High-Cellulose Diet Ameliorates Cognitive Impairment by Modulating Gut Microbiota and Metabolic Pathways in Mice

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.