A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms

ABSTRACT

Alzheimer’s disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a modified Mediterranean-ketogenic diet (MkD) on AD-related neurocognitive pathophysiology and underlying mechanisms related to the gut-microbiome-brain axis. The findings revealed that MkD induces profound shifts in the gut microbiome community and microbial metabolites. Most notably, MkD promoted growth of the Lactobacillus population, resulting in increased bacteria-derived lactate production. We discovered elevated levels of microbiome- and diet-derived metabolites in the serum as well, signaling their influence on the brain. Importantly, these changes in serum metabolites upregulated specific receptors that have neuroprotective effects and induced alternations in neuroinflammatory-associated pathway profiles in hippocampus. Additionally, these metabolites displayed strong favorable co-regulation relationship with gut-brain integrity and inflammatory markers, as well as neurobehavioral outcomes. The findings underscore the ameliorative effects of MkD on AD-related neurological function and the underlying gut-brain communication via modulation of the gut microbiome-metabolome arrays.

GRAPHICAL ABSTRACT

KEYWORDS:

• Alzheimer’s disease
• gut-brain axis
• ketogenic diet
• Mediterranean diet
• metabolome
• microbiome
• neurocognition
• neurodegenerative disease
• neuroinflammation

Acknowledgments

The authors wish to thank the members of the FSU Institutional Animal Care & Use Committee (ACUC) and the FSU Laboratory Animal Resources (LAR) for help with animal husbandry and supervision, and the members of the FSU Biological Core Laboratory for assistance with metagenomic sequencing. The authors are also thankful to fellow lab members and colleagues who provided miscellaneous helps, suggestions, and resources pertaining to this work. Additionally, the authors thank Ngan Nguyen (from North Carolina A&T State University) for help with metabolomics analysis and Karen McFarland (from University of Florida) for help with the NanoString assay.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

R.N. conceived and designed the study. G.P., S.K., N.H., J.P., B.W., P.C., G.S., and R.N. performed the experiments. G.P. and S.K. performed the data analysis and visualization. G.P. wrote the first draft of the manuscript. G.P., S.K., P.C., P.E., J.S., and R.N. reviewed and edited the manuscript. All authors reviewed and approved the final version of the manuscript.

Data availability statement

The data that support the findings of this study are openly available in National Center for Biotechnology Information (NCBI)-Sequence Read Archive (SRA) at https://www.ncbi.nlm.nih.gov/sra, reference number PRJNA1011002 (16S rRNA sequencing dataset) and PRJNA1010986 (ITS rRNA sequencing dataset).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2323752

Additional information

Funding

The study was supported by the Florida State University Council on Research & Creativity (FSU-CRC) funding program and the FSU College of Health & Human Sciences new investigator funding to RN. RN also acknowledges funding from the Infectious Diseases Society of America (IDSA), the United States Department of Agriculture (USDA-ARS #440658), and the Florida Department of Health (23A02 and 24A05). BW would like to thank the National Science Foundation (NSF; Grant No. 2245530) for support in metabolomics studies. The findings in this publication have not been formally disseminated by the funders and should not be construed to represent any agency determination or policy.