RÉSUMÉ
Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety-like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1ß, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note, we found a relationship between the effect of treatment on dentate gyrus neurons and spatial memory. These findings may prove valuable for introducing novel approaches to treat some of the comorbidities associated with MetS.
Sujet(s)
Comportement animal , Microbiome gastro-intestinal , Syndrome métabolique X/métabolisme , Syndrome métabolique X/microbiologie , Prébiotiques/administration et posologie , Animaux , Bifidobacterium , Barrière hémato-encéphalique/métabolisme , Modèles animaux de maladie humaine , Encéphalite/métabolisme , Encéphalite/microbiologie , Hippocampe/métabolisme , Hypothalamus/métabolisme , Inflammation/métabolisme , Inflammation/microbiologie , Mâle , Souris de lignée C57BL , Souris obèse , Mémoire spatialeRÉSUMÉ
Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1ß and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1ß production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.