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.
Highlights
More than 2000 years ago Hippocrates, the father of modern medicine, stated that all the diseases begin in the gut
This review summarizes a number of studies that contributed to shed light on the mechanisms linking dietary components to alterations of the main biological systems responsible for intestinal health, eventually leading to altered homeostasis and Colorectal cancer (CRC)
Supplementation of high fat diet (HFD) with glucose resulted in inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and reverted the favourable effects of ketogenic diet [42]. These findings reveal how diet-mediated control of βOHB signalling in intestinal stem cells (ISCs) helps to fine-tune stem cell adaptation during intestinal homeostasis and injury
Summary
More than 2000 years ago Hippocrates, the father of modern medicine, stated that all the diseases begin in the gut. Besides eliciting transient adaptive responses in ISCs, HFD increases the tumorigenicity of intestinal progenitors [9,15] These observations are in line with several epidemiological studies showing that different diets are able to modulate the risk of intestinal cancer development [17,18]. A crucial issue in studies investigating the effects of dietary factors concerns the level of carbohydrates associated to a fat-rich diet, either in humans or in animal models [41]. Supplementation of HFD with glucose resulted in inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) (which produced beneficial ketone bodies) and reverted the favourable effects of ketogenic diet [42] These findings reveal how diet-mediated control of βOHB signalling in ISCs helps to fine-tune stem cell adaptation during intestinal homeostasis and injury. Keeping in mind the complex challenges related to the investigation of dietary factors will help the interpretation of sometimes contrasting results in molecular and epidemiological studies linking diet and cancer
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