Dietary EGCG reshapes metabolic-epigenetic interplay to induce transgenerational host defense

Parental diet is a key determinant of offspring health and immune function, in part through epigenetic regulation. Metabolic and epigenetic networks integrate nutrient sensing with chromatin dynamics to maintain cellular and organismal homeostasis. However, the mechanism by which specific dietary bioactive compounds reshape metabolic-epigenetic networks to drive transgenerational adaptive responses remains poorly understood.

Here, we investigate whether and how epigallocatechin-3-gallate (EGCG), a well-characterized dietary bioactive compound, modulates heritable host defense through metabolic-epigenetic crosstalk.

To address both physiological relevance and mechanistic insight, we employed mouse and Drosophila melanogaster models. Parental animals were administered EGCG, and offspring were subsequently assessed for immune function upon infection with Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus. By integrating transcriptomics, metabolite analysis, and isotopic tracing, we analyzed metabolism-related pathways and constructed a dynamic network linking metabolic changes to epigenetic modifications in Drosophila.

In mice, EGCG administration led to a decrease in Escherichia coli burden across multiple tissues in paternal and male offspring in a sex-specific manner, accompanied by metabolic and pro-inflammatory factor changes. In Drosophila melanogaster, early-life EGCG exposure increased survival upon Pseudomonas aeruginosa or Staphylococcus aureus infection and persisted for two subsequent generations. Mechanistically, EGCG reduced intestinal amino acids, thereby moderately inducing activation of activating transcription factor 4 (ATF4), which in turn enhanced maternal glycolysis and immune adaptation. Tyrosine supplementation abolished the enhanced host defense and metabolic changes. Furthermore, ATF4-induced activation of glycolysis promoted ovarian lactate production, serving as a substrate for increased global H3K27 acetylation in the offspring.

Together, these findings suggest that dietary bioactive compounds modulate metabolic and gene regulatory processes, with functional evidence supporting a role for amino acid metabolism and lactate in linking metabolic remodeling to enhanced resistance to infection in the offspring. This work provides mechanistic insight into how diet can shape heritable immune function through metabolic-epigenetic interplay.