With its unique cellular plasticity, the small intestinal mucosa exhibits efficient adaptability upon feeding. However, little is known about the effect of high-fat diet (HFD) feeding on this adaption and its underlying mechanism. Herein, we demonstrated that the cell proliferation ability, mitochondrial morphology, and global transcriptomic profile of the small intestine exhibited a prominent discrepancy between the fasted and refed state in mice, which were markedly attenuated by long-term HFD feeding. The retinol (Vitamin A, VA) metabolism pathway was dramatically affected by HFD feeding in the small intestine. Both VA and its active metabolite retinoic acid (RA), with the administration of lipid micelles, promoted the expression of genes involved in lipid absorption and suppressed the expression of genes involved in the cell proliferation of intestinal organoids. Via chip-qPCR and RT-qPCR, genes involved in lipid metabolism and cell proliferation were target genes of RARα/RXRα in small intestinal organoids treated with RA and lipid micelles. The role of VA in the in vivo attenuation of intestinal adaptability, in response to HFD, was evaluated. Mice were fed a normal chow diet, HFD, or HFD diet supplemented with additional 1.5-fold VA for 12 weeks. VA supplementation in HFD accelerated the attenuation of intestinal adaptability upon feeding induced by HFD, promoted lipid absorption gene expression, and increased body weight and serum cholesterol levels. In conclusion, the discrepancy of the small intestine between the fasted and refed state was dramatically attenuated by HFD feeding, in which VA and RA might play important roles.

小肠粘膜以其独特的细胞可塑性，在摄食时表现出高效的适应性。然而，人们对高脂饮食（HFD）对这种适应的影响及其潜在机制知之甚少。在此，我们证明，小鼠的细胞增殖能力、线粒体形态和小肠的整体转录组谱在禁食和进食状态之间表现出显着的差异，而长期高脂饮食会显着减弱这种差异。视黄醇（维生素 A、VA）代谢途径受到小肠中 HFD 喂养的显着影响。 VA及其活性代谢物视黄酸（RA）在脂质胶束的作用下，促进了参与脂质吸收的基因的表达，并抑制了参与肠道类器官细胞增殖的基因的表达。通过芯片qPCR和RT-qPCR，在用RA和脂质胶束处理的小肠类器官中，参与脂质代谢和细胞增殖的基因是RARα/RXRα的靶基因。评估了 VA 在响应 HFD 的体内肠道适应性减弱中的作用。给小鼠喂食正常食物、HFD 或添加 1.5 倍 VA 的 HFD 饮食，持续 12 周。 HFD中添加VA加速了HFD诱导的肠道适应性减弱，促进脂质吸收基因表达，增加体重和血清胆固醇水平。总之，HFD 喂养大大减弱了禁食和进食状态之间小肠的差异，其中 VA 和 RA 可能发挥重要作用。