Editors' ChoiceInflammation

I’ll have a turkey and cheese sandwich

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Science Translational Medicine  08 Jun 2016:
Vol. 8, Issue 342, pp. 342ec91
DOI: 10.1126/scitranslmed.aag1870

The role of gut bacteria in normal host physiology is being increasingly recognized. Two recent reports highlight the importance of bacterial metabolism of tryptophan in the diet for suppressing inflammation. Tryptophan is an essential amino acid found in foods such as turkey and cheese and is a precursor of neurotransmitters such as serotonin and melatonin. In addition to the host, gut microbiota can also metabolize tryptophan to produce indole compounds that act as ligands for the aryl hydrocarbon receptor (AHR). Tryptophan catabolites have been shown to modulate production of IL22 via AHR, thereby influencing the mucosal immune system.

Lamas et al. now demonstrate in an elegant set of gnotobiotic mouse experiments that decreased capacity of the gut microbiota to catabolize tryptophan led to a reduction in AHR ligands predisposing the mice to colitis, which in turn was mitigated by giving the mice Lactobacillus strains that produced AHR ligands. Additionally, the authors showed a relative lack of tryptophan-catabolizing bacteria in Card9–/– mice suggesting a role for CARD9, a gene implicated in inflammatory bowel disease, in shaping the gut microbiota. In a complementary study, Rothhammer et al. report a decrease in circulating tryptophan-derived AHR agonists in patients with multiple sclerosis (MS). They showed in a mouse model of experimental autoimmune encephalitis (analogous to human MS) that AHRs mediate the suppressive effects of interferon-β (first line therapy for MS), thus implicating AHR ligands in interferon-mediated suppression of inflammation in the central nervous system (CNS). In support of this hypothesis, the authors demonstrated that indoxyl-3-sulphate, a microbial metabolite resulting from tryptophan catabolism, crossed the blood-brain barrier and activated AHRs in CNS astrocytes.

These two studies call attention to the importance of studying changes in functional attributes of the gut microbiota in addition to compositional changes when trying to elucidate the biological effects of the gut microbiota. Furthermore, they underscore the importance of the microbiota-gut-brain axis for showing how microbial metabolism of a single amino acid can have beneficial effects on inflammation in the gut and in the CNS. The identification of such microbial metabolic pathways will be crucial for development of targeted approaches to treat microbiota-mediated pathological processes.

B. Lamas et al., CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 10.1038/nm.4102 (2016). [Abstract]

V. Rothhammer et al., Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 10.1038/nm.4106 (2016). [Abstract]

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