Faculty Opinions recommendation of Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses.

2018 ◽  
Author(s):  
Jeff Karp ◽  
Benjamin Mead
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Intestinal Inflammation ◽  
Aryl Hydrocarbon

scholarly journals Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2427
Author(s):  
Ivan Qi Han Ngui ◽  
Agampodi Promoda Perera ◽  
Rajaraman Eri
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Strong Association ◽  
Signalling Pathways ◽  
Inflammasome Activation ◽  
Intestinal Immunity ◽  
Aryl Hydrocarbon

Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some degree of the inflammatory process to maintain a healthy immune system. A pivotal component in the maintenance of such intestinal homeostasis is the innate immunity component, inflammasomes. Inflammasomes are large, cytosolic protein complexes formed following stimulation of microbial and stress signals that lead to the expression of pro-inflammatory cytokines. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been extensively studied in part due to its strong association with colitis and CAC. The aryl hydrocarbon receptor (AhR) has recently been acknowledged for its connection to the immune system aside from its role as an environmental sensor. AhR has been described to play a role in the inhibition of the NLRP3 inflammasome activation pathway. This review will summarise the signalling pathways of both the NLRP3 inflammasome and AhR; as well as new-found links between these two signalling pathways in intestinal immunity and some potential therapeutic agents that have been found to take advantage of this link in the treatment of colitis and CAC.

scholarly journals Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation

2020 ◽  
Vol 12 (566) ◽  
pp. eaba0624 ◽  
Author(s):  
Bruno Lamas ◽  
Leticia Hernandez-Galan ◽  
Heather J. Galipeau ◽  
Marco Constante ◽  
Alexandra Clarizio ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Gut Microbiota ◽  
Aryl Hydrocarbon Receptor ◽  
Intestinal Inflammation ◽  
Susceptibility Gene ◽  
Rrna Gene ◽  
Microbiota Composition ◽  
Aryl Hydrocarbon ◽  
Pathway Activation ◽  
Gut Microbiota Composition

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with Lactobacillus reuteri that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16S rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer L. reuteri, or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.

scholarly journals Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

2020 ◽  
Author(s):  
Xiufang Cui ◽  
Jiajia Li ◽  
Di Wang ◽  
Yan Yang ◽  
Chunhua Jiao ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cell ◽  
Aryl Hydrocarbon Receptor ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Treg Cells ◽  
Receptor Activation ◽  
Surface Markers ◽  
Cytochrome P450 1A1 ◽  
Aryl Hydrocarbon

Abstract Background Intestinal immune dysfunction is involved in the onset of Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis. Methods Bone marrow derived DCs were incubated with or without FICZ(100 nM) which was a kind of AhR for 12 hours, subsequently the cells were stimulated to mature. Scanning electron microscope (SEM) was used to observe dendritic formation on DC surface. Proliferation of T lymphocytes was evaluated by proliferation experiment. The expression of surface markers in DCs were detected by flow cytometry and the gene expression levels of cytokines were measured using RT-qPCR. The levels of cytokines in cell supernatants were determined by ELISA. The expression of cytochrome P450 1A1(CYP1A1) and forkhead box P3 (Foxp3) were measured by Western blotting. TolDCs were transferred to murine colitis model and the intestinal inflammation were evaluated. T-helper (Th) 17 cells and Treg in spleens and mesenteric lymph nodes (MLNs) were analyzed by flow cytometry. Results AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1β, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by FICZ. Such DCs with FICZ-mediated activation of AhR, namely tolDCs, inhibited CD4+ T cell proliferation and promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by decreasing the frequency of Th17 cells and increasing the frequency of Treg cells. Conclusions Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.

scholarly journals Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

Cell ◽  
2018 ◽  
Vol 173 (5) ◽  
pp. 1123-1134.e11 ◽  
Author(s):  
Shankar S. Iyer ◽  
Thomas Gensollen ◽  
Amit Gandhi ◽  
Sungwhan F. Oh ◽  
Joana F. Neves ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Intestinal Inflammation ◽  
Aryl Hydrocarbon

scholarly journals MicroRNA-124 Promotes Intestinal Inflammation by Targeting Aryl Hydrocarbon Receptor in Crohn’s Disease

2016 ◽  
Vol 10 (6) ◽  
pp. 703-712 ◽  
Author(s):  
Ye Zhao ◽  
Teng Ma ◽  
Weixu Chen ◽  
Yanfang Chen ◽  
Ming Li ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Intestinal Inflammation ◽  
Aryl Hydrocarbon ◽  
Microrna 124

scholarly journals Gut SymbiontsLactobacillus reuteriR2lc and 2010 Encode a Polyketide Synthase Cluster That Activates the Mammalian Aryl Hydrocarbon Receptor

2018 ◽  
Vol 85 (10) ◽  
Author(s):  
Mustafa Özçam ◽  
Restituto Tocmo ◽  
Jee-Hwan Oh ◽  
Amin Afrazi ◽  
Joshua D. Mezrich ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Gene Cluster ◽  
Polyketide Synthase ◽  
Lactobacillus Reuteri ◽  
Intestinal Inflammation ◽  
Host Immune System ◽  
Content Type ◽  
Aryl Hydrocarbon

ABSTRACTA mechanistic understanding of microbe-host interactions is critical to developing therapeutic strategies for targeted modulation of the host immune system. Different members of the gut symbiont speciesLactobacillus reuterimodulate host health by, for example, reduction of intestinal inflammation. Previously, it was shown thatL. reuteriactivates the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that plays an important role in the mucosal immune system, by the production of tryptophan catabolites. Here, we identified a novel pathway by whichL. reuteriactivates AhR, which is independent of tryptophan metabolism. We screened a library of 36 L. reuteristrains and determined that R2lc and 2010, strains with a pigmented phenotype, are potent AhR activators. By whole-genome sequencing and comparative genomics, we identified genes unique to R2lc and 2010. Our analyses demonstrated that R2lc harbors two genetically distinct polyketide synthase (PKS) clusters, functionally unknown (fun) andpks, each carried by a multicopy plasmid. Inactivation ofpks, but notfun, abolished the ability of R2lc to activate AhR.L. reuteri2010 has a gene cluster homologous to thepkscluster in R2lc with an identical gene organization, which is also responsible for AhR activation. In conclusion, we identified a novel PKS pathway inL. reuteriR2lc and 2010 that is responsible for AhR activation.IMPORTANCETemporary changes in the composition of the microbiota, for example, by oral administration of probiotics, can modulate the host immune system. However, the underlying mechanisms by which probiotics interact with the host are often unknown. Here, we show thatLactobacillus reuteriR2lc and 2010 harbor an orthologous PKS gene cluster that activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that plays a key role in a variety of diseases, including amelioration of intestinal inflammation. Understanding the mechanism by which a bacterium modulates the immune system is critical for applying rational selection strategies for probiotic supplementation. Finally, heterologous and/or optimized expression of PKS is a logical next step toward the development of next-generation probiotics to prevent and treat disease.

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