Gut microbiota changed by tryptophan modulates anti-tumor CTL responses against brain tumor

Abstract

Abstract Glioblastoma multiforme (GBM) is one of the most common brain tumors, and both conventional therapies and current immunotherapies are not effective. Thus, a novel approach is required for GBM treatment. Commensal microbiota reside in the body and are involved in both healthy and disease states of the host. To date, research into the role of microbiota has mainly focused on the gastrointestinal tract. It remains unclear how gut microbes may affect brain and how they may play a role in GBM. Here, we observed a distinct change in gut microbial composition and metabolism during GBM progression using 16S rRNA sequencing in two different animal models. The amount of tryptophan was significantly reduced in GBM-bearing mice. Based on these results, we considered tryptophan supplementation. This diet improved the survival in a commensal microbiota-dependent manner. Surprisingly, some microbiota were restored by tryptophan to levels comparable to those of normal mice. Next, we observed improved survival of GBM-bearing mice co-housed with normal mice. Furthermore, we identified a bacterial species that was present at significantly different levels depending co-housing. Colonization with this bacterium led to increased survival. This bacterium required tryptophan for its growth. Cytotoxic T cells showed more potent immune responses in the tumor microenvironment in tryptophan-supplemented mice and mice colonized with the bacterium. In addition, bacterial metabolites increased apoptosis in glioma tumor cell lines. Collectively, we identified a bacterial species that is critical for defense against GBM and demonstrated that this bacterium potentiates cytotoxic T lymphocyte effector functions and induces the apoptosis of tumor cells.