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An Atlas of Inter-Organ Metabolite Trafficking in Health and Atherogenic Conditions

ABSTRACT:

Mammalian organs continuously exchange circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, hormone arrays and multiple metabolic disease models in pigs, we generated a blueprint of ~1300 circulating metabolites trafficking across 10 organs during fasting/feeding, Western diet and cardiovascular disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous feeding-dependent and -independent inter-organ metabolite trafficking events and mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and hormone imbalances. Surprisingly, both Western diet and LDLR deficiency trigger release of bile acids by multiple extra-hepatic organs. Such abnormality dramatically elevates circulating bile acids, which induce atherogenic inflammation. These findings and resources in highly relevant pig models reveal intricate inter-organ crosstalk across pathophysiological conditions, offering unparalleled insights into diet effects and disease mechanisms.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS10288 | MetaboLights | 2025-05-12

REPOSITORIES: MetaboLights

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Project description:The importance of brain-body interactions in the progresses of diseases are increasingly noticed, and understanding the associated processes could vastly improve the health of whole organism. A comprehensive, whole-organism analysis of organ dynamics to identify the molecular processes within and between organs after brain injury caused by ischemic stroke has been lacking. Mice models of 24 hours ischemic brain injury are constructed. Proteomics and metabolomics are used to detect the changes of organ’s proteome and metaboleome, respectively, and multiple bioinformatics analysis are performed to investigate the changing signatures across organs after stroke. Then, the organ proteomics data combined with aging mouse organ transcriptome data and mouse organ scRNA-seq data to reveal the biological age of organs and cellular resource of differentially expressed proteins (DEPs) of organs after stroke, respectively. Finally, we cross-referenced stroke-related DEPs in plasma with their corresponding protein expression in each organ to investigate the original source of plasma proteins by using spearman’s correlation analysis. Bioinformatics analysis showing the synchronization and asynchronization of the stroke-related proteins involved in multiple regulatory pathways are universally across organs. Although significant inter-organ correlations exist without influenced by stroke, the protein expression changes may better reflect the inter-organ correlation after brain injury by sharing some common changing signatures. Then, hundreds of DEPs in organs with the greatest numbers of DEPs are revealed in heart, and they are unique and common expressed between organs. Notably, an integrate analysis of these DEPs with mouse aging RNA-seq data reveal ageing-like changes in organs, suggesting increased biological ages of organs. Furthermore, a conjoint analysis of our proteomic data with scRNA-seq data confirms the cellular source of DEPs originated from intrinsic cells and immune cells, and the latter are widely located and activated in organs. Finally, we find that some DEPs in plasma are highly correlated with corresponding protein levels in distinct organs, potentially resulting in the stroke of the systemic circulation. Together, this study demonstrates a similar yet asynchronous inter- and intra-organ progression of stroke, providing a fundamental resource for understanding the molecular mechanisms underlying brain-body interaction and potential interventions for brain injury.

Project description:BackgroundAging is a complex biological process characterized by progressive molecular alterations across multiple organ systems, significantly influencing disease susceptibility and mortality. Unraveling molecular interactions driving aging is crucial for interventions promoting healthy aging and mitigating senescence. However, the systemic mechanisms governing both inter-organ interactions and organ-specific aging trajectories remain incompletely characterized.MethodsTo investigate the molecular dynamics of aging, we conducted a systematic multi-omics analysis of 400 tissue samples collected from 10 organs (brain, heart, intestine, kidney, liver, lung, muscle, skin, spleen, and stomach) in mice at four distinct life stages: 4, 8, 12, and 20 months (from youth to elderly). Proteomic profiling was performed using data-independent acquisition (DIA) technology, while metabolomic analysis was performed in both positive and negative ion modes. Differential expression analysis of proteins and metabolites was employed to construct a comprehensive multi-organ aging dataset. ResultsProteomic profiling across ten organs at four age stages identified a total of 14,763 protein groups (PGs). Of these, 18 proteins, including Ighm, C4b, and Hpx, exhibited consistent age-related differential expression patterns across all ten organs. Functional enrichment analysis highlighted the humoral immune response as a primary driver of age-related expression changes. Additionally, this study mapped a set of age-unique proteins, such as Hp, Egf, and Arg, with distinct expression patterns in aging organs. Metabolic analysis identified 3,779 metabolites, with key aging-related metabolites such as NAD+, inosine, xanthine, and hypoxanthine showing significant expression changes across multiple organs. Pathway enrichment analysis revealed consistent alterations in purine metabolism, pyrimidine metabolism, riboflavin metabolism, and nicotinate/nicotinamide metabolism during multi-organ aging.ConclusionsThis study provides a multi-omics atlas of multi-organ aging, revealing both intra- and inter-organ similarities and heterogeneities. These findings offer valuable insights into the molecular mechanisms underlying geriatric health decline and serve as a foundational resource for organism-systematic early warning and targeted interventions against aging-associated pathologies.

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	FP1_Neg_000m_FV.raw	Raw
	FP1_Neg_000m_H.raw	Raw

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An Atlas of Inter-Organ Metabolite Trafficking in Health and Atherogenic Conditions

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