CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Lamas, Bruno; Richard, Mathias L.; Leducq, Valentin; Pham, Hang-Phuong; Michel, Marie‐Laure; Costa, Grégory Da; Bridonneau, Chantal; Jégou, Sarah; Hoffmann, Thomas; Natividad, Jane M.; Brot, Loïc; Taleb, Soraya; Couturier-Maillard, Aurélie; Nion–Larmurier, Isabelle; Merabtene, Fatiha; Seksik, Philippe; Bourrier, Anne; Cosnes, Jacques; Ryffel, Bernhard; Beaugerie, Laurent; Launay, Jean Marie; Langella, Philippe; Xavier, Ramnik J.; Sokol, Harry

doi:10.1038/nm.4102

Cited by 1,095 publications

(1,199 citation statements)

References 52 publications

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“…Indeed, studies investigating intestinal epithelial-specific TLR5 deficiency or full-body ablation of Card9 or IL-33 showed that weaning these genetic mouse models and their WT littermates in separate cages resulted in differential gut microbiota communities after 4–6 weeks of separation. 36-38 Together, these several mouse genetic studies show that analyzing separately housed littermates is a well-controlled and valid approach for dissecting host genetic effects on intestinal ecosystems.…”

Section: Resultsmentioning

confidence: 99%

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

et al. 2018

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Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions.

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Section: Resultsmentioning

confidence: 99%

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

et al. 2018

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“…In intestinal tissues, multiple other PRRs are activated, the outcomes of which might in turn be modulated by additional IBD risk loci. Polymorphisms resulting in both decreased (e.g., NOD2, IL18RAP, ICOSL, ATG16L1, CARD9) and increased (e.g., MAP3K8, TNFSF15, IRF5) PRR-mediated signaling and downstream outcomes can be associated with intestinal inflammation (2)(3)(4)(5)(6)(7)(8)(9)(10)(11), thereby highlighting the critical role of balance in regulation of PRR-initiated outcomes in intestinal tissues. Despite the success in identification of IBD-associated loci (12), altered functions for most of the IBD loci are unknown.…”

Section: Introductionmentioning

confidence: 99%

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

Yan¹,

Hedl²,

Abraham³

2017

Journal of Clinical Investigation

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“…A notable association of gut microbiome-generated tryptophan metabolites with inflammatory bowel disease (IBD) has recently been demonstrated. Reduced production of tryptophan-generated AHR ligands has been observed in the microbiome from individuals with IBD, particularly in carriers of CARD9 risk alleles associated with IBD (Lamas et al, 2016).…”

Section: Development Of the Neonatal Immune Systemmentioning

confidence: 99%

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

Bock¹

2016

Biological Chemistry

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Metabolism of aryl hydrocarbons and toxicity of dioxins led to the discovery of the aryl hydrocarbon receptor (AHR). Tremendous advances have been made on multiplicity of AHR signaling and identification of endogenous ligands including the tryptophan metabolites FICZ and kynurenine. However, human AHR functions are still poorly understood due to marked species differences as well as cell-type-and cell context-dependent AHR functions. Observations in dioxin-poisoned individuals may provide hints to physiologic AHR functions in humans. Based on these observations three human AHR functions are discussed: (1) Chemical defence and homeostasis of endobiotics. The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals and primates expressing the Ala381 variant while affinity to indoles remains unimpaired. (2) Homeostasis of stem/progenitor cells. Dioxins dysregulate homeostasis in sebocyte stem cells. (3) Modulation of immunity. In addition to microbial defence, AHR may be involved in a 'disease tolerance defence pathway'. Further characterization of physiologic AHR functions may lead to therapeutic options.

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CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Cited by 1,095 publications

References 52 publications

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

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