{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:02:59Z","timestamp":1790758979025,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Colorectal cancer (CRC) is traditionally viewed as the result of the sequential accumulation of molecular alterations and the clonal expansion of transformed cells. However, the state of morphologically non-neoplastic mucosa preceding the development of neoplasia remains considerably less well characterized. This narrative review aims to integrate evidence on biliary and lipid metabolism, intestinal transit, microbial metabolism, and field cancerization and to formulate a testable model of early metabolic remodeling in the distal colon. We propose that a chronically altered biliary\u2013metabolic environment, combined with prolonged luminal and mucosa-associated exposure, may promote lipid\u2013metabolic remodeling of morphologically non-neoplastic mucosa. This state is considered not as a new disease entity but as a potential tissue phenotype capable of altering the barrier, metabolic, and regenerative properties of the epithelium. Subsequent exposure to nitrogen-containing products of microbial metabolism may sustain repeated cycles of injury and regeneration, thereby creating conditions for clonal selection. Following the emergence of a neoplastic clone, the same local environment may potentially assume a different biological role and become part of a metabolic niche that supports further clonal expansion. The proposed model extends the concept of field cancerization by incorporating a metabolic dimension and generates a series of spatial and temporal predictions amenable to experimental and prospective clinical testing. Validation of this model may provide a basis for investigating morphologically non-neoplastic mucosa as potential tissue at risk and for developing earlier preventive and diagnostic approaches.<\/jats:p>","DOI":"10.3390\/cancers18193160","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:17:27Z","timestamp":1790756247000},"page":"3160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Bile Dysmetabolism to Lipid\u2013Metabolic Remodeling of the Distal Colon: A Vectorial Concept of Colorectal Carcinogenesis (Part I)"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4792-4353","authenticated-orcid":false,"given":"Maria A.","family":"Sukhanova","sequence":"first","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1938-9481","authenticated-orcid":false,"given":"Zakhar A.","family":"Akulov","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4335-3987","authenticated-orcid":false,"given":"Zelimkhan G. M.","family":"Berikkhanov","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey L.","family":"Shestakov","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksey G.","family":"Kotelnikov","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey M.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7802-4588","authenticated-orcid":false,"given":"Vadim S.","family":"Razumovsky","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1847-711X","authenticated-orcid":false,"given":"Evgeniy A.","family":"Tarabrin","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-6230","authenticated-orcid":false,"given":"Milena Yu.","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrshad","family":"Ebrahimnezhad","sequence":"additional","affiliation":[{"name":"Cardiology Department No. 2, Yudin City Hospital of Moscow, The Patrice Lumumba Peoples\u2019 Friendship University of Russia (RUDN), Moscow 117198, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1493-0351","authenticated-orcid":false,"given":"Sergey Yu.","family":"Muraviev","sequence":"additional","affiliation":[{"name":"Department of Hospital Surgery No. 2, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41575-019-0230-y","article-title":"Epigenetics of colorectal cancer: Biomarker and therapeutic potential","volume":"17","author":"Jung","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00210","DOI":"10.14309\/ctg.0000000000000210","article-title":"Oncogenic features in histologically normal mucosa: Novel insights into field effect from a mega-analysis of colorectal transcriptomes","volume":"11","author":"Dampier","year":"2020","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1158\/1940-6207.CAPR-22-0258","article-title":"Epigenome-wide study identifies epigenetic outliers in normal mucosa of patients with colorectal cancer","volume":"15","author":"Ghosh","year":"2022","journal-title":"Cancer Prev. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s12943-024-02159-9","article-title":"Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies","volume":"23","author":"Ikuta","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mukund, K., Syulyukina, N., Ramamoorthy, S., and Subramaniam, S. (2020). Right and left-sided colon cancers\u2014Specificity of molecular mechanisms in tumorigenesis and progression. