Shay, J. E. S. & Yilmaz, ÖH. Dietary and metabolic effects on intestinal stem cells in health and disease. Nat. Rev. Gastroenterol. Hepatol. 22, 23–38 (2025).
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
Lien, E. C. & Heiden, M. G. V. A framework for examining how diet impacts tumour metabolism. Nat. Rev. Cancer 19, 651–661 (2019).
Jagelman, D. G., Decosse, J. J., Bussey, H. J. R. & The Leeds Castle Polyposis Group. Upper gastrointestinal cancer in familial adenomatous polyposis. Lancet 331, 1149–1151 (1988).
Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A. & Speizer, F. E. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N. Engl. J. Med. 323, 1664–1672 (1990).
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Mehta, R. S. et al. Dietary patterns and risk of colorectal cancer: analysis by tumor location and molecular subtypes. Gastroenterology 152, 1944–1953 (2017).
Zaborowski, A. M. et al. Characteristics of early-onset vs late-onset colorectal cancer. JAMA Surg. 156, 865 (2021).
GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).
Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).
Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935 (2021).
Mana, M. D. et al. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell Rep. 35, 109212 (2021).
DeClercq, V., McMurray, D. N. & Chapkin, R. S. Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Lett. 369, 336–343 (2015).
Wasan, H. S., Novelli, M., Bee, J. & Bodmer, W. F. Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice. Proc. Natl Acad. Sci. USA 94, 3308–3313 (1997).
Newmark, H. L. et al. A Western-style diet induces benign and malignant neoplasms in the colon of normal C57BL/6 mice. Carcinogenesis 22, 1871–1875 (2001).
Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778 (2018).
Cheng, C.-W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131 (2019).
Pak, H. H. et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nat. Metab. 3, 1327–1341 (2021).
Bruens, L. et al. Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine. Cell Rep. 32, 107937 (2020).
Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(min) mice through different mechanisms. Cancer Res. 63, 1752–1755 (2003).
Mitchell, S. J. et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 29, 221–228 (2019).
Yilmaz, ÖH. et al. MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
Imada, S. et al. Short-term post-fast refeeding enhances intestinal stemness via polyamines. Nature 633, 895–904 (2024).
Roberts, M. N. et al. Short article. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546 (2017).
Newman, J. C. & Verdin, E. β-Hydroxybutyrate: a signaling metabolite. Ann. Rev. Nutrit. 37, 51–76 (2017).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Dmitrieva-Posocco, O. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022).
Nugent, K. P., Spigelman, A. D. & Phillips, R. K. S. Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis. Colon Rectum 36, 1059–1062 (1993).
Groves, C. J., Saunders, B. P., Spigelman, A. D. & Phillips, R. K. S. Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 50, 636 (2002).
Weiss, J. M. et al. NCCN Guidelines® insights: genetic/familial high-risk assessment: colorectal, version 1.2021. J. Natl Compr. Cancer Netw. 19, 1122–1132 (2021).
Karstensen, J. G. et al. Cancer in patients with familial adenomatous polyposis: a nationwide Danish cohort study with matched controls. Gastroenterology 165, 573–581 (2023).
Taylor, S. R., Falcone, J. N., Cantley, L. C. & Goncalves, M. D. Developing dietary interventions as therapy for cancer. Nat. Rev. Cancer 22, 452–466 (2022).
Goto, N. et al. Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury. Cell Stem Cell 29, 1246–1261 (2022).
Gao, R. et al. Integrated analysis of colorectal cancer reveals cross-cohort gut microbial signatures and associated serum metabolites. Gastroenterology 163, 1024–1037 (2022).
Aliluev, A. et al. Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice. Nat. Metab. 3, 1202–1216 (2021).
Tsenkova, M. et al. Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate. Nat. Commun. 16, 1792 (2025).
Müller-Dott, S. et al. Expanding the coverage of regulons from high-confidence prior knowledge for accurate estimation of transcription factor activities. Nucleic Acids Res. 51, 10934–10949 (2023).
Shou, J. et al. Minimum dietary fat threshold for effective ketogenesis and obesity control in mice. Nutrients 17, 3203 (2025).
Yeh, C. et al. Ketogenesis is dispensable for the metabolic adaptations to caloric restriction. Aging Cell 25, e70318 (2026).
Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).
Xia, S. et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 25, 358–373 (2017).
Lien, E. C. et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature 599, 302–307 (2021).
Vieira, R. F. et al. Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth. Cancer Metab. 13, 39 (2025).
Colnot, S. et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab. Investig. 84, 1619–1630 (2004).
Marjou, F. E. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004).
Horton, J. L. et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 4, e124079 (2019).
Cotter, D. G., Schugar, R. C., Wentz, A. E., D’Avignon, D. A. & Crawford, P. A. Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation. Am. J. Physiol. Endocrinol. Metabol. 304, E363–E374 (2013).
Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).
Hsieh, W.-Y., Williams, K. J., Su, B. & Bensinger, S. J. Profiling of mouse macrophage lipidome using direct infusion shotgun mass spectrometry. STAR Protoc. 2, 100235 (2021).
Su, B. et al. A DMS shotgun lipidomics workflow application to facilitate high-throughput, comprehensive lipidomics. J. Am. Soc. Mass. Spectrom. 32, 2655–2663 (2021).
Korotkevich, G. et al. Fast gene set enrichment analysis. Preprint at bioRxiv https://doi.org/10.1101/060012 (2021).