Moeka Tanabe

Multiple sclerosis (MS) is a common autoimmune demyelinating disease of the central nervous system (CNS). Although activation of the kynurenine (KYN) pathway has been observed in patients with MS, its pathological significance remains unclear. In this study, we investigated the role of the KYN pathway in MS using an experimental autoimmune encephalomyelitis (EAE) mouse model, a widely recognized animal model of MS. We found an increase in the expression of kynureninase (KYNU), a key enzyme in the KYN pathway that is specifically localized within monocytes in the spinal cord of EAE mice. This was accompanied by a significant accumulation of quinolinic acid (QUIN) in the spinal cord. Importantly, similar increases in KYNU expression and QUIN levels were observed in the spinal cord of proteolipid protein overexpressing mice (PLP-tg mice), another model of demyelination. Notably, KYNU knockout (KO) reduced EAE severity and monocyte recruitment to the spinal cord of EAE model mice. These findings suggest that the increase in KYNU expression and the subsequent accumulation of QUIN may contribute to the exacerbation of MS. Taken together, our results indicate that KYNU could be a novel therapeutic target for MS.

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.

BACKGROUND: Nutrition is a key factor in cognitive function, and safe dietary interventions are promising to prevent cognitive impairment in pediatric psychiatric disorders. We previously demonstrated that childhood social isolation (SI) stress affects colonic function, leading to cognitive impairment. Cellulose, an insoluble dietary fiber, shows benefits to intestinal health, but its potential impact on cognitive impairment has not been explored. OBJECTIVES: This study investigated whether a high-cellulose diet ameliorates cognitive impairment induced by SI through modulation of gut microbiota and metabolic pathways. METHODS: C57BL/6J male mice (3 wk old; n = 10-15/group) were randomly divided into 2 groups: individually housed (SI) group and housed 5 mice per cage (group-housed) group. Each group received either a normal diet (5% cellulose) or a high-cellulose diet (30% cellulose) for 5 wk daily until the end of the behavioral testing. We evaluated behavior abnormalities, gut microbiota composition, and metabolites, and performed 2-way analysis of variance. RESULTS: Intake of a high-cellulose diet ameliorated cognitive impairment, including decreased time spent in a novel location of SI mice in novel object location test (NOLT; +30%; P < 0.01) with reduction of Iba-1 positive cells, microglia, in the hippocampus (-33%; P < 0.05). The high-cellulose diet indicated a significant difference in gut microbiota clustering plots (P < 0.01) and enhanced the variation in malate-aspartate shuttle pathways in SI mice (P < 0.01). Notably, fecal microbiota transplantation (FMT) from SI mice fed a high-cellulose diet after antibiotic treatment, replicated amelioration of cognitive impairment in NOLT (+46%; P < 0.01). Additionally, the FMT replicated a decrease of Iba-1 positive cells indicating suppressed hippocampal microglial activation (-52%; P < 0.01), and enhanced the variation in malate-aspartate shuttle pathways (P < 0.01). CONCLUSIONS: These findings suggest that a high-cellulose diet may ameliorate pediatric-specific cognitive impairment through modulation of the gut microbiota and metabolic pathways.

Demyelinating diseases including multiple sclerosis (MS) are chronic inflammatory diseases of the central nervous system. Indoleamine 2,3-dioxygenase 2 (Ido2) is a recently identified as catalytic enzyme involved in the rate-limiting step of the tryptophan-kynurenine pathway that influences susceptibility to inflammatory diseases. However, the pathological role of Ido2 in demyelination remains unclear. In this study, we investigated whether Ido2 deficiency influences the pathogenesis of proteolipid protein transgenic (Plp tg) mice, an animal model of chronic demyelination. Ido2 deficiency exacerbates impairments of motor function in the locomotor activity test, wire hanging test, and rotarod test. Ido2 deficiency caused severe demyelination associated with CD68-positive microglial activation in Plp tg mice. In the cerebellum of Plp tg mice, Ido2 deficiency significantly increased the expression of Tnfα. Ido2 deficiency reduced tryptophan metabolite kynurenine (KYN) levels and subsequent aryl hydrocarbon receptor (AhR) activity, which play an important role in anti-inflammatory response. These results suggest that Ido2 has an important role in preventing demyelination through AhR. Taken together, Ido2 could be a potential therapeutic target for demyelinating diseases.

Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.