Toshitaka Nabeshima

Abstract Background and Purpose Lifestyle is closely related to major depressive disorder (MDD). Given the growing focus on the impact of diet on mental health, this study examined how dietary habits affect the pathophysiology of MDD. Experimental Approach Health check‐up data were analysed. Mice received sucrose under chronic unpredictable mild stress (CUMS) and were evaluated by behavioural, neurochemical and metabolic analysis. Key Results Health check‐up data showed increased sucrose intake in MDD patients. When mice received sucrose under CUMS, hyperactivity and aggression were attenuated, although social deficits or behavioural despair induced by CUMS persisted, and recognition memory was impaired. The behavioural changes were associated with dysfunction of the locus coeruleus‐prefrontal cortex circuit, caused by impaired noradrenaline release due to presynaptic α ₂ ‐adrenoceptor upregulation, and postsynaptic α ₁ ‐adrenoceptor and β ₁ ‐adrenoceptor downregulation. α ₂ ‐Adrenoceptor antagonism by atipamezole rescued behavioural changes induced by sucrose intake under CUMS, whereas α ₂ ‐adrenoceptor agonism by guanfacine in CUMS mice mimicked these behavioural changes. Among the antidepressants, mirtazapine effectively increased noradrenaline release and rescued behavioural changes induced by sucrose intake under CUMS. Sucrose intake under CUMS induced peripheral hyperglycaemia and dysregulation of central glucose metabolism. Glucose transporter inhibition by phloretin rescued behavioural changes induced by sucrose intake under CUMS. Intracerebroventricular and systemic streptozotocin administration reproduced these behavioural changes and α ₂ ‐adrenoceptor upregulation. Conclusions and Implications Our findings suggest that the observed behavioural changes are associated with dysfunction of the noradrenergic α ₂ ‐adrenoceptor system induced by impaired glucose metabolism. These insights targeting the noradrenergic‐metabolic axis might be a new strategy for sugar‐induced depression subtypes.

ABSTRACT Psychiatric disorders such as major depressive disorder are closely linked to the intestinal environment, suggesting intestinal health may contribute to their prevention. Prebiotics, which enhance intestinal health, are promising candidates for preventing psychiatric disorders. 1‐Kestose (kestose), a type of prebiotics, has shown potential, but its effects on psychiatric disorders remain unclear. In this study, we investigated whether kestose prevents abnormal behaviors induced by social isolation (SI) stress and which underlies mechanisms of preventive effects. C57BL/6J male mice (3 weeks old) were divided into two groups: individually housed (SI) group and housed five mice per cage (GH) group. Each group received either a normal diet or a kestose diet (5% kestose) for 5 weeks daily until the end of the behavioral testing. Kestose prevented the SI‐induced abnormal behaviors including reduced sociality, impaired spatial recognition, and heightened anxiety, which were associated with suppressed microglial activation in the hippocampus. Kestose altered the diversity of gut microbiota and increased the abundance of Bacteroides sartorii . Furthermore, short‐chain fatty acids (SCFAs) such as butyric acid, acetic acid, and propionic acid, produced by intestinal microbiota, were increased after kestose supplementation. Positive correlations were observed between B. sartorii abundance and SCFA levels, suggesting that B. sartorii contributes to SCFA production. Notably, both B. sartorii and SCFAs were strongly associated with the abnormal behaviors by SI. These findings suggest that kestose prevents SI‐induced abnormal behaviors by modulating gut microbiota, particularly B. sartorii , through an increase of SCFA production. Taken together, kestose could be used as a promising prebiotic intervention for psychiatric disorders. image