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

Remie, L. B.; van Loenen, M. R.; Grootte Bromhaar, M. M.; Overwater, N. M. P.; van Overbeek, J.; Anesi, A.; Vrhovsek, U.; Rehman, A.; Steinert, R. E.; Mes, J. J.; Hooiveld, G. J. E. J.; Steegenga, W. T.; Oosterman, J. M.; van Trijp, M. P. H.; Aarts, E.

doi:10.64898/2026.03.10.709744

bioRxiv · 10.64898/2026.03.10.709744

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

Remie, L. B.·van Loenen, M. R.·Grootte Bromhaar, M. M.·Overwater, N. M. P.·van Overbeek, J.·Anesi, A.·Vrhovsek, U.·Rehman, A.·Steinert, R. E.·Mes, J. J.·Hooiveld, G. J. E. J.·Steegenga, W. T.·Oosterman, J. M.·van Trijp, M. P. H.·Aarts, E.

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Abstract

BackgroundVitamins 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 axiss emerging role in cognitive aging. ObjectiveWe investigated the effect of a colon-delivered multivitamin (CDMV) supplement on intestinal health and neurocognitive outcomes in older adults at risk of cognitive decline. MethodsWithin 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. ResultsAfter 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; p{superscript 2}=0.09) and dorsolateral prefrontal cortex (dlPFC) (p=0.06; p{superscript 2}=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 ({rho}=0.31; p=0.02) and WM performance ({rho}=0.43; p=0.001). ConclusionsOur 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.

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Remie, L. B., van Loenen, M. R., Grootte Bromhaar, M. M., Overwater, N. M. P., van Overbeek, J., Anesi, A., Vrhovsek, U., Rehman, A., Steinert, R. E., Mes, J. J., Hooiveld, G. J. E. J., Steegenga, W. T., Oosterman, J. M., van Trijp, M. P. H., Aarts, E.. 2026-03-12. Colon-delivered multivitamin supplementation enhances working memory-related fMRI responses in older adults: a randomized, placebo-controlled trial. https://doi.org/10.64898/2026.03.10.709744

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