Dietary interventions constitute powerful approaches for disease prevention and treatment. However, the molecular mechanisms through which diet affects health remain underexplored in humans. Here, we compare plasma metabolomic and proteomic profiles between dietary states for a unique group of individuals who alternate between omnivory and animal product restriction (APR) for religious reasons. We find that short-term APR is associated with extensive metabolic reprogramming not detected in a control group of continuously omnivorous individuals. We identify reductions in the levels of branched-chain amino acids and of most lipid classes, driving a metabolic profile associated with decreased risk for all-cause mortality. We show that 23% of APR-associated proteins are drug targets, and highlight eight proteins displaying the greatest magnitude of change upon APR (FGF21, FOLR2, SUMF2, HAVCR1, PLA2G1B, OXT, HPGDS, SPP1). We find that APR-associated reprogramming improves metabolic health and emphasise high-value targets for pharmacological intervention.

The authors have declared no competing interest.

This work was funded by an ERC grant to Dr Antigone Dimas (FastBio 716998). Dr Ozvan Bocher has received funding from the European Union Horizon 2020 research and innovation programme under Grant Agreement No 101017802 (OPTOMICS).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of BSRC Alexander Fleming gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors. Proteomics and metabolomics summary statistics are available at Zenodo.

https://zenodo.org/records/10985423