Abstract
Accumulating evidence from studies in humans and animal models has elucidated that gut microbiota, acting as a complex ecosystem, contributes critically to colorectal cancer (CRC). The potential mechanisms often reported emphasize the vital role of carcinogenic activities of specific pathogens, but in fact, a series of metabolites produced from exogenous dietary substrates or endogenous host compounds occupy a decisive position similarly. Detrimental gut microbiota-derived metabolites such as trimethylamine-N-oxide, secondary bile acids, hydrogen sulfide and N-nitroso compounds could reconstruct the ecological composition and metabolic activity of intestinal microorganisms and formulate a microenvironment that opens susceptibility to carcinogenic stimuli. They are implicated in the occurrence, progression and metastasis of CRC through different mechanisms, including inducing inflammation and DNA damage, activating tumorigenic signaling pathways and regulating tumor immunity. In this review, we mainly summarized the intimate relationship between detrimental gut microbiota-derived metabolites and CRC, and updated the current knowledge about detrimental metabolites in CRC pathogenesis. Then, multiple interventions targeting these metabolites for CRC management were critically reviewed, including diet modulation, probiotics/prebiotics, fecal microbiota transplantation, as well as more precise measures such as engineered bacteria, phage therapy and chemopreventive drugs. A better understanding of the interplay between detrimental microbial metabolites and CRC would hold great promise against CRC.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide and the morbidity and mortality of colorectal cancer (CRC) are still rising [1]
A convergence of basic research, epidemiological and clinical studies is illuminating the contribution of detrimental gut microbiota-derived metabolites to the initiation and progression of CRC
It is known that the detrimental gut microbiota metabolites contribute to intestinal malignant lesions in numerous ways, most of them have not yet been functionally characterized
Summary
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide and the morbidity and mortality of CRC are still rising [1]. During the development of CRC, tumor-promoting inflammation induced by gut microbiota usually involves the first two, characterized by the exaggerated production of cytokines by resident innate immune cells and the establishment of an immunosuppressive TME [45,46,47]. These proinflammatory mediators interact with epithelia to compromise barrier function and further amplify the response by recruiting and activating additional immune cells.
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