Epigenetic Changes Following Maternal Gut Microbiota Improvement With Dietary Fibre Lead To Cardio-protection In The Offspring

Dietary fibre is fermented by the gut microbiota and protects against the development of cardiovascular disease (CVD) through the production of gut microbial metabolites. We hypothesised dietary fibre intake during pregnancy may prevent the development of CVD in the offspring via in utero epigenetic mechanisms. To investigate this, we fed C57BL/6J female mice diets high or low in resistant starches (‘high-fibre’ and ‘low-fibre’, respectively) during gestation. At 6-weeks of age, we performed single-cell RNA-sequencing in the offspring (n=8/group) or they were challenged with saline (sham) or angiotensin II (Ang II, 0.25mg/kg/day, n=18-23/group). Maternal diet resulted in a distinct gut microbial composition ( P =0.001). This was still evident in the adult offspring, with high-fibre offspring having a different gut microbial colonisation ( P =0.001), irrespective of sham/Ang II treatment. Maternal fibre intake significantly changed the cardiac cellular and molecular landscape and promoted differential gene signatures in the offspring. This included upregulation of genes associated with extracellular matrix production in the offspring from low-fibre mothers. When challenged with Ang II, low-fibre offspring developed increased cardiac hypertrophy ( P =0.034) and fibrosis ( P =0.01) compared to high-fibre offspring. This was accompanied with decreased ejection fraction ( P =0.001) and increased left ventricular posterior wall thickness ( P= 0.017). These changes were independent of blood pressure. High-fibre offspring had decreased expression of natriuretic peptides ( Nppa , P =0.03, Nppb , P =0.002) compared to low-fibre offspring. Chromatin-immunoprecipitation assay revealed decrease in H3-acetylation at the cis-regulatory region of Nppa gene in Ang II-treated high-fibre offspring (P=0.002), suggesting that maternal fibre intake influences the epigenetic changes of the Nppa gene in the offspring’s heart. Together, these data reveal maternal high-fibre intake leads to foetal epigenetic reprogramming, likely through maternal to foetal transfer of gut microbial-derived metabolites.