¹Fujita Health University, Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Toyoake, Japan, ²Fujita Health University, Department of Disease Systems Analysis Medicine, Toyoake, Japan, ³Fujita Health University, Division of Neuroimmunology, International Center for Brain Science (ICBS), Toyoake, Japan, ⁴Fujita Health University, Department of Gastroenterology and Hepatology, Toyoake, Japan, ⁵Fujita Health University, Department of Medical Research on Prebiotics and Probiotics, Toyoake, Japan, ⁶Fujita Health University, Department of Joint Research Laboratory of Clinical Medicine, Toyoake, Japan, ⁷Fujita Health University, Laboratory of Health and Medical Science Innovation, Toyoake, Japan, ⁸Fujita Health University, Advanced Diagnostic System Research Laboratory, Toyoake, Japan, ⁹Fujita Health University, Division of Neurochemistry, International Center for Brain Science (ICBS), Toyoake, Japan

Background: Adolescent stress is more likely to impact brain development and increase the risk of psychiatric disorders in adulthood (Burke et al. 2017). Standard treatments for psychiatric disorders typically use drugs that alter the functions of neurotransmission in the brain. However, antidepressants can cause side effects (Wang et al. 2018), and approximately 30% of patients with depression do not respond to them (Kubitz et al. 2013). They underlie the necessity for new preventive strategies for psychiatric disorders. One promising alternative to pharmacotherapy is the improvement of intestinal microbiota (Li et al. 2020). Recent studies suggest that gut microbiota influences not only gut health but also brain development and behavior (Luczynski et al. 2016). Prebiotics are commonly used to improve intestinal microbiota (Sanders 2008) and can routinely incorporate nutrients from childhood (Selvamani et al. 2023), indicating that which is useful for preventive strategies. 1-Kestose (kestose) available as prebiotics is known for its ability to promote the growth of beneficial intestinal bacteria effectively (Tanno et al. 2021). However, the preventive effect of kestose on psychiatric disorders remains unknown.

Aims & Objectives: In this study, we investigated whether kestose prevents abnormal behaviors induced by social isolation (SI) stress and what mechanisms underlies the preventive effects.

Method: 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. Sociality, spatial recognition, and anxiety-like behavior were evaluated by social interaction test, novel object location test, and cliff avoidance test, respectively. After behavioral testing, the gut microbiota was analyzed by metagenomic analysis in the feces. Short-chain fatty acids (SCFAs) analysis in the fecal sample was analyzed using a Short- and Long-Chain Fatty Acid Analysis Kit.

Results: Kestose prevented the SI-induced abnormal behaviors including reduced sociality and 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 (B. sartorii). Furthermore, the levels of SCFAs, such as butyric acid, acetic acid, and propionic acid, produced by intestinal microbiota, were increased in response to the kestose supplementation. Positive correlations were observed between B. sartorii abundance and SCFA levels, suggesting that B. sartorii contributes to SCFA production. In addition, each B. sartorii or SCFAs were strongly associated with the abnormal behaviors by SI.

Discussion & Conclusions: 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.