Fasting-Mimicking Diet Remodels Neural Responses Associated with Colorectal Cancer Progression

Fasting-mimicking diet (FMD) exerts antitumor effects in multiple cancer types, but the role of neural regulation remains unclear. Here, we investigated the involvement of peripheral and central nervous systems in FMD-mediated suppression of colorectal cancer using a murine MC38 tumor model. Cyclic FMD treatment significantly inhibited tumor growth. Three-dimensional imaging revealed abundant neural fibers within colorectal tumor tissues. To assess the contribution of distinct neural pathways, enteric denervation, vagotomy, sympathetic denervation, and sensory nerve ablation were performed. Enteric denervation markedly attenuated the antitumor effect of FMD, whereas vagal, sympathetic, and sensory denervation had limited impact. In addition, c-Fos immunofluorescence demonstrated region-specific central neural responses to FMD, including increased neuronal activation in the arcuate nucleus and insular cortex and altered activity in the rostral ventrolateral medulla. These findings suggest that neural signaling contributes to the antitumor effects of FMD and implicate enteric nerves in this response. Our study highlights the potential involvement of both peripheral and central neural pathways in the regulation of colorectal cancer progression during dietary intervention.