Abstract

Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment.

Key points

• The gastrointestinal tract is continuously renewed by LGR5⁺ intestinal stem cells (ISCs) that reside at the crypt base and are influenced by diet, micronutrients and metabolites.

• LGR5⁺ ISCs exhibit distinct metabolic programmes, particularly in comparison to mature differentiated cell types.

• An obesogenic high-fat diet increases ISC self-renewal through various mechanisms that likely also contribute to increased rates of intestinal tumorigenesis, including peroxisome proliferator-activated receptor signalling pathways and fatty acid oxidation, ceramide production, cholesterol-dependent membrane remodelling and altered bile acid pools.

• Dietary interventions such as caloric restriction, intermittent fasting and a ketogenic diet enhance stem cell function and seem to be beneficial in various intestinal tumour models through increased clonal competition and alterations in fatty acid oxidation, with downstream effects on ketone body metabolism.

• Host diet has effects beyond the intestinal epithelium, with wide-ranging effects on microbial composition, infiltrating immune cells and mesenchymal populations, among others. This, in turn, influences ISC fate decisions and barrier composition.