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Marion Rincel a soutenu sa thèse intitulée "Role of the gut-brain axis in early-stress-induced emotional vulnerability" vendredi 15 décembre 2017 à 14h dans la salle de l'auditorium Neurocampus du centre Broca Nouvelle Aquitaine.

Son jury de thèse était composé de :

- Prof John Cryan, Cork

- Prof Stefania Maccari, Université de Lille

- Prof Gérard Eberl, Paris

- Prof Vassilia Theodorou, INRA Toulouse

- Dr Lucile Capuron, INRA, NutriNeuro, Bordeaux

- Prof Muriel Darnaudéry, NutriNeuro, Université de Bordeaux, directrice de thèse

Keywords : animal models of psychiatric disorders; behavior; early-life adversity; gut permeability; gut microbiota; HPA axis, stress, sex differences

Résumé :

Early-life adversity is a main risk factor for psychiatric disorders at adulthood; however the mechanisms underlying the programming effect of stress during development are still unknown. In rodents, chronic maternal separation has long lasting effects in adult offspring, including hyper-anxiety and hyper-responsiveness to a novel stress, along with gastrointestinal dysfunctions. Moreover, recent studies report gut barrier hyper-permeability in rat pups submitted to maternal separation, an effect that could potentially lead to dysbiosis and altered brain-gut communication.
Therefore, the aim of my PhD was to unravel the role of the brain-gut axis in the neurobehavioral effects of early-life stress. We recently reported that some neural, behavioral and endocrine alterations associated with maternal separation in rats could be prevented by maternal exposure to a high-fat diet. We first addressed the effects of maternal high-fat diet on brain and gut during development in the maternal separation model. We show that maternal high-fat diet prevents the stress-induced spines density decrease and altered dendrites morphology in the medial prefrontal cortex. Moreover maternal high-fat also attenuates the exacerbated intestinal permeability associated with maternal separation. To explore a potential causal role of gut on brain functions, we then examined the impact of manipulations of intestinal permeability on brain and behavior.
We report 1) that restoration of gut barrier function attenuates some of the behavioral alterations associated with maternal separation and 2) that transgenic mice over-expressing intestinal CA-MLCK leading to chronic gut leakiness exhibited the same phenotype than animals exposed to maternal separation. Finally, we examined the effects of multifactorial early-life adversity on behavior, gut function and microbiota composition in males and females using a combination of prenatal inflammation and maternal separation in mice. At adulthood, offspring exposed to early adversity displayed sex-specific behavioral (social behavior deficits in males and hyper-anxiety in females) and intestinal phenotypes.
In conclusion, our work demonstrates an impact of gut dysfunctions, in particular gut leakiness, on the emergence of emotional alterations. Further studies are needed to unravel the role of the gut dysbiosis in the expression of the behavioral phenotypes associated with early-life adversity.

de gauche à droite : Dr Lucile Capuron, Prof Vassilia Theodorou, Prof Gérard Eberl, Prof Muriel Darnaudéry, Dr Marion Rincel, Prof John Cryan, Prof Stefania Maccari