Abstract
Gut microbiota metabolizes tryptophan into indole, which can influence brain and behavior. Indeed, some oxidized derivatives of indole, formed in the liver, have neuroactive properties, and indole overproduction by the gut microbiota induces an anxio-depressive phenotype in rodents. The aim of this study was to investigate in humans whether there was a relationship between recurrent depressive symptoms and indole production by the gut microbiota. A case-control study was conducted in 45–65-year-old women, who were participants in the observational prospective NutriNet-Santé Study. Cases were defined as having two Center for Epidemiological Studies-Depression Scales (CES-D) scores ≥ 23 at a two-year interval (recurrent depressive symptoms, n = 87). Each case was matched with two controls (two CES-D <23; n = 174). Urinary excretion of 3-indoxylsulfate, the major final metabolite of indole, was used as a biomarker of indole production by the gut microbiota. Conditional logistic regression models for paired data showed a positive association between urinary 3-indoxylsulfate concentrations, grouped in tertiles, and recurrent depressive symptoms (odds ratio = 2.46, p for trend = 0.0264 in the final model adjusted for confounding factors). This association suggested that indole production by the gut microbiota may play a role in the onset of mood disorders in humans.
Highlights
A large number of studies in laboratory animals definitively demonstrated the existence of a crosstalk between the gut microbiota and the brain, leading to the concept of the gut microbiome–brain axis [1]
We showed previously in gnotobiotic rodent models that indole produced by microbial hydrolysis of tryptophan in the large intestine intensified the anxiety-like and depressivelike phenotypes, as assessed by several behavioral tests [7,8]
Women with recurrent depressive symptoms lived more alone than women of the control group (35.6% versus 18.4%; p = 0.004)
Summary
A large number of studies in laboratory animals definitively demonstrated the existence of a crosstalk between the gut microbiota and the brain, leading to the concept of the gut microbiome–brain axis [1] On this basis, the challenges today are (i) to characterize the microbial actors, the communication pathways they use to signal to the brain, and the mechanisms by which they interact with specific brain structures, (ii) and to identify to which extent the observations made in laboratory animals can translate to humans [2]. Microorganisms 2021, 9, 716 was accompanied by an enrichment of the plasma with a host-microbiome co-metabolite derived from tyrosine, the 4-ethylphenylsulfate. Systemic administration of this molecule to naïve mice induced anxiety-like behavior. In humans with mild to moderate anxiety and/or depression, the probiotic Bifidobacterium longum NCC3001 reduced the urinary excretion of several host-microbiome co-metabolites derived from aromatic amino acids; among them, p-cresol sulfate correlated positively with depression scores [6]
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