Exploring the Immunomodulatory Effects of Fasting-Mimicking Diet in Healthy Individuals: A Pilot Study

Background: Fasting-mimicking diets (FMDs) induce metabolic changes associated with immunomodulation in preclinical studies, yet little is known about the effects of FMD on the human circulating immune system. Methods: In the single-arm FIND pilot study (NCT04833439), six of nine healthy participants completed two cycles of a 4-day FMD separated by 3 weeks of regular diet in a repeated-measures design. Blood samples were collected at baseline, after an overnight fast, and the morning after completion of the second FMD cycle. Peripheral blood mononuclear cells (PBMCs) were analyzed by transcriptomic profiling and spectral flow cytometry. Results: FMD was associated with reduced plasma glucose and insulin-like growth factor-1 and increased ketone levels. Transcriptomic analysis showed increased expression of genes involved in the TNFα, IFNγ and IFNα signaling pathway after two FMD cycles. Fifteen of the 39 leading-edge genes of the TNFα signature that have previously been associated with myeloid activity and rapid stress responses corresponded with the increased frequencies of circulating CD14-CD11b-CD11c+ dendritic cells (DCs), CD123+ plasmacytoid DCs, and CD14+ CD16+ intermediate monocytes. Moreover, the frequencies of HLA-DR-expressing CD4+ and CD8+ T-cells increased (p < 0.05) after two FMD cycles. Conclusions: In healthy volunteers, two cycles of FMD were associated with metabolic changes and alterations in circulating myeloid and T-cell populations consistent with activation of selected inflammatory pathways. These exploratory findings warrant larger validation studies in healthy volunteers in combination with functional analyses.