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Impact of Intestinal Propionate Metabolism on Systemic Metabolic Homeostasis

ABSTRACT: Propionate is an abundant short-chain fatty acid in mammals, largely derived from gut microbiota production. Due to its abundance, propionate metabolism is essential to maintain systemic homeostasis. Inborn errors of essential metabolic enzymes in this pathway causes severe illness, such as the development of Propionic Acidemia in cases of Propionyl-CoA Carboxylase (PCC) deficiency. We and others have previously developed mouse models deficient in Pcca, encoding the alpha subunit of PCC, to study the systemic and liver-specific mechanisms of propionic acidemia. However, the role of PCC in the intestine, where propionate is primarily absorbed, is understudied. To investigate the gut-specific role of PCC, we developed a mouse knockout of Pcca using Villin-Cre (Pcca Vill) on a floxed Pcca (Pcca ff) background. Here, we demonstrate the phenotypes present in this model provided both a standard (chow) and high fat (HFD) diets.

ORGANISM(S): Mus musculus

PROVIDER: GSE329264 | GEO | 2026/05/02

REPOSITORIES: GEO

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Project description:Propionate is a common three-carbon intermediate produced from the breakdown of propiogenic substrates, such as branched-chain amino acids and odd-numbered fatty acids, and by gut bacteria. Propionate can chemically modify proteins, and if this involves histones, it may underpin a disease-relevant link between short-chain acyls and gene expression in the heart. Here, we sought to characterize how propionate-dependent modifications to histones affect cardiac gene expression and contractile function in a mouse model producing elevated levels of propionate/propionyl-CoA. An adult mouse model of propionic acidaemia (PA) was used to investigate how propionate affects histones and gene expression in the heart, an organ strongly affected in PA patients. Mass spectrometry confirmed elevated plasma propionate in 8-week PA mice, reaching levels detected in PA patient serum. Metabolomic analyses confirmed a metabolic signature of PA, but male mice had enhanced propionate processing towards -alanine. Female PA hearts had expanded end-diastolic and end-systolic volumes, and weaker systolic contractions, without major electrocardiographic changes. Ca2+ signals were deranged in female PA mice (raised diastolic Ca2+), consistent with contractile dysfunction. Differentially-expressed genes (DEGs) included Pde9a and Mme, previously linked to cardiac dysfunction. These DEGs also responded to 48-h culture of wild-type myocytes with propionate as well as butyrate, an HDAC inhibitor, suggesting a role for increased histone acetylation alongside propionylation in inducing these genes. Indeed, histone acetylation (H3K27ac) and propionylation were elevated genome-wide in the PA heart and at the promoters of Pde9a and Mme. These propionate-associated epigenetic responses were more pronounced in female PA mice. The greater prominence of epigenetic, transcriptional, and functional responses in female PA mice, despite a mostly sex-indiscriminate overall metabolic milieu, argues that histone acylation plays a defining role in the cardiac phenotype. We conclude that perturbed propionate metabolism in vivo alters histone acylation and gene expression, which impacts cardiac contractile function.

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Impact of Intestinal Propionate Metabolism on Systemic Metabolic Homeostasis

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