AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.

Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease

“…TCDD-elicited gut dysbiosis is in agreement with observed effects in published in vivo studies following treatment with endogenous (i.e., FICZ) and exogenous (i.e., TCDD and TCDF) AhR agonists [8,9,11,[28][29][30]. More specifically, we observed an increased Firmicutes/Bacteroides ratio with dose-dependent increases in Lactobacillus species [28,30].…”

“…However, responses in various AhR models are in agreement regarding increased secondary bile acids [8,9] and effects on segmented filamentous bacteria [8,11,27]. AhR knockout models, and treatment with TCDD or other endogenous compounds also demonstrate strong correlations between AhR activation and enrichment of Lactobacillus species, i.e., L. reuteri [26][27][28][29][30]. Tryptophan catabolism to AhR ligands by Lactobacillus species is a proposed mechanism for gut microbial regulation of AhR signaling that modulates intestinal and gut microbiome homeostasis [26].…”

The Ability of AhR Ligands to Attenuate Delayed Type Hypersensitivity Reaction Is Associated With Alterations in the Gut Microbiota

“…Recently, several studies, including those from our laboratory, have shown that AhR plays a vital and important role in maintaining intestinal homeostasis, both when conditions are healthy and when not ( 58 – 62 ). In the current study, we noted that not only did the gut microbiota alter following DTH induction but also caused further changes in the microbiota in the administration of AhR ligands.…”

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

“…Intrahepatic cholangiocarcinoma patient data also support the role of bacteria in tumor progression, which shows that those with lower expression of TLR4 have longer overall survival [127]. Gut dysbiosis that occurs after exposure to the carcinogenic compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also leads to an accumulation of MDSCs in the peritoneal cavity of mice [128].…”