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-06784-7"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"G361","DOI":"10.1152\/ajpgi.00283.2019","article-title":"Distal colonic transit is linked to gut microbiota diversity and microbial fermentation in humans with slow colonic transit","volume":"318","author":"Hermes","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.7150\/ijbs.52452","article-title":"The association of metabolic syndrome and its components with the incidence and survival of colorectal cancer: A systematic review and meta-analysis","volume":"17","author":"Han","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Liu, Y., Zhang, S., Zhou, W., Hu, D., Xu, H., and Ji, G. (2022). Secondary bile acids and tumorigenesis in colorectal cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.813745"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Salita, T., Rustam, Y.H., Mouradov, D., Sieber, O.M., and Reid, G.E. (2022). Reprogrammed lipid metabolism and the lipid-associated hallmarks of colorectal cancer. Cancers, 14.","DOI":"10.3390\/cancers14153714"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"108212","DOI":"10.1016\/j.celrep.2020.108212","article-title":"Genetic and microbial associations to plasma and fecal bile acids in obesity relate to plasma lipids and liver fat content","volume":"33","author":"Chen","year":"2020","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1053\/j.gastro.2021.08.041","article-title":"High-fat diet promotes colorectal tumorigenesis through modulating gut microbiota and metabolites","volume":"162","author":"Yang","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12964-022-00890-8","article-title":"Cholecystectomy promotes colon carcinogenesis by activating the Wnt signaling pathway by increasing the deoxycholic acid level","volume":"20","author":"Yao","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.immuni.2024.02.014","article-title":"Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions","volume":"57","author":"Cong","year":"2024","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.semcancer.2020.10.003","article-title":"Dietary fat, bile acid metabolism and colorectal cancer","volume":"73","author":"Ocvirk","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"s4","DOI":"10.5604\/01.3001.0010.5493","article-title":"Bile Acid Physiology","volume":"16","author":"Garruti","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1194\/jlr.TR119000439","article-title":"Lipid rafts as signaling hubs in cancer cell survival\/death and invasion: Implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts","volume":"61","author":"Mollinedo","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41580-018-0085-z","article-title":"Dynamics and functions of lipid droplets","volume":"20","author":"Olzmann","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41392-022-01119-3","article-title":"Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver\/steatohepatitis (NAFL\/NASH)","volume":"7","author":"Xu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S216","DOI":"10.1093\/ajcn\/31.10.S216","article-title":"Diet and cell growth modulation by ammonia","volume":"31","author":"Visek","year":"1978","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1158\/1940-6207.CAPR-22-0469","article-title":"Clonal evolution in healthy and premalignant tissues: Implications for early cancer interception strategies","volume":"16","author":"Rane","year":"2023","journal-title":"Cancer Prev. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sphyris, N., Hodder, M.C., and Sansom, O.J. (2021). Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell. Cancers, 13.","DOI":"10.3390\/cancers13051000"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20837","DOI":"10.1038\/s41598-024-69570-6","article-title":"Gradient-induced instability in tumour spheroids unveils the impact of microenvironmental nutrient changes","volume":"14","author":"Ascione","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Br\u00e1s, M.M., Sousa, S.R., Carneiro, F., Radmacher, M., and Granja, P.L. (2022). Mechanobiology of colorectal cancer. Cancers, 14.","DOI":"10.3390\/cancers14081945"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/path.70087","article-title":"Tumor Invasive Border Index (TIBI) in colorectal cancer: Linking infiltrative morphology to molecular insights","volume":"270","author":"Kehusmaa","year":"2026","journal-title":"J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13045-022-01358-5","article-title":"Warburg effect in colorectal cancer: The emerging roles in tumor microenvironment and therapeutic implications","volume":"15","author":"Zhong","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"C1073","DOI":"10.1152\/ajpcell.00139.2021","article-title":"Intratumoral metabolic heterogeneity of colorectal cancer","volume":"325","author":"Hirose","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Janssen, K.P., Basic, M., Bolsega, S., Metwaly, A., Jokisch, F., von Gamm, S., Scheiber, J., Burkhardt, R., Liebisch, G., and Neuhaus, K. (2026). Extrinsic lipids are absorbed and accumulate in colorectal cancer. Gut.","DOI":"10.1136\/gutjnl-2025-336377"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.tcb.2020.02.005","article-title":"Nitrogen metabolism in cancer and immunity","volume":"30","author":"Kurmi","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"mjaf007","DOI":"10.1093\/jmcb\/mjaf007","article-title":"Novel roles of ammonia in physiology and cancer","volume":"17","author":"Chen","year":"2025","journal-title":"J. