Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

Abstract

The substantial burden of colorectal cancer and increasing trend in young adults highlight the importance of lifestyle modification as a complement to screening for colorectal cancer prevention. Several dietary and lifestyle factors have been implicated in the development of colorectal cancer, possibly through the intricate metabolic and inflammatory mechanisms. Likewise, as a key metabolic and immune regulator, the gut microbiota has been recognized to play an important role in colorectal tumorigenesis. Increasing data support that environmental factors are crucial determinants for the gut microbial composition and function, whose alterations induce changes in the host gene expression, metabolic regulation, and local and systemic immune response, thereby influencing cancer development. Here, we review the epidemiologic and mechanistic evidence regarding the links between diet and lifestyle and the gut microbiota in the development of colorectal cancer. We focus on factors for which substantial data support their importance for colorectal cancer and their potential role in the gut microbiota, including overweight and obesity, physical activity, dietary patterns, fiber, red and processed meat, marine omega-3 fatty acid, alcohol, and smoking. We also briefly describe other colorectal cancer-preventive factors for which the links with the gut microbiota have been suggested but remain to be mechanistically characterized, including vitamin D status, dairy consumption, and metformin use. Given limitations in available evidence, we highlight the need for further investigations in the relationship between environmental factors, gut microbiota, and colorectal cancer, which may lead to development and clinical translation of potential microbiota-based strategies for cancer prevention.

Keywords: Chemoprevention; Clinical Trial; Nutrition; Young-Onset Colorectal Cancer.

Conflict of interest statement

Conflict of interest

Andrew T. Chan previously served as a consultant for Bayer Pharma AG, Pfizer Inc., Janssen, for work unrelated to the topic of this manuscript. This study was not funded by Bayer Pharma AG, or Pfizer Inc. No other conflict of interest exists.

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Framework for the interplay between diet and gut microbiota in colorectal cancer through influences on the host metabolism and immunity. Diet is a major determinant of the gut microbial community structure, whereas some bacteria in the gut are important for processing and synthesis of certain nutrients. The interaction between diet and gut microbiota may influence colorectal carcinogenesis through alterations in the host metabolism and immune system.

Figure 2.

Gut microbiota-related mechanisms through which obesity may increase risk of colorectal cancer. Obesity-induced changes in the gut microbiota lead to 1) increased levels of microbial-derived proinflammatory molecules that disrupt the gut barrier function; 2) epigenetic remodeling and modification of the gene expression in colonic epithelial cells; 3) alterations in the gut microbial metabolites that can cause DNA damage and dampen antitumor immunity. LPS, Lipopolysaccharides; PGE2, Prostaglandin E2.

Figure 3.

Potential benefits of short-chain fatty acids that may contribute to the anticancer effects of fiber. Short-chain fatty acids may epigenetically modulate expression of numerous cancer-related genes through inhibition of the activity of histone deacetylase, suppress inflammation by interaction with the G protein-coupled receptors (e.g., GPR43, GPR109a) at the colonic epithelial cell surface, and support intestinal immune homeostasis by modulation of the function of regulatory T cells.

Figure 4.

Potential role of the gut microbiota in mediating the effect of carcinogenic factors in red meats. Heme iron may damage the mucus barrier function by increasing the abundance of mucin-degrading bacteria (e.g., Akkermansia muciniphila). Increased production of secondary bile acids associated with high red meat consumption can promote carcinogenesis through increased oxidative stress and regulation of host metabolism. Excess production of hydrogen sulfide by sulfur-reducing bacteria in the colon may promote carcinogenesis through DNA damage, impaired colonocyte nutrition, reduced integrity of the mucus layer, induction of epithelial hyperproliferation, and increased inflammation.

Figure 5.

Pathways linking marine omega-3 fatty acid, gut microbiota, and immune function in colorectal cancer. Marine omega-3 fatty acid increases the abundance of Bifidobacterium and Lactobacillus genera and reduces the abundance of Fusobacterium nucleatum and lipopolysaccharide (LPS)-producing bacteria (e.g., Escherichia coli), possibly by altering the production of microbiota regulators (e.g., intestinal alkaline phosphatase [IAP]) via changes in tissue lipid mediators (e.g., resolvin) or by modifying the gut environmental conditions that in turn confer selective pressure on the microbial community. The changes in the microbial composition can, either directly or indirectly via microbial metabolites (e.g., hydroxyl fatty acids and short-chain fatty acids), help preserve intestinal immune homeostasis and protect against colorectal cancer, whereas some immune factors can conversely affect the makeup of the microbiota, promoting a reciprocal host-microbe interaction.