| Summary: | Sleeplessness (insomnia) is a significant symptom associated with stress-induced depression/anxiety. In the present study, we selected <i>Bifidobacterium longum</i> P77, which increased serotonin production in corticosterone-stimulated SH-SY5Y cells, from the fecal bacteria collection of healthy volunteers and examined the effects of <i>B. longum</i> on depression, anxiety, and sleeplessness induced by immobilization stress or by transplantation of cultured fecal microbiota (cFM) from patients with depression. Orally administered <i>B. longum</i> P77 decreased depression/anxiety- and sleeplessness-like behaviors in immobilization stress-exposed mice. <i>B. longum</i> P77 reduced immobilization stress-induced corticosterone, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 expression and the cell population of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)<sup>+</sup> in the prefrontal cortex, while the expression levels of immobilization stress-suppressed IL-10, γ-aminobutyric acid (GABA), its receptor GABA<sub>A</sub>Rα1, serotonin, and its receptor 5-HT<sub>1A</sub>R increased. <i>B. longum</i> P77 also alleviated immobilization stress-induced colitis: it decreased TNF-α and IL-6 expression and increased IL-10 expression in the colon. Furthermore, <i>B. longum</i> P77, <i>Lactiplantibacillus plantarum</i> P72, and their combination decreased cFM- or immobilization stress-induced depression-, anxiety-, and sleeplessness-like behaviors. They also decreased cFM-induced, corticosterone, TNF-α, and IL-6 expression levels in the prefrontal cortex and colon, while increasing cFM- or immobilization stress-suppressed GABA, GABA<sub>A</sub>Rα1, serotonin, and 5-HT<sub>1A</sub>R expression levels in the prefrontal cortex. In particular, the combination of <i>B. longum</i> P77 and <i>L. plantarum</i> P72 (P7277) additively or synergistically alleviated depression-, anxiety-, and sleeplessness-like behaviors, along with their associated biomarkers. Heat-killed P7277 also alleviated immobilization stress-induced depression/anxiety- and sleeplessness-like symptoms. These results imply that <i>L. plantarum</i> P72 and/or <i>B. longum</i> P77 can mitigate depression/anxiety and sleeplessness by upregulating GABAergic and serotonergic systems, along with the suppression of NF-κB activation.
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