Lacticaseibacillus rhamnosus KF7 ameliorates cognition impairments via prolactin signaling modulation in senescence mice induced by D-galactose

Abstract Aging-related cognitive decline poses a significant public health challenge with limited preventive options. Probiotics show promise in ameliorating aging-related diseases via the microbiota-gut-brain axis (MGBA). This study demonstrated that L. rhamnosus KF7 protected against D-galactose-induced aging in mice. L. rhamnosus supplementation significantly improved cognitive deficits in these mice. Crucially, L. rhamnosus reduced cerebral neuroinflammation markers (IL-1β, IL-6) and oxidative stress (MDA), inhibited monoamine oxidase (MAO) activity, and restored neurotransmitter balance. Transcriptomics revealed L. rhamnosus KF7 modulated Prolactin signaling, and then enhanced NRF2 expression. Metabolomics and 16S rRNA sequencing showed L. rhamnosus KF7 restored microbial metabolic disturbances, increased the abundance of Lactobacillus murinus, and elevated levels of the Indole-3-lactic acid (ILA, a neuroprotective metabolite) in gut. These findings provided compelling evidence that L.rhamnosus KF7 conferred protection against cognitive impairment in this aging model, mediated via the MGBA. Mechanically, L. rhamnosus KF7 enhances the production of gut microbiota-derived ILA, which activates the prolactin signaling pathway in pituitary and then upregulates the expression of NRF2 in hippocampus, ultimately ameliorating multiple indicators associated with D-galactose-inuced cognitive impairment. The study established a foundation for developing probiotics against aging-related cognitive decline.