Abstract
Accumulating evidence indicates that breakdown of the+ protective mucosal barrier of the gut plays a role in colorectal cancer (CRC) development. Inflammation and oxidative stress in the colonic epithelium are thought to be involved in colorectal carcinogenesis and the breakdown of the integrity of the colonic barrier may increase the exposure of colonocytes to toxins from the colonic milieu, enhancing inflammatory processes and release of Reactive Oxygen Species (ROS). The aetiological importance of the gut microbiome and its composition – influenced by consumption of processed meats, red meats and alcoholic drinks, smoking, physical inactivity, obesity - in CRC development is also increasingly being recognized. The gut microbiome has diverse roles, such as in nutrient metabolism and immune modulation. However, microbial encroachment towards the colonic epithelium may promote inflammation and oxidative stress and even translocation of species across the colonic lumen. Recent research suggests that factors that modify the above mechanisms, e.g., obesity and Western diet, also alter gut microbiota, degrade the integrity of the gut protective barrier, and expose colonocytes to toxins. However, it remains unclear how obesity, lifestyle and metabolic factors contribute to gut-barrier integrity, leading to metabolic disturbance, colonocyte damage, and potentially to CRC development. This review will discuss the interactive roles of gut-barrier dysfunction, microbiome dysbiosis, and exposure to endogenous toxins as another mechanism in CRC development, and how biomarkers of colonic mucosal barrier function may provide avenues for disease, prevention and detection.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer related death and the third most commonly diagnosed in the world, with 1.8 million new cases in 2018 [1]
We summarize the latest findings regarding the protein and metabolite markers of colonic mucosal barrier integrity and how these may provide new insights into colorectal cancer (CRC) pathogenesis and as biomarkers of disease detection and prevention
One hypothesis for the primary role of microbial dysbiosis associated with a leaky gut in the development of several diseases, including CRC, is that the weakness of the gut barrier causes a shift in the microbial community whereon the commensal bacteria within the epithelial cells may become pathogenic by acquiring virulence factors [29]
Summary
Colorectal cancer (CRC) is the second leading cause of cancer related death and the third most commonly diagnosed in the world, with 1.8 million new cases in 2018 [1]. We discuss the dynamic role of colonic mucosal barrier dysfunction (focusing on the mucus layer and epithelial cell lining components of the gut barrier), microbiome dysbiosis, and exposure to endogenous toxins as co-factors in CRC development. Demonstrating the utility of such data, a recent study, using the random forest algorithm, established a novel CRC predictive model able to distinguish cancer from healthy subjects based on gut microbial single nucleotide variant markers [64] Using such integrative, multi-omic approaches that combine tumour molecular features, metagenomic, microbiome/ human metabolomics, proteomics and nutrigenomics, MPE can add novel insights into the tumour pathology and host/microbiome interactions, potentially providing microbiome-modulating strategies for cancer prevention and treatment [65, 66]
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