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2205563","DOI":"10.1002\/advs.202205563","article-title":"Role of the gut microbiota and its metabolites in tumorigenesis or development of colorectal cancer","volume":"10","author":"Qu","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1874815","DOI":"10.1080\/19490976.2021.1874815","article-title":"Spatial analysis of gut microbiome reveals a distinct ecological niche associated with the mucus layer","volume":"13","author":"Duncan","year":"2021","journal-title":"Gut Microbes"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Coleman, O.I., and Haller, D. (2021). Microbe-mucus interface in the pathogenesis of colorectal cancer. Cancers, 13.","DOI":"10.3390\/cancers13040616"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00432-022-04422-2","article-title":"Implication of gut microbes and its metabolites in colorectal cancer","volume":"149","author":"Kumar","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Snelson, M., and Coughlan, M.T. (2019). Dietary advanced glycation end products: Digestion, metabolism and modulation of gut microbial ecology. Nutrients, 11.","DOI":"10.3390\/nu11020215"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41575-019-0250-7","article-title":"Regulation of intestinal lipid metabolism: Current concepts and relevance to disease","volume":"17","author":"Ko","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13525","DOI":"10.3390\/ijms140713525","article-title":"Colorectal carcinogenesis: A cellular response to sustained risk environment","volume":"14","author":"Fung","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Blachier, F. (2023). Amino acid-derived bacterial metabolites in the colorectal luminal fluid: Effects on microbial communication, metabolism, physiology, and growth. Microorganisms, 11.","DOI":"10.3390\/microorganisms11051317"},{"key":"ref_38","first-page":"100195","article-title":"What we know about protein gut metabolites: Implications and insights for human health and diseases","volume":"13","year":"2021","journal-title":"Food Chem. X"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1136\/gutjnl-2011-300865","article-title":"Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum","volume":"61","author":"Yamauchi","year":"2012","journal-title":"Gut"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Halama, A., and Suhre, K. (2022). Advancing cancer treatment by targeting glutamine metabolism\u2014A roadmap. Cancers, 14.","DOI":"10.3390\/cancers14030553"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nicolini, A., and Ferrari, P. (2024). Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1353787"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"458","DOI":"10.14309\/ajg.0000000000001122","article-title":"ACG Clinical Guidelines: Colorectal Cancer Screening 2021","volume":"116","author":"Shaukat","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4568","DOI":"10.1038\/s41467-026-71136-1","article-title":"IL-22 induces Paneth cell metaplasia in the colonic epithelium of ulcerative colitis, promoting wound healing via REG3A","volume":"17","author":"Muto","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"415","DOI":"10.14309\/ajg.0000000000000544","article-title":"Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer","volume":"115","author":"Gupta","year":"2020","journal-title":"Am. J. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s12276-025-01599-7","article-title":"Colorectal microenvironment determines the prognosis of colorectal cancer","volume":"58","author":"Bang","year":"2026","journal-title":"Exp. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e0001822","DOI":"10.1128\/msystems.00018-22","article-title":"Surgical Treatment for Colorectal Cancer Partially Restores Gut Microbiome and Metabolome Traits","volume":"7","author":"Shiroma","year":"2022","journal-title":"mSystems"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:30:33Z","timestamp":1790757033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":46,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193160"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193160","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}