肥胖是癌症发展方面的可修改性风险因素，尤其对胃肠道癌症而言。虽然结直肠癌的病因已被腺瘤-癌序列彻底描述，但肥胖如何影响结直肠癌的发展仍不清楚。高脂肪饮食中的膳食成分以及肥胖已被证明通过扰乱肠道干细胞的稳态来调节癌症风险，然而肥胖如何影响基因组不稳定性的发展还未研究。突变签名是了解复杂生物反应如何影响基因组稳定性的有力方法。我们利用一种饮食诱导肥胖的小鼠模型，在体内以实验性高脂肪饮食曝光48周后研究了肠道隐窝细胞的突变谱。通过在器官样培养中使单个隐窝衍生细胞克隆富集并获得全基因组序列，我们分析并比较了来自正常饮食和高脂肪饮食小鼠的肠道上皮细胞的突变谱。我们的队列中存在的单核苷酸替代和插入/缺失突变签名在两种饮食组中均表现出相等的活性，并反映了正常衰老、细胞复制以及器官样培养过程中产生的氧化应激等生物过程。因此，我们证明了在没有活化突变或化学暴露的情况下，单纯的高脂肪饮食不足以增加基因组不稳定性。©2023年 Springer Nature Limited.

Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.© 2023. Springer Nature Limited.