Microbiota-gut-brain Axis-involved Modulation of Amyloid-β by NVP-2106 Improves Cognitive Function in MCI Subjects

Background: Emerging evidence suggests that gut microbiota dysregulation may contribute to the development of mild cognitive impairment (MCI) through amyloidogenic and inflammatory pathways along the microbiota-gut-brain axis. NVP-2106, also referred to as NVP-NK4146, is a dual-strain probiotic mixture composed of Lactobacillus mucosae NK41 and Bifidobacterium longum NK46. This study evaluated the clinical efficacy of NVP-2106 in older adults with MCI and examined cognitive outcomes in relation to changes in biomarkers and gut microbiota composition.

Methods: In this 12-week, randomized, double-blind, placebo-controlled trial, adults aged 60 years or older with MCI were assigned to receive NVP-2106 at 1 × 10¹⁰ CFU/day or placebo. Cognitive performance was assessed using ADAS-Cog13 and computerized neurocognitive tests. Blood biomarkers, including Aβ42, Aβ40, the Aβ42/40 ratio, brain-derived neurotrophic factor, and inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as gut microbiota composition, were measured at baseline and week 12. Group differences were evaluated using ANCOVA, and correlations among cognitive outcomes, biomarkers, and gut microbiota changes were analyzed.

Results: Compared with placebo, NVP-2106 significantly improved ADAS-Cog13 total scores, memory domain scores, and memory-related items, including word recall and delayed word recall. Attention and memory domains in computerized neurocognitive tests were also improved in the NVP-2106 group. NVP-2106 administration increased blood Aβ42 levels and the Aβ42/40 ratio. Changes in BDNF, IL-1β, IL-6, and TNF-α were correlated with amyloid parameters and ADAS-Cog13 domain scores. Gut microbiota analyses showed compositional shifts toward taxa associated with anti-inflammatory or neuroprotective profiles, including increases in Megasphaera, Coprococcus, and Senegalimassilia. Microbial alterations were correlated with cognitive and biomarker responses. No clinically meaningful safety concerns were identified.

Conclusion: NVP-2106 demonstrated improvements in cognitive performance, particularly in the memory recall domain. These cognitive changes were accompanied by modulation of amyloid-related, inflammatory, and microbiota profiles. These findings suggest that NVP-2106 may provide a promising microbiome-based approach for early cognitive decline.

Keywords: Mild cognitive impairment; MCI; NVP-2106; NVP-NK4146; Probiotics; Lactobacillus mucosae NK41; Bifidobacterium longum NK46; Microbiota-gut-brain axis; Amyloid beta; Aβ42; Aβ40; Aβ42/40 ratio; ADAS-Cog13; Computerized neurocognitive tests; BDNF; Inflammatory cytokines; Gut microbiota; Randomized controlled trial