Combination of vitamin D3 and fructooligosaccharides upregulates colonic vitamin D receptor in C57BL/6J mice and affects anxiety-related behavior in a sex-specific manner

Depression and anxiety disorders are among the most common mental health disorders that affect US adults today, frequently related to vitamin D (VD) insufficiency. Along with VD, growing evidence suggests gut microbiota likely play a role in neuropsychiatric disorders. Here, we investigated if modulation of gut microbiota would disrupt host VD status and promote behaviors related to depression and anxiety in adult mice. Six-week-old male and female C57BL/6J mice (n = 10/mice/group) were randomly assigned to receive (1) control diet (CTR), control diet treated with antibiotics (AB), control diet with total 5000 IU of VD (VD), VD treated with antibiotics (VD + AB), VD supplemented with 5% w/w fructooligosaccharides (FOS; VF), and VF diet treated with antibiotics (VF + AB), respectively, for 8 weeks. Our study demonstrated that VD status was not affected by antibiotic regimen. VD alone ameliorates anxiety-related behavior in female mice, and that combination with FOS (i.e., VF) did not further improve the outcome. Male mice, in contrast, exhibit greater anxiety with VF, but not VD, when compared with CTR mice. Colonic VD receptor was elevated in VF-treated mice in both sexes, compared with CTR, which was positively correlated to colonic TPH1, a rate-limiting enzyme for serotonin synthesis. Taken together, our data indicate that the effect of VF on anxiety-related behavior is sex-specific, which may partially be attributed to the activation of colonic VD signaling and subsequent serotonin synthesis. The synergistic or additive effect of VD and FOS on mood disorders remained to be investigated. The combination of Vitamin D3 and fructooligosaccharides affects anxiety-related behavior in a sex-specific manner, in which the intervention reduces anxiety in female mice but promotes anxiety in male mice. These phenotype changes are aligned with the circulating serotonin concentrations. In addition, colonic VDR mRNA expression is elevated in mice receiving VD + FOS, suggesting a regulatory role of FOS in colonic Vitamin D signaling and subsequent mood disorders. Abbreviations: FOS, fructooligosaccharides; VD, Vitamin D3; VDR, Vitamin D receptor. [Display omitted]