The gut microbiota metabolite indole increases emotional responses and adrenal medulla activity in chronically stressed male mice

Hayatte-Dounia Mir, Alexandre Milman, Magali Monnoye, Véronique Douard, Catherine Philippe, Agnès Aubert, Nathalie Castanon, Sylvie Vancassel, Nathalie C. Guérineau, Laurent Naudon, Sylvie Rabot
Psychoneuroendocrinology. 2020-09-01; 119: 104750
DOI: 10.1016/j.psyneuen.2020.104750

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Mir HD(1), Milman A(2), Monnoye M(3), Douard V(4), Philippe C(5), Aubert A(6), Castanon N(7), Vancassel S(8), Guérineau NC(9), Naudon L(10), Rabot S(11).

Author information:
(1)Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .
(2)IGF, Univ. Montpellier, CNRS, INSERM, 34000 Montpellier, France. Electronic
address: .
(3)Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .
(4)Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .
(5)Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .
(6)Université de Bordeaux, INRAE, UMR NutriNeurO, 33000 Bordeaux, France.
Electronic address: .
(7)Université de Bordeaux, INRAE, UMR NutriNeurO, 33000 Bordeaux, France.
Electronic address: .
(8)Université de Bordeaux, INRAE, UMR NutriNeurO, 33000 Bordeaux, France.
Electronic address: .
(9)IGF, Univ. Montpellier, CNRS, INSERM, 34000 Montpellier, France. Electronic
address: .
(10)Université Paris-Saclay, INRAE, AgroParisTech, CNRS, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .
(11)Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350
Jouy-en-Josas, France. Electronic address: .

BACKGROUND AND AIMS: The gut microbiota produces metabolites that are an integral
part of the metabolome and, as such, of the host physiology. Changes in gut
microbiota metabolism could therefore contribute to pathophysiological processes.
We showed previously that a chronic and moderate overproduction of indole from
tryptophan in male individuals of the highly stress-sensitive F344 rat strain
induced anxiety-like and helplessness behaviors. The aim of the present study was
to extend the scope of these findings by investigating whether emotional
behaviors of male mice that are moderately stress-sensitive but chronically
exposed to environmental stressors would also be affected by indole.
METHODS: We colonized germ-free male C3H/HeN mice with a wild-type
indole-producing Escherichia coli strain, or with the non-indole producing
mutant. Gnotobiotic mice were subjected to an unpredictable chronic mild stress
procedure, then to a set of tests aimed at assessing anxiety-like (novelty and
elevated plus maze tests) and depression-like behaviors (coat state, splash,
nesting, tail suspension and sucrose tests). Results of the individual tests were
aggregated into a common z-score to estimate the overall emotional response to
chronic mild stress and chronic indole production. We also carried out
biochemical and molecular analyses in gut mucosa, plasma, brain hippocampus and
striatum, and adrenal glands, to examine biological correlates that are usually
associated with stress, anxiety and depression.
RESULTS: Chronic mild stress caused coat state degradation and anhedonia in both
indole-producing and non-indole producing mice, but it did not influence
behaviors in the other tests. Chronic indole production did not influence mice
behavior when tests were considered individually, but it increased the overall
emotionality z-score, specifically in mice under chronic mild stress.
Interestingly, in the same mice, indole induced a dramatic increase of the
expression of the adrenomedullary Pnmt gene, which is involved in catecholamine
biosynthesis. By contrast, systemic tryptophan bioavailability, brain serotonin
and dopamine levels and turnover, as well as expression of gut and brain genes
involved in cytokine production and tryptophan metabolism along the serotonin and
kynurenine pathways, remained similar in all mice.
CONCLUSIONS: Chronic indole production by the gut microbiota increased the
vulnerability of male mice to the adverse effects of chronic mild stress on
emotional behaviors. It also targeted catecholamine biosynthetic pathway of the
adrenal medulla, which plays a pivotal role in body’s physiological adaptation to
stressful events. Future studies will aim to investigate the action mechanisms
responsible for these effects.

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