T cell AHR activity tunes the Gut Microenvironment to Sustain Autoimmunity [sephouse_feces]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200438 | GEO | 2022/04/10
REPOSITORIES: GEO
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Project description:The contribution of the environment and, in particular, the gut flora to multiple sclerosis (MS) etiology is well documented but not well understood. The aryl hydrocarbon receptor (AHR) binds numerous molecules present in the environment and is a therapeutic target for MS: however, its precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that CD4 specific Ahr knockout drives recovery in an animal model of MS driven by a decrease in T cell fitness. At the mechanistic level, we show that the absence of AHR changes the gut microenvironment composition to generate metabolites, such as bile salts and short chain fatty acids, that impact T cell viability. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota while identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.
2022-04-10 | GSE200437 | GEO
Project description:The contribution of the environment and, in particular, the gut flora to multiple sclerosis (MS) etiology is well documented but not well understood. The aryl hydrocarbon receptor (AHR) binds numerous molecules present in the environment and is a therapeutic target for MS: however, its precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that CD4 specific Ahr knockout drives recovery in an animal model of MS driven by a decrease in T cell fitness. At the mechanistic level, we show that the absence of AHR changes the gut microenvironment composition to generate metabolites, such as bile salts and short chain fatty acids, that impact T cell viability. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota while identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.
2022-04-10 | GSE200436 | GEO
Project description:The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression both in mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut Tregs in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role at least in part by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating Treg intestinal homing under the steady state and during inflammation, and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes.
2020-07-29 | GSE137171 | GEO
Project description:To find the signalling pathway involved in WT/2D2 CD4+ gut T cell (CD4+ intraepithelial lymphocytes, CD4+IEL) differentiation, particulary to determine whether aryl hydrocarbon receptor (AHR) pathway is involved. Gene expression was analyzed ex vivo in CD4+ T cells that were sorted from Wild type-Gut / 2D2 mouse-Gut / Wild type-Spleen / 2D2 mouse-Spleen (N=3 per group). The genes highly expressed in WT/2D2 Gut compared to WT/2D2 Spleen were selected by k-means clustering. AHR pathway related genes (IPA software) were further selected.
2016-04-01 | E-GEOD-79748 | biostudies-arrayexpress
Project description:To find the signalling pathway involved in WT/2D2 CD4+ gut T cell (CD4+ intraepithelial lymphocytes, CD4+IEL) differentiation, particulary to determine whether aryl hydrocarbon receptor (AHR) pathway is involved.
2016-04-01 | GSE79748 | GEO
Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. We found that gut environmental sensor Aryl hydrocarbon receptor (AhR) is induced in colonic neurons in response to microbiota colonisation and regulates intestinal peristalsis in an AhR ligand-dependent manner. In this experiment, we used RNA sequencing to identify genes regulated in mouse colonic neurons by AhR activation.
2019-11-13 | GSE140292 | GEO
Project description:The microbial population that live within the gut of animals influences their physiology. We used axenic and recolonized flies to identify genes whose expression is modulated by the presence of a bacterial flora in the gut. We identified several up regulated genes, most of which are described as enriched in the midgut, and related either to immunity or to metabolism. This work also suggests that most microbiota regulated genes are Relish dependent. We raised axenic Flies and either : (1) kept them germ free or (2) recolonized their environment with a set of 4 known commensal bacteria of lab-raised drosophila (Commensalibacter intestini, Lactobacillus plantarum, Lactobacillus brevis, Acetobacter pomorum). Flies were maintained in their respective (axenic or recolonized) environment from emergence to 7 days of age. Then females were collected, and total RNA extraction was performed on groups of 20 whole bodies.
2014-03-26 | E-GEOD-56173 | biostudies-arrayexpress
Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. However the molecular mechanisms by which gut enviromental factors regulate ENS homeostasis remain unknown. In order to address this issue, we used RNA sequencing to identify genes specifically upregulated in mouse colonic neurons in response to microbial colonisation.
2019-11-13 | GSE140291 | GEO
Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. However the molecular mechanisms by which gut enviromental factors regulate ENS homeostasis remain unknown. In order to address this issue, we used RNA sequencing to identify genes specifically upregulated in mouse colonic neurons in response to microbial colonisation.
2019-11-13 | GSE140290 | GEO
Project description:Here, we generated mouse genetic models to ablate or activate Ahr expression specifically in Tregs. We showed that Ahr was expressed more abundantly by peripherally induced Treg (pTregs) in the gut than by Tregs in other lymphoid organs, and its expression was independent of microbiota. Ahr was important for Treg gut homing and function. Ahr inhibited pro-inflammatory cytokines produced by Tregs but was dispensable for Treg stability. Furthermore, Ahr-expressing Tregs had enhanced in vivo suppressive activity compared to Tregs lacking Ahr expression in a T cell transfer model of colitis. Our data suggest that Ahr signaling in Tregs may be important for gut immune homeostasis.
2017-11-21 | GSE106083 | GEO