, Y. (2023). Immunostimulating Commensal Bacteria and Their Potential Use as Therapeutics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115644"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1316","DOI":"10.1002\/iid3.1316","article-title":"Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor","volume":"12","author":"Tian","year":"2024","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1016\/j.jcmgh.2021.08.021","article-title":"The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease","volume":"12","author":"Yip","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zubair, K., You, C., Kwon, G., and Kang, K. (2021). Two Faces of Macrophages: Training and Tolerance. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111596"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.coi.2019.11.011","article-title":"Gut macrophages: Key players in intestinal immunity and tissue physiology","volume":"62","author":"Muller","year":"2020","journal-title":"Curr. Opin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.mucimm.2024.02.008","article-title":"Epithelial regulation of microbiota-immune cell dynamics","volume":"17","author":"Didriksen","year":"2024","journal-title":"Mucosal Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1111\/febs.16888","article-title":"Interleukin-1 family cytokines at the crossroads of microbiome regulation in barrier health and disease","volume":"291","author":"Walsh","year":"2024","journal-title":"FEBS J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Acevedo, O.A., Berrios, R.V., Rodr\u00edguez-Guilarte, L., Lillo-Dapremont, B., and Kalergis, A.M. (2021). Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.745332"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.immuni.2020.10.011","article-title":"The Intersection of Epigenetics and Metabolism in Trained Immunity","volume":"54","author":"Fanucchi","year":"2021","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"114736","DOI":"10.1016\/j.celrep.2024.114736","article-title":"Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation","volume":"43","author":"Wang","year":"2024","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Anshory, M., Effendi, R.M.R.A., Kalim, H., Dwiyana, R.F., Suwarsa, O., Nijsten, T.E.C., Nouwen, J.L., and Thio, H.B. (2023). Butyrate Properties in Immune-Related Diseases: Friend or Foe?. Fermentation, 9.","DOI":"10.3390\/fermentation9030205"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1111\/lam.13775","article-title":"Deciphering the interdependent labyrinth between gut microbiota and the immune system","volume":"75","author":"Saini","year":"2022","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e70168","DOI":"10.1002\/mco2.70168","article-title":"Gut Microbiota Dysbiosis: Pathogenesis, Diseases, Prevention, and Therapy","volume":"6","author":"Shen","year":"2025","journal-title":"MedComm"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic Induction of Trained Immunity through the Mevalonate Pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1251086","DOI":"10.1126\/science.1251086","article-title":"Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity","volume":"345","author":"Saeed","year":"2014","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bastida, G., M\u00ednguez, A., Nos, P., and Moret-Tatay, I. (2023). Immunoepigenetic Regulation of Inflammatory Bowel Disease: Current Insights into Novel Epigenetic Modulations of the Systemic Immune Response. Genes, 14.","DOI":"10.3390\/genes14030554"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kaminsky, L.W., Al-Sadi, R., and Ma, T.Y. (2021). IL-1\u03b2 and the Intestinal Epithelial Tight Junction Barrier. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.767456"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Andrews, C., McLean, M.H., and Durum, S.K. (2018). Cytokine Tuning of Intestinal Epithelial Function. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01270"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"538988","DOI":"10.2147\/JIR.S538988","article-title":"Bidirectional crosstalk between intestinal epithelium and immune microenvironment in inflammatory bowel disease: Mechanisms and therapeutic implications","volume":"19","author":"Shen","year":"2026","journal-title":"J. Inflamm. