Research Highlights: How Western-Style Diet, Aging, May Impact Cancer Risk in Intestinal Cells

A healthier diet has been associated with reduced risk of a number of diseases, including cancer, but the mechanisms of how that actually works continue to be investigated, including in laboratory and animal studies. The following studies carried out by DCP grantees are looking to understand the process on a molecular level. 

Mice Fed Western-Style Diet Have Increased Tumor Risk

Research has shown that changing dietary patterns trigger complex changes in the body’s intestinal cells, altering health and increasing the risk for some types of cancer. In a recent study, investigators used single cell analyses, coupled with genetic targeting of a key gene, to reveal metabolic reprogramming of intestinal stem cells, and the cells they generate, in mice consuming a Western-style diet, compared to animals fed a healthier control diet, for either 4 days or up to 66-70 days. Findings from the study were published in the journal Molecular Cancer Research.

The researchers fed mice a Western-style diet designed to better reflect such a diet consumed by humans at high risk for tumors, in that it had higher fat, lower calcium, lower vitamin D, lower folate and other methyl donating elements, and lower fiber. They found this caused rapid, reversible early pro-carcinogenic shifts in two major energy-producing pathways—the tricarboxylic acid cycle and oxidative phosphorylation—altering which and how stem cells contribute to intestinal maintenance, and consequently reprogramming early cell development. The metabolic shift was seen in the altered structure of mitochondria in stem cells, the specialized structure within a cell in which these metabolic pathways are carried out.  

Notably, when mice were switched from the Western-style diet to the healthier (lower fat, higher nutrient) control diet, these pathways of energy metabolism recovered normal cell levels in maintaining the intestinal mucosa, the key nutrient-absorbing tissue in the body. These findings suggest that a Western-style dietary pattern reprograms intestinal stem cell physiology and function by promoting intestinal metabolic shifts that favor tumorigenesis. This shifts intestinal cell energy-producing pathways needed to support normal stem cell function, creating an environment favoring abnormal intestinal cell proliferation, delayed developmental maturation of intestinal cells, and tumor development. 

While the study was conducted in mice, and confirmatory studies are needed, the findings provide pre-clinical evidence into possible physiological and cell biophysical-based mechanisms explaining how consuming a Western-style diet might drive intestinal tumorigenesis.  

Reference: Choi J, Zhang X, Li W, Houston M, Peregrina K, Dubin R, Ye K, Augenlicht L. Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis. Mol Cancer Res. 2023; 21(8):808–824.

Diet May Change Effects of Aging in Mouse Intestinal Tract

A companion paper published in Aging Cell by the same laboratory also used single cell analysis to dissect alterations of intestinal stem cells and lineages in aging mice, another fundamental risk factor for intestinal tumor development that is linked to long-term dietary patterns over an organism’s lifespan. The researchers found that as intestinal stem cells developed abnormally, intestinal maturation was delayed, but this delay could be reversed if animals were given metformin or rapamycin, both geroprotectors, a type of drug that can slow the rate of aging and increase the lifespan. 

The researchers found in the two studies that the underlying biochemical and molecular changes in dietary-induced risk and in aging, while overlapping, were not identical. Therefore, a key question under investigation is the potential synergy between nutritional intervention and intervention with geroprotectors in restoring properly regulated cell functions in the mucosa to reduce tumor risk.  

Reference: Choi J, Houston M, Wang R, Ye K, Li W, Zhang X, Huffman DM, Augenlicht LH. Intestinal stem cell aging at single‐cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics. Aging Cell. 2023 May;22(5):e13802.