Caspase recruitment domain 9, microbiota, and tryptophan metabolism: dangerous liaisons in inflammatory bowel

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Bruno Lamas1, Mathias L Richard, Harry Sokol

  • 1aSorbonne University-Pierre and Marie Curie University bINSERM ERL 1157, Avenir Team Gut Microbiota and Immunity cCNRS UMR 7203 dLaboratoire de BioMolécules (LBM), CHU Saint-Antoine eMicalis Institute, INRA, Agro Paris Tech, Université Paris-Saclay, Jouy-en-Josas fInflammation-Immunopathology-Biotherapy Department (DHU i2B) gDepartment of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, Pierre and Marie Curie University, Paris, France.

Current Opinion in Clinical Nutrition and Metabolic Care
|April 12, 2017
PubMed

Insights

Caspase recruitment domain 9 (CARD9) gene variants impair gut bacteria's ability to produce tryptophan metabolites, increasing susceptibility to inflammatory bowel diseases (IBD). Restoring these microbial functions may be a therapeutic strategy for IBD.

Area of Science:

  • Microbiology
  • Immunology
  • Genetics

Background:

  • Inflammatory bowel diseases (IBD) result from genetic, microbial, and environmental factors.
  • Caspase recruitment domain 9 (CARD9) is an identified IBD susceptibility gene.
  • Gut microbiota plays a crucial role in maintaining intestinal homeostasis.

Purpose of the Study:

  • To investigate the role of CARD9 in colitis susceptibility.
  • To explore the link between CARD9, gut microbiota, and tryptophan metabolism.
  • To understand the mechanism of CARD9-associated IBD pathogenesis.

Main Methods:

  • Analysis of CARD9-deficient mice models.
  • Assessment of gut microbiota composition and function.
  • Measurement of tryptophan metabolites and interleukin-22 production.
  • Evaluation of aryl hydrocarbon receptor (AhR) activation.

Main Results:

  • CARD9-deficient mice exhibit increased susceptibility to colitis.
  • Impaired interleukin-22 signaling is observed in CARD9 mice.
  • Gut microbiota in CARD9 mice shows defective tryptophan metabolism, leading to reduced AhR ligand production.
  • Reduced AhR ligand production is also noted in IBD patients with CARD9 risk alleles.

Conclusions:

  • CARD9 influences colitis susceptibility by shaping gut microbiota's tryptophan metabolism.
  • Defective AhR activation due to impaired microbial tryptophan metabolism contributes to IBD pathogenesis.
  • Restoring microbial production of AhR ligands presents a potential therapeutic avenue for IBD.
Abstract

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