Efficacy and Safety of Lactobacillus delbrueckii subsp. lactis CKDB001 Supplementation on Cognitive Function in Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Background: Modulation of the gut–brain axis using probiotics present a promising approach for enhancing cognitive function in mild cognitive impairment (MCI). In prior non-clinical research, Lactobacillus delbrueckii subsp. lactis CKDB001 (LL) exhibited potential to enhance cognitive function. We therefore conducted a clinical trial to assess the efficacy and safety of LL supplementation in MCI. Methods: A 12-week, randomized, double-blind, placebo-controlled, multi-center trial was performed in 100 participants aged 55–80 years. Subjects were randomly assigned to receive LL (n = 50, 5.0 × 109 CFU/day) or placebo (n = 50). Efficacy and safety were evaluated at baseline and after 12 weeks. Results: LL supplementation resulted in significantly greater improvements than placebo in the Alzheimer’s Disease Assessment Scale–Cognition 13 total score, the memory sub-score, reaction time for Part A of the Trail Making Test, and word/color reaction times on the Stroop test. Taxonomic and metabolomic profiling of fecal samples showed significantly greater changes in the relative abundance of beneficial microorganisms in the LL group, with the most pronounced shifts at the family (Lactobacillaceae, Bifidobacteriaceae) and genus (Lactobacillus) levels. In addition, the LL group exhibited significantly higher fecal levels of indole-derived metabolites, including 5-hydroxyindole-3-acetic acid, indole-3-lactic acid, and indole-3-glycol. Safety assessments indicated LL was safe and well-tolerated, with no clinically relevant changes in laboratory findings or adverse events. Conclusions: These findings suggest that LL supplementation may enhance cognitive function in MCI by modulating the gut–brain axis through effects on gut microbiota and related metabolites, and could serve as a safe functional food to support cognitive health.