Brook, J. R. | bioRxiv Science

bioRxiv2025

Branched-chain ketoacid antioxidants mediate disease tolerance to sepsis

Metabolic adaptation is crucial for surviving systemic infection and withstanding the pathological host response to infection known as sepsis. The liver orchestrates key metabolic adaptation programs that enable disease tolerance in sepsis, yet the impact of liver metabolites on sepsis susceptibility is not well understood. By broadly profiling liver metabolite landscapes in mice surviving or succumbing to bacterial sepsis, we found that dysregulation of the branched-chain amino acid metabolite family is associated with sepsis non-survival. Administration of branched-chain ketoacids (BCKAs) during Klebsiella pneumoniae-induced sepsis in mice enhanced survival, yet not through enhanced bacterial clearance or BCKA catabolism. Instead, BCKAs served as antioxidants by directly neutralizing hydrogen peroxide, preventing tissue lipid peroxidation. Targeted metabolomics in sepsis patients revealed low BCKA abundance as an early prognostic biomarker of sepsis non-survival. Our results identify BCKAs as a systemic shield against oxidative damage and highlight new metabolite targets to enhance disease tolerance to sepsis.

pathology↗

bioRxiv2023

Persistent DNA methylation changes associated with prenatal NO2 exposure in a Canadian prospective birth study

BackgroundAccumulating evidence suggests prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. However, it remains unclear whether prenatal DNAm alterations persist through early life. Identifying DNAm changes that persist from birth into childhood would provide greater insight into the molecular mechanisms that most likely contribute to the association of prenatal air pollution exposure with health outcomes such as atopic disease. ObjectivesThis study investigated the persistence of DNAm changes associated with prenatal NO2 exposure (a surrogate measure of traffic-related air pollution) at age one to begin characterizing which DNAm changes most likely to contribute to atopic disease. MethodsWe used an atopy-enriched subset of CHILD study participants (N=145) to identify individual and regional cord blood DNAm differences associated with prenatal NO2, followed by an investigation of persistence in age one peripheral blood. As we had repeated DNAm measures, we also isolated postnatal-specific DNAm changes and examined their association with NO2 exposure in the first year of life. MANOVA tests were used to examine the association between DNAm changes associated with NO2 and child wheeze and atopy. ResultsWe identified 24 regions of altered cord blood DNAm, with several annotated to HOX genes. Two regions annotated to MPDU1 and C5orf63 were significantly associated with age one wheeze. Further, we found the effect of prenatal NO2 exposure across CpGs within all altered regions remained similar at age one. A single region of postnatal-specific DNAm annotated to HOXB6 was associated with year one NO2 and age one atopy. DiscussionRegional cord blood DNAm changes associated with prenatal NO2 exposure persist through at least the first year of life, and some of these changes are associated with age one wheeze. The early-postnatal period remains a sensitive window to DNAm perturbations that may also influence child health.

genetics↗