Colon-delivered multivitamin supplementation enhances working memory-related fMRI responses in older adults: a randomized, placebo-controlled trial

Abstract Background Vitamins are important modulators of intestinal health and may affect the gut-brain axis through microbial metabolites such as short-chain fatty acids (SCFAs). However, the neurocognitive effects of colon-delivered vitamins in older adults remain unexplored – a critical gap given the gut-brain axis’s emerging role in cognitive aging. Objective We investigated the effect of a colon-delivered multivitamin (CDMV) supplement on intestinal health and neurocognitive outcomes in older adults at risk of cognitive decline. Methods Within the double-blind randomized placebo-controlled trial COMBI (ClinicalTrials.govID: NCT05675007 ), we included 75 older adults (60-75 years) at risk of cognitive decline based on lifestyle-related factors. Participants consumed a colon-delivered capsule with vitamins B2, B3, B6, B9, C and D3, or a placebo, daily for six weeks. Pre- and post-intervention, we employed neuroimaging, feces- and blood collection. Primary outcomes were fecal SCFA concentrations, working memory (WM)-related fMRI responses, and WM performance measured with the n-back task. Results After adjusting for baseline values, we found no significant between-group differences in total fecal SCFA levels (p=0.30) and WM performance (p=0.50). Post-intervention WM-related fMRI responses in the hippocampus (p=0.01; ηp²=0.09) and dorsolateral prefrontal cortex (dlPFC) (p=0.06; ηp²=0.04), driven by the right dlPFC (p=0.02), were higher in the CDMV group compared to placebo. Independent of intervention group, post-pre increases in fecal SCFA levels were significantly correlated to increases in dlPFC fMRI responses (ρ=0.31; p=0.02) and WM performance (ρ=0.43; p=0.001). Conclusions Our findings suggest that CDMV supplementation increases WM-related responses of the dlPFC and hippocampus in older adults, but this effect was not accompanied by changes in fecal SCFA levels or WM performance. The positive correlation of within-subject changes in fecal SCFAs with changes in WM dlPFC responses and performance across intervention groups provides human evidence for gut-brain communication in cognitive aging beyond cross-sectional associations.