Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Global CRC burden is expected to increase by 60% in the next decade, with low-income countries experiencing an escalation of CRC incidence and mortality in parallel to the adoption of western lifestyles. CRC incidence is also sharply increasing in individuals younger than 50 years, often presenting at advanced stages and with aggressive features. Both genetic and environmental factors have been recognized as major contributors for the development of CRC, the latter including diet-related conditions such as chronic inflammation and obesity. In particular, a diet rich in fat and sugars (Western-style diet, WSD) has been shown to induce multiple pathophysiological changes in the intestine linked to an increased risk of CRC. In this scenario, dietary factors have been recently shown to play novel unexpected roles in the regulation of intestinal stem cells (ISCs) and of the gut microbiota, which represent the two main biological systems responsible for intestinal homeostasis. Furthermore, diet is increasingly recognized to play a key role in the neoplastic transformation of ISCs and in the metabolic regulation of colorectal cancer stem cells. This review illustrates novel discoveries on the role of dietary components in regulating intestinal homeostasis and colorectal tumorigenesis. Particular focus is dedicated to new areas of research with potential clinical relevance including the effect of food components on ISCs and cancer stem cells (CSCs), the existence of CRC-specific microbial signatures and the alterations of intestinal homeostasis potentially involved in early-onset CRC. New insights on the role of dietary factors in intestinal regulation will provide new tools not only for the prevention and early diagnosis of CRC but also for improving the effectiveness of current CRC therapies.

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

“…Several studies have contended that organismal nutritional status, quality of nutrient intake, and different dietary regimens modulate ISC behaviour and regenerative capacity as well as impact the composition and diversity of the gut microbiota. As the roles of dietary factors and host–microbiota crosstalk in intestinal homeostasis and disease have been extensively reviewed [ 167 , 168 , 169 , 170 , 171 , 172 , 173 ], herein we highlight key findings that inform on how nutrients and microbiota contribute to the niche in homeostasis, and how they erode ISC function in tumour progression.…”

“…The gut microbiota—a complex ecosystem of bacteria, archaea, eukaryotes, and viruses that inhabit the intestinal tract—benefit from host nutrient intake and, in turn, influence host metabolism, physiology, nutrition, and immune function. The gut microbiota ferment indigestible by-products of host digestion, such as dietary fibre, and metabolize ingested nutrients, xenobiotics, and bile acids to produce energy, short-chain fatty acids, lactate, various vitamins, and other nutritious metabolites [ 168 , 169 , 170 , 171 , 172 , 173 ].…”

“…Ingested dietary nutrients can, therefore, drastically alter the microbiota landscape and metabolic output. In turn, microbiota-derived metabolites can directly impact ISC function and gut homeostasis in multiple ways [ 168 , 169 , 170 , 171 , 172 , 173 ]. For example, dietary fibre is fermented by commensal bacteria in the colon, generating short-chain fatty acids such as butyrate, a pleiotropic metabolite which functions both as an energy source and an HDAC inhibitor.…”

“…The intestinal microbiota can impact each of these processes in multiple different ways. These include curtailing or promoting inflammation, impairing or reinforcing gut-barrier integrity, perturbing invasive bacterial species from colonizing the gut, influencing the host immune response, generating genotoxins that damage the host DNA, modulating the balance between ISC self-renewal and differentiation, and altering the metabolic milieu (reviewed in [ 167 , 168 , 169 , 170 , 171 , 173 ]). Moreover, dysbiosis—an imbalance of the commensal and pathogenic microbial communities in the gut—has been increasingly recognized as a prelude to colonic inflammation [ 215 ] and a catalyst of inflammation-associated CRC initiation and progression [ 167 , 216 , 217 , 218 , 219 ].…”

Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids

“…The gastrointestinal (GI) tract interacts dynamically with a variety of environmental factors, including different dietary components and ethanol (EtOH). Dietary fats are among the most important factors contributing to intestinal homeostasis and basic functions, and are tightly regulated in order to maintain intestinal health and overall well-being 1 , 2 . Dietary nutrients can also shape the GI microbiota and intestinal immunity 3 .…”