Abstract
Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.
Highlights
These results indicate that microbiota are capable of producing biologically relevant levels of indoles, and inducing changes in innate and adaptive immune response that may be important in colon cancer pathogenesis
We present the following therapeutic modalities to be considered for study as interventions among individuals with colorectal cancer (CRC) and high IDO1 or aryl hydrocarbon receptor (AhR) expression, and discuss the current understanding and opportunities for future research around Trp metabolism and indole production for therapeutic intervention in CRC
It is well established that overexpression of oncogene, c-Myc, which is evident in about 70% of all colon cancer cases [186,187,188], is an important metabolic reprogramming in colon cancer initiation and progression [189,190]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Trp is required for protein and niacin biosynthesis and is a precursor of serotonin and melatonin Apart from these fundamental functions, Trp is appreciated for its influence on both host and microbial metabolism via two distinct pathways: the Kynurenine (Kyn) Pathway and Indolic Pathway. Downstream metabolites (Figure 1) via the Kyn pathway These metabolites include Lkynurine acid, 3-hydroxykynurine, anthralinic acid, quinolinic acid, 3-hydroxyanthralininc acid, picolinic acid, most of which produce NAD+ and ATP in host cells, and play a vital role in inflammation, immune tolerance, and neurotransmission [5,9,10,11]. A ligand for serotonin receptors, can affect gut motility and transit time, downstream metabolites These metabolites include the abundance of such receptors in the GI tract [23]. About 4–6% of unabsorbed Trp moves along the gastrointestinal tract and is metabolized by thePathway microbiome indole and indolic compounds including indole-3
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