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1161\/ATVBAHA.120.315452","article-title":"Trained Immunity and Reactivity of Macrophages and Endothelial Cells","volume":"41","author":"Drummer","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41392-024-01954-6","article-title":"Metabolic regulation of the immune system in health and diseases: Mechanisms and interventions","volume":"9","author":"Hu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11821","DOI":"10.2147\/JIR.S534447","article-title":"Macrophage Metabolic Reprogramming in Inflammatory Bowel Diseases: From Pathogenesis to Therapy","volume":"18","author":"Zhang","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e106610","DOI":"10.7554\/eLife.106610","article-title":"Hematopoietic stem and progenitor cells as a reservoir for trained immunity","volume":"14","author":"Tran","year":"2025","journal-title":"eLife"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.jaci.2024.06.005","article-title":"Central trained immunity and its impact on chronic inflammatory and autoimmune diseases","volume":"154","author":"Hajishengallis","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chen, J., Wang, C., Chen, S., Cai, H., Wang, M., Chang, J., Cai, X., Yang, J., and Cao, P. (2025). Trained immunity modulators: A new frontier in immunoregulation and disease intervention. J. Adv. Res., advance online publication.","DOI":"10.1016\/j.jare.2025.09.029"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Xu, J., Xu, H.M., Yang, M.F., Liang, Y.J., Peng, Q.Z., Zhang, Y., Tian, C.M., Wang, L.S., Yao, J., and Nie, Y.Q. (2022). New Insights Into the Epigenetic Regulation of Inflammatory Bowel Disease. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.813659"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1093\/jimmun\/vkaf135","article-title":"Epigenetic and metabolic regulation of macrophage responsiveness and memory","volume":"214","author":"Daskalaki","year":"2025","journal-title":"J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1093\/ecco-jcc\/jjac194","article-title":"Mass-Cytometry-Based Quantification of Global Histone Post-Translational Modifications at Single-Cell Resolution Across Peripheral Immune Cells in IBD","volume":"17","author":"Bai","year":"2023","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1002\/ibd.22934","article-title":"Epigenetics: Concepts and relevance to IBD pathogenesis","volume":"18","author":"Scarpa","year":"2012","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Appiah, J.K., Hayat, U., Garg, N., Asante, R., Donneyong, E., Haider, M.U., Patel, P., Khan, Z., and Siddiqui, A.A. (2025). Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176119"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"107643","DOI":"10.5662\/wjm.v15.i4.107643","article-title":"Future of inflammatory bowel disease treatment: A review of novel treatments beyond guidelines","volume":"15","author":"Hafez","year":"2025","journal-title":"World J. Methodol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/jcmm.13342","article-title":"Metformin protects against intestinal barrier dysfunction via AMPK\u03b11-dependent inhibition of JNK signalling activation","volume":"22","author":"Deng","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_69","first-page":"655","article-title":"Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK\/mTOR\/NLRP3 inflammasome singling pathway","volume":"11","author":"Qing","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"40981","DOI":"10.1021\/acsomega.5c03232","article-title":"Naringenin Alleviates the Autophagy-Associated AMPK-Akt\/mTOR Pathway to Regulate Inflammation and Barrier Function, Decreasing DSS-Induced Intestinal Fibrosis","volume":"10","author":"Wang","year":"2025","journal-title":"ACS Omega"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.2147\/JIR.S503033","article-title":"Metformin Ameliorates Ulcerative Colitis Through Inhibiting NLRP3 Inflammasome Activation","volume":"18","author":"Cao","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhong, M., Cui, B., Xiang, J., Wu, X., Wen, Q., Li, Q., and Zhang, F. (2021). Rapamycin is Effective for Upper but not for Lower Gastrointestinal Crohn\u2019s Disease-Related Stricture: A Pilot Study. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.617535"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1016\/j.crohns.2014.08.014","article-title":"The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children","volume":"8","author":"Mutalib","year":"2014","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Xu, Q., Zhou, X., Strober, W., and Mao, L. (2021). Inflammasome Regulation: Therapeutic Potential for Inflammatory Bowel Disease. Molecules, 26.","DOI":"10.3390\/molecules26061725"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Cai, B., Qin, X., Huang, X., He, X., Zhong, H., Yu, Y., Cui, J., and Wen, Y. (2025). Molecular mechanisms of dragon\u2019s blood in treating ulcerative colitis based on NF-\u03bab\/NLPR3\/Caspase-1 pyroptosis signaling pathway. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0331570"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.it.2021.11.007","article-title":"The cholesterol pathway: Impact on immunity and cancer","volume":"43","author":"King","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/imb.12900","article-title":"Inhibition of mevalonate pathway by macrophage-specific delivery of atorvastatin prevents their pro-inflammatory polarisation","volume":"33","author":"Ruphuy","year":"2024","journal-title":"Insect Mol. