The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

Dong, Fangcong; Perdew, Gary H.

doi:10.1080/19490976.2020.1859812

Cited by 89 publications

(74 citation statements)

References 139 publications

(171 reference statements)

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“…Although AhR may affect immunity and inflammation by acting through the different branches of the innate and adaptive immune system [ 3 ], an interesting observation of the present study points to AhR agonists as capable of affecting inflammation indirectly, through an action on the local microbiota composition. Consistent with the ability of AhR to mediate the host–microbiota interplay [ 41 ], AhR-deficient mice have indeed an increased abundance of Verrucomicrobia and segmented filamentous bacteria in the gut, which is directly linked to elevated intestinal inflammation and promotion of Th17 differentiation [ 42 ]. We found that 3-IAld affected the airway and gut microbial composition in CF mice by decreasing the expansion of Proteobacteria, which are known to contribute to inflammatory pathology in CF [ 43 ], while increasing the expansion of Firmicutes and Bacteroidetes.…”

Section: Discussionmentioning

confidence: 93%

Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Puccetti

Pariano

Renga

et al. 2021

Cells

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Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), a ligand of the aryl hydrocarbon receptor (AhR), may encompass such an activity. We resorted to biopharmaceutical technologies in order to deliver 3-IAld directly into the lung, via dry powder inhalation, or into the gut, via enteric microparticles, in murine models of CF infection and inflammation. We found the site-specific delivery of 3-IAld to be an efficient strategy to restore immune and microbial homeostasis in CF organs, and mitigate lung and gut inflammatory pathology in response to fungal infections, in the relative absence of local and systemic inflammatory toxicity. Thus, enhanced delivery to target organs of AhR agonists, such as 3-IAld, may pave the way for the development of safe and effective anti-inflammatory agents in CF.

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Section: Discussionmentioning

confidence: 93%

Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Puccetti

Pariano

Renga

et al. 2021

Cells

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“…The reduced colonic inflammation was accompanied by the induction of IL-10-producing regulatory T cells (Treg) (figure 6F), as revealed by the reversal of DNA hypermethylation of Foxp3 promoter, likely occurring via butyrate (figure 6F), as already shown. 44 Indeed, the finding that the protective activity of feces from 3-IAld-treated mice involved host IL-22 more than IL-10 (figure 6G-I), indicates that the beneficial activity of 3-IAld may occur through different pathways that include the modification of the composition and function of the microbiota, the increase intestinal barrier via the AhR/IL-22 axis and the control of inflammation via Treg cells.…”

Section: Open Accessmentioning

confidence: 99%

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Renga

Nunzi

Pariano

et al. 2022

J Immunother Cancer

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BackgroundDespite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.MethodsTo this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.ResultsOn administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.ConclusionsThis study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.

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“…The cecal metabolome exhibited substantially fewer differences as a whole between TCDD and VEH mice when compared with changes in the serum; however, the changes observed indicated that TCDD exposure may still yield immediate changes in intestinal inflammation that modulate gut microbiota composition and metabolism, as has been demonstrated with a variety of other AHR ligands [ 45 ]. Purine-mediated inflammatory responses have been extensively explored indicating an evolved extracellular role as danger signals released during events such as cell lysis, apoptosis, and degranulation [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile

Dopkins

Neameh

Hall

et al. 2021

IJMS

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as “dioxins”. TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.

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The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

Cited by 89 publications

References 139 publications

Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile

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