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

By B. Lamas, Mathias L. Richard, Valentin Leducq, H. Pham, Marie‐Laure Michel, G. Da Costa, C. Bridonneau, Sarah Jégou, Thomas W. Hoffmann, J. Natividad and 14 more. Nature Medicine, 2016

1,307 citations recorded by the source corpus.

Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9−/− mice are more susceptible to colitis. The microbiota is altered in Card9−/− mice, and transfer of the microbiota from Card9−/− to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9−/− mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.

Subfields: Biological Psychiatry, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/cc4fc0c8a5991c81c78d7c1b2de95f127c80d45f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biological Psychiatry

1. J. Cryan
2. Ted G. Dinan
3. G. Clarke
4. P. Kennedy
5. F. Quintana
6. J. Foster
7. L. Rinaman
8. C. Stanton

In Immunology

1. Cristina Gutiérrez-Vázquez
2. F. Quintana
3. T. Kanai
4. Ted G. Dinan
5. G. Clarke
6. K. Matsuoka
7. J. Cryan

In Molecular Biology

1. J. Cryan
2. Ted G. Dinan
3. G. Clarke
4. P. Kennedy
5. Eric A. Franzosa
6. T. Kanai
7. K. Matsuoka
8. Curtis Huttenhower

Citations in the corpus

• Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. (2019, background): “The oral administration of 3 tryptophan-metabolizing Lactobacillus strains to colitis-susceptible mice promote microbial tryptophan metabolism aryl hydrocarbon receptor (Ah)dependent signaling, thereby influencing the peripheral tryptophan availability (62).”
• Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism (2018, background): “In IBD patients, levels of IAA (anti-inflammatory function in the intestine) are reduced in feces, suggesting that reduced bacterial Trp metabolism may contribute to the etiology of IBD (Lamas et al., 2016).”
• Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. (2018, neutral): “We recently uncovered the decreased production of AhR ligands by the microbiota of IBD patients, which was influenced by genetic factors (Lamas et al., 2016), and AhR expression in intestinal tissues was decreased compared with that in healthy subjects (Monteleone et al.”
• Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. (2017, background): “Supporting this hypothesis, recent studies have shown that microbial tryptophan metabolites such as indole-3-aldehyde, indole 3-propionate, and indole-3-acetic acid signal through AhR to increase IL-22 secretion by innate-like lymphoid cells and T cells, leading to protection from chemically induced”
• Interaction between the gut microbiome and mucosal immune system (2017, background): “The intestinal microbial structure was altered and susceptible to intestinal fungus infection in CARD9 knockout mice, indicating that the deletion of CARD9 led to IBD dysbiosis [72].”
• Kynurenine pathway metabolism and the microbiota‐gut‐brain axis (2017, background): “, 2016), and administration of an aryl hydrocarbon receptor agonist attenuates intestinal inflammation in a preclinical model of colitis (Lamas et al., 2016).”
• The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “, 2016), and supplementation with three Lactobacillus strains capable of metabolizing tryptophan, or treatment with an aryl hydrocarbon receptor agonist, restored intestinal IL-22 production and attenuated intestinal inflammation (Lamas et al., 2016).”