The Gut Microbiota, Kynurenine Pathway, and Immune System Interaction in the Development of Brain Cancer

Abstract

Human gut microbiota contains a large, complex, dynamic microbial community of approximately 10¹⁴ microbes from more than 1,000 microbial species, i.e., equivalent to 4 × 10⁶ genes. Numerous evidence links gut microbiota with human health and diseases. Importantly, gut microbiota is involved in the development and function of the brain through a bidirectional pathway termed as the gut-brain axis. Interaction between gut microbiota and immune responses can modulate the development of neuroinflammation and cancer diseases in the brain. With respect of brain cancer, gut microbiota could modify the levels of antioxidants, amyloid protein and lipopolysaccharides, arginase 1, arginine, cytochrome C, granulocyte-macrophage colony-stimulating factor signaling (GM-CSF), IL-4, IL-6, IL-13, IL-17A, interferon gamma (IFN-γ), reactive oxygen species (ROS), reactive nitrogen species (e.g., nitric oxide and peroxynitrite), short-chain fatty acids (SCFAs), tryptophan, and tumor necrosis factor-β (TGF-β). Through these modifications, gut microbiota can modulate apoptosis, the aryl hydrocarbon receptor (AhR), autophagy, caspases activation, DNA integrity, microglia dysbiosis, mitochondria permeability, T-cell proliferation and functions, the signal transducer and activator of transcription (STAT) pathways, and tumor cell proliferation and metastasis. The outcome of such interventions could be either oncolytic or oncogenic. This review scrutinizes the oncogenic and oncolytic effects of gut microbiota by classifying the modification mechanisms into (i) amino acid deprivation (arginine and tryptophan); (ii) kynurenine pathway; (iii) microglia dysbiosis; and (iv) myeloid-derived suppressor cells (MDSCs). By delineating the complexity of the gut-microbiota-brain-cancer axis, this review aims to help the research on the development of novel therapeutic strategies that may aid the efficient eradication of brain cancers.

Keywords: 3-dioxygenase-1; anti-tumor T-cells; glioblastoma; gut microbiota; indoleamine 2; kynurenine pathway; myeloid-derived suppressor cells; tryptophan.

FIGURE 1

Interaction between gut microbiota, immune system and tryptophan metabolism in brain tumor development. The gut microbiota can influence the brain tumor cells proliferation and metastasis through direct and indirect regulation of tryptophan and arginine metabolism, inflammatory cytokine production, release of short chain fatty acids, aryl hydrocarbon receptor modulation, microglia maturation, and T cell proliferation. AhR, aryl hydrocarbon receptor; Arg, arginine; ARNT, AhR nuclear translocator; ATF4, activating transcription factor 4; eIF2α, eukaryotic initiation factor 2α (eIF2 α); GCN2, general control nonderepressible-2; HDAC, histone deacetylase; MDSCs, myeloid-derived suppressor cells; ROS, reactive oxygen species; SCFAs, short chain fatty acids; STAT, signal transducer and activator of transcription.

FIGURE 2

Kynurenine pathway, the main route of tryptophan catabolism (Dehhaghi et al., 2019a).