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

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates T cell function. The aim of this study was to investigate the effects of AhR ligands, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), and 6-Formylindolo[3,2-b]carbazole (FICZ), on gut-associated microbiota and T cell responses during delayed-type hypersensitivity (DTH) reaction induced by methylated bovine serum albumin (mBSA) in a mouse model. Mice with DTH showed significant changes in gut microbiota including an increased abundance of Bacteroidetes and decreased Firmicutes at the phylum level. Also, there was a decrease in Clostridium cluster XIV and IV, which promote anti-inflammatory responses, and an increase in Prevotella copri that facilitates pro-inflammatory responses. Interestingly, treatment of mice with TCDD attenuated the DTH response, induced Tregs, suppressed Th17 cells in the mesenteric lymph nodes (MLNs), and reversed the gut microbiota composition toward normalcy. In contrast, FICZ exacerbated the DTH response, induced heightened Th17 cells, and failed to cause a major shift in gut microbiota. Furthermore, TCDD but not FICZ caused an increase in the levels of short-chain fatty acids (SCFA), n-butyric acid, and acetic acid. Administration of sodium butyrate into mice with DTH suppressed the response, increased Tregs, and reduced Th17 cells IL17. Butyrate also caused an increase in the abundance of Clostridium and a decrease in Prevotella. Lastly, TCDD, as well as butyrate but not FICZ, were able to inhibit proinflammatory Histone deacetylases (HDACs) class I and II. Together, our data suggest that AhR ligands, such as TCDD that suppress DTH response, may mediate this effect by reversing the gut dysbiosis induced during this inflammatory response, while FICZ may fail to suppress the DTH response because of its inability to overturn the dysbiosis.

Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome through Modulation of Microbiome in the Gut-Lung Axis

“…Lymph nodes are considered the site of immune response initiation against pathogens [ 82 ]. Previous studies from our lab have demonstrated the role of MLNs in the modulation of microbiomes [ 35 ]. Another important study has shown that mesenteric lymph nodes significantly attenuated inflammatory biomarkers of the lung to preserve barriers in a septic model of rats [ 83 ].…”

“…The MLN cells were stained using fluorescent conjugated antibodies (anti-CD3 Brilliant Violet 785, anti-CD4 Phycoerythrin (PE), anti-CD8 Alexa Fluor 700, anti-Vβ8 FITC (Fluorescein isothiocyanate), and anti-NK1.1-PE/Dazzle. The staining of cells for dual markers was performed as described previously [ 35 ]. In brief, Fc receptor block was added to the MLN cells which were incubated for 10 min at room temperature, followed by staining of the cells using appropriate antibodies then incubation at 4 °C for 20–30 min.…”

“…The mice were then euthanized on day 2 (48 h after SEB exposure) for further analysis of ARDS. The dose was based on our previous studies [ 35 ].…”

Characteristics of the Gut Microbiome and Its Relationship With Peripheral CD4+ T Cell Subpopulations and Cytokines in Rheumatoid Arthritis

“…Interaction between gut microbiota and the host is important for maintaining immune homeostasis (Chu and Mazmanian, 2013). Gut bacteria have been shown to influence the polarization of lymphocyte subpopulations and their cytokines and thereby regulate immune functions (Abdulla et al, 2021).…”

Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases

“…In addition to the exogenous ligands (2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD), benzo[a]pyrene, β-naphthoflavone, etc. ), that have been examined extensively [ 51 , 52 , 53 , 54 ], many other endogenous and dietary AhR ligands have been identified and show differential properties upon ligand activation [ 55 , 56 ].…”