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Influence de l'indole produit par le microbiote intestinal sur les comportements émotionnels chez la souris

Abstract : Depression is the most spread neuropsychiatric disorder worldwide. It is a socio-economical burden and efficacy of the treatments is very limited. Mechanisms underlying this disorder are mainly unknown. However, a growing number of data has highlighted the potential role of gut microbiota dysbioses in the pathophysiology of depression. Particularly, an unbalance in the diversity and abundance of metabolites produced by the gut microbiota might be implicated. Indole is a tryptophan derivative produced by the gut microbiota. It is known to influence (i) the bacterial physiology and quorum sensing within the gut microbial ecosystem, (ii) the intestinal cells functioning, and (iii) some of its derivatives are known to affect the brain. The aim of this work is to investigate how an overproduction of indole by the gut microbiota can modulate the brain and behaviour in the context of depression and its main co-morbidity, anxiety. This thesis work contains 3 sections.In the first one, we investigated whether an intestinal microbiota dysbiosis leading to an overproduction of indole could confer vulnerability toward anxiety and depression. We also looked for potentially associated biochemical and molecular changes. A behavioural study in gnotobiotic mice overproducing or non producing indole showed the overproduction of indole exacerbated the anxiety-like and depressive-like behaviours induced by a chronic mild stress. Gene expression analysis in the adrenal glands showed chronically stressed mice overproducing indole up-regulated the expression of one gene implicated in adrenaline synthesis. Brain neurotransmitters quantification and gene expression in the brain and intestinal mucosa were also carried out. The second part of the thesis work focused on the brain neurocircuitry of indole. Conventional mice were force-fed with indole and the c-Fos protein was labelled by immunohistochemistry in all brain areas from brainstem to prefrontal cortex. In the third and last part, we modulated dietary tryptophan availability in the gastro-intestinal tract of mice, to study how this modulation could affect the composition and the indole production ability of the gut microbiota. The mice fecal microbiota composition was determined by 16S rRNA sequencing, and fecal tryptophan and indole concentrations were measured by HPLC.In summary, this work improves the understanding of the role of indole in the behavioural and neuro-endocrine responses to stress. This study also initiated the deciphering of brain circuits activated by indole. Finally, it brings some evidence about how modulating food digestibility can impact the gut microbiota composition and its indole production capacity.
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Submitted on : Friday, June 14, 2019 - 4:14:08 PM
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Hayatte-Dounia Mir. Influence de l'indole produit par le microbiote intestinal sur les comportements émotionnels chez la souris. Médecine humaine et pathologie. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLA041⟩. ⟨tel-02156733⟩



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