Lactococcus lactis and Bifidobacterium bifidum alleviate postmenopausal symptoms by suppressing NF-κB signaling and microbiota dysbiosis

To understand the action mechanism of probiotics against postmenopausal symptoms, we examined the effects of Lactococcus lactis P32 (P_L) and Bifidobacterium bifidum P45 (P_B), which suppressed interleukin (IL)-6 and receptor activator of nuclear factor-κB (RANK) ligand (RNAKL) expression in Gardnerella vaginalis (Gv)-stimulated macrophages, on vaginitis, osteoporosis, and depression/cognitive impairment (DC) in mice with vaginally infected Gv, ovariectomy (Ov), or Ov/Gv (oG). Oral administration of P_L or P_B decreased Gv-induced DC-like behavior and tumor necrosis factor (TNF)-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, hypothalamus, hippocampus, and colon, while Gv-suppressed bone osteoprotegerin and brain serotonin and brain-derived neurotrophic factor (BDNF) levels increased. They partially shifted vaginal and gut dysbiosis in Gv-infected mice to the gut microbiota composition in normal control mice. In mice with oG, oral administration of P_L or P_B decreased oG-induced DC-like behavior and TNF-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, brain, and colon, while oG-suppressed bone osteoprotegerin and brain serotonin and BDNF levels increased. They also alleviated oG-induced vaginal and gut dysbiosis: they decreased Proteobacteria population. P_L and P_B (4:1) mix (P_M) suppressed DC-like behavior in mice with Gv, Ov, or oG. P_M also suppressed TNF-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, colon, and brain. P_M alleviated Gv-induced vaginal and gut dysbiosis: it decreased Proteobacteria population. These findings suggest that P_L and P_B, singly or together, can alleviate postmenopausal symptoms including vaginitis, colitis, osteoporosis, and DC by suppressing RANK/RANKL-mediated NF-κB activation and alleviating vaginal/gut microbiota dysbiosis.