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"19237","DOI":"10.1038\/s41598-025-02418-9","article-title":"Anti-inflammatory effect of fluvastatin on polarized macrophages and its dependence on the mevalonate pathway","volume":"15","author":"Muffova","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1093\/ibd\/izaf077","article-title":"Statin Use is Associated with a Less Severe Disease Course In Inflammatory Bowel Disease: A Nationwide Cohort Study 2006\u20132020","volume":"31","author":"Khalili","year":"2025","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e00940","DOI":"10.1002\/prp2.940","article-title":"2-Deoxy-d-glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation","volume":"10","author":"Uehara","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Burgos-Molina, A.M., T\u00e9llez Santana, T., Redondo, M., and Bravo Romero, M.J. (2024). The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116188"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00384-024-04748-y","article-title":"Inflammatory bowel disease, colitis, and cancer: Unmasking the chronic inflammation link","volume":"39","author":"Shahgoli","year":"2024","journal-title":"Int. J. Color. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41392-024-01953-7","article-title":"Signaling pathways involved in colorectal cancer: Pathogenesis and targeted therapy","volume":"9","author":"Li","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Rembia\u0142kowska, N., Kocik, Z., K\u0142osi\u0144ska, A., K\u00fcbler, M., Pa\u0142kiewicz, A., Rozmus, W., S\u0119dzik, M., Wojciechowska, H., and Gajewska-Naryniecka, A. (2025). Inflammation-Driven Genomic Instability: A Pathway to Cancer Development and Therapy Resistance. Pharmaceuticals, 18.","DOI":"10.3390\/ph18091406"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Triantaphyllopoulos, K.A., Ragia, N.D., Panagiotopoulou, M.E., and Sourlingas, T.G. (2025). Integrating Inflammatory and Epigenetic Signatures in IBD-Associated Colorectal Carcinogenesis: Models, Mechanisms, and Clinical Implications. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202508.1820.v1"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/s41422-020-0332-7","article-title":"Interaction between microbiota and immunity in health and disease","volume":"30","author":"Zheng","year":"2020","journal-title":"Cell Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1097\/CM9.0000000000003617","article-title":"Intestinal dysbiosis and colorectal cancer","volume":"138","author":"Kang","year":"2025","journal-title":"Chin. Med. J."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Lu, S., Wang, C., Ma, J., and Wang, Y. (2024). Metabolic mediators: Microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1456030"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41392-025-02264-1","article-title":"Pattern recognition receptors: Function, regulation and therapeutic potential","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor-associated macrophages: From mechanisms to therapy","volume":"41","author":"Noy","year":"2014","journal-title":"Immunity"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.7150\/ijbs.115515","article-title":"Recent Advances of Trained immunity in Macrophages","volume":"21","author":"Li","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Sun, S., Aguirre-Gamboa, R., and Barreiro, L.B. (2023). Transmission of stimulus-induced epigenetic changes through cell division is coupled to continuous transcription factor activity. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1129577"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"13786","DOI":"10.1074\/jbc.R117.813485","article-title":"Emerging roles of transcriptional enhancers in chromatin looping and promoter-proximal pausing of RNA polymerase II","volume":"293","author":"Meng","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Deng, K., Liang, L., Yang, Y., Wu, Y., Li, Y., Zhang, R., Tian, Y., and Lu, C. (2024). The Wdr5-H3K4me3 Epigenetic Axis Regulates Pancreatic Tumor Immunogenicity and Immune Suppression. Int. J. Mol. Sci., 25.","DOI":"10.21203\/rs.3.rs-4435258\/v1"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Gaggi, G., Hausman, C., Cho, S., Badalamenti, B.C., Trinh, B.Q., Di Ruscio, A., and Ummarino, S. (2025). LncRNAs Ride the Storm of Epigenetic Marks. Genes, 16.","DOI":"10.3390\/genes16030313"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s42003-020-01391-5","article-title":"Tet2 at the interface between cancer and immunity","volume":"3","author":"Jiang","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"111267","DOI":"10.1016\/j.jbc.2026.111267","article-title":"TET2 in epigenetic control of immune cells: Implications for inflammatory responses and age-related pathologies","volume":"302","author":"Obrebski","year":"2026","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Peng, Z., and Saito, S. (2023). Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1176956"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1017\/erm.2024.9","article-title":"Epigenetic tuning of tumour-associated macrophages (TAMs): A potential approach in hepatocellular carcinoma (HCC) immunotherapy","volume":"26","author":"Helal","year":"2024","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13073-025-01511-y","article-title":"Epigenomic preconditioning of peripheral monocytes determines their transcriptional response to the tumor microenvironment","volume":"17","author":"Kiss","year":"2025","journal-title":"Genome Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Larionova, I., Patysheva, M., Iamshchikov, P., Kazakova, E., Kazakova, A., Rakina, M., Grigoryeva, E., Tarasova, A., Afanasiev, S., and Bezgodova, N. (2023). PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1080501"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Bisht, V., Nash, K., Xu, Y., Agarwal, P., Bosch, S., Gkoutos, G.V., and Acharjee, A. (2021). Integration of the Microbiome, Metabolome and Transcriptomics Data Identified Novel Metabolic Pathway Regulation in Colorectal Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115763"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e01333","DOI":"10.1002\/advs.202501333","article-title":"MALMPS: A Machine Learning-Based Metabolic Gene Prognostic Signature for Stratifying Clinical Outcomes and Molecular Heterogeneity in Stage II\/III Colorectal Cancer","volume":"12","author":"Chen","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Schardey, J., Lu, C., Neumann, J., Wirth, U., Li, Q., Jiang, T., Zimmermann, P., Andrassy, J., Bazhin, A.V., and Werner, J. (2023). Differential Immune Infiltration Profiles in Colitis-Associated Colorectal Cancer versus Sporadic Colorectal Cancer. Cancers, 15.","DOI":"10.3390\/cancers15194743"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s40001-022-00720-0","article-title":"Prognostic and tumor immunity implication of inflammatory bowel disease-associated genes in colorectal cancer","volume":"27","author":"Wang","year":"2022","journal-title":"Eur. J. Med. Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Zhou, D., Duan, Z., Li, Z., Ge, F., Wei, R., and Kong, L. (2022). The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1091779"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1097\/CAD.0000000000000472","article-title":"2-Deoxy-D-glucose suppresses the migration and reverses the drug resistance of colon cancer cells through ADAM expression regulation","volume":"28","author":"Park","year":"2017","journal-title":"Anti-Cancer Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e00738","DOI":"10.1002\/adbi.202400738","article-title":"Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment","volume":"9","author":"Li","year":"2025","journal-title":"Adv. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.trecan.2021.04.003","article-title":"Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy","volume":"7","author":"Yang","year":"2021","journal-title":"Trends Cancer"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Lagunas-Rangel, F.A. (2025). Cholesterol effects on the tumor immune microenvironment: From fundamental concepts to mechanisms and implications. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1579054"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41581-022-00633-5","article-title":"Trained immunity\u2014Basic concepts and contributions to immunopathology","volume":"19","author":"Ochando","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41522-026-00912-0","article-title":"Oral microbiota-driven immune modulation along the oral-gut axis: From local signals to systemic inflammation","volume":"12","author":"Li","year":"2026","journal-title":"NPJ Biofilms Microbiomes"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e108276","DOI":"10.7554\/eLife.108276","article-title":"Innate immune memory: The evolving role of macrophages in therapy","volume":"14","author":"Khanna","year":"2025","journal-title":"eLife"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev-immunol-101721-035114","article-title":"Cellular and Molecular Mechanisms of Innate Memory Responses","volume":"43","author":"Mhlanga","year":"2025","journal-title":"Annu. Rev. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e70599","DOI":"10.1002\/mco2.70599","article-title":"Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation","volume":"7","author":"Bao","year":"2026","journal-title":"MedComm"},{"key":"ref_116","first-page":"745","article-title":"Monocyte\/macrophage-mediated trained immunity in disease prevention and immunotherapy","volume":"59","author":"Zhang","year":"2026","journal-title":"Bioact. Mater."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/202\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:11:58Z","timestamp":1777176718000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":116,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["medsci14020202"],"URL":"https:\/\/doi.org\/10.3390\/medsci14020202","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}