Microbial Metabolite Dysbiosis and Colorectal Cancer

The global burden of colorectal cancer (CRC) is expected to continuously increase. Through research performed in the past decades, the effects of various environmental factors on CRC development have been well identified. Diet, the gut microbiota and their metabolites are key environmental factors that profoundly affect CRC development. Major microbial metabolites with a relevance for CRC prevention and pathogenesis include dietary fiber-derived short-chain fatty acids, bile acid derivatives, indole metabolites, polyamines, trimethylamine-N-oxide, formate, and hydrogen sulfide. These metabolites regulate various cell types in the intestine, leading to an altered intestinal barrier, immunity, chronic inflammation, and tumorigenesis. The physical, chemical, and metabolic properties of these metabolites along with their distinct functions to trigger host receptors appear to largely determine their effects in regulating CRC development. In this review, we will discuss the current advances in our understanding of the major CRC-regulating microbial metabolites, focusing on their production and interactive effects on immune responses and tumorigenesis in the colon.

Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis

Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article.

Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation

T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.