Suppression of local type I interferon by gut microbiota–derived butyrate impairs antitumor effects of ionizing radiation

Abstract

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

“…Clinical and experimental evidence suggest gut bacteria play a pivotal role in governing immune responses during IBD. For instance, the bacterial metabolite, butyrate, has been demonstrated to suppress the expression of type I IFN genes in DCs by preventing phosphorylation of TBK1 and IRF3, suggesting one mechanism by which the microbiota can attenuate type I IFN function (21). Moreover, glycolipids from commensal Bacteroides have been reported to promote anti-viral function via IFNβ expression in DCs (22).…”

Microbiota-Associated Metabolites and Related Immunoregulation in Colorectal Cancer

“…Indeed, butyrate can either enhance or dampen tumor-suppressive responses depending on a specific treatment. For example, in both MC38 and B16F1 tumor models, butyrate abrogated the anti-cancer effect of ionizing radiation by inhibiting the upregulation of STING-activated IFN-I in DCs, which is required for tumor-specific cytotoxic T cell function [56]. As we discussed earlier, SCFAs represented by butyrate could facilitate the differentiation towards functional Tregs, which are potent anti-inflammatory cells, to suppress the chronic inflammation and subsequent tumorigenesis [43].…”

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model

“…The cell cycle may subsequently be shortened and proliferation may be accelerated. 27 In this manner, the immune function of the body was improved. Compared with the control group, the spleen index of the rabbits in the 75-mGy group was significantly higher (P < 0.05).…”