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Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiota–gut–brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota–gut–brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut–microbiota–brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight.

Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERα36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1–F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERα36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERα36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility.