Project description:A multi-omic approach in a clinical experimental study identified circulating biomarkers reflecting glucocorticoid exposure. Background: Endogenous glucocorticoids (GC) are mechanistically linked to common diseases and are important as drugs in the treatment of many disorders. There is no marker that can measure and quantify GC action. Our aim was to identify circulating biomarkers of GC action using a clinical experimental study. Methods: In a randomized, crossover, single-blind trial, subjects with primary adrenal insufficiency received intravenous hydrocortisone infusion in a circadian pattern (physiological GC exposure) or isotonic saline (GC withdrawal) over 22 hours. Samples were collected at 7 AM (end of infusion). Integrated multi-omic analysis was used because of the complexity in GC action and the low number of subjects. The transcriptome in peripheral blood mononuclear cells (PBMCs) and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions. Replication of the plasma miRNA findings was performed in three independent studies. Results: During GC withdrawal, overnight urinary cortisol and cortisone excretion were undetectable. Correlation and hypernetwork analyses identified a transcriptomic profile derived from PBMCs and adipose tissue predictive of GC exposure, and a multi-omic cluster predictive of GC exposure. From the circulating ‘omic data, decreased expression of plasma miR-122-5p was associated with increased GC exposure. This finding was reproduced in three independent studies. Conclusion: We developed a human experimental model for physiological GC exposure and withdrawal. The integrated multi-omic data identified circulating miRNAs and metabolites associated with GC-responsive genes. In independent studies, miR-122-5p was shown to be associated with GC exposure. Background: Endogenous glucocorticoids (GC) are mechanistically linked to common diseases and are important as drugs in the treatment of many disorders. There is no marker that can measure and quantify GC action. Our aim was to identify circulating biomarkers of GC action using a clinical experimental study.

Project description:BackgroundBritain's native oak species are currently under threat from acute oak decline (AOD), a decline-disease where stem bleeds overlying necrotic lesions in the inner bark and larval galleries of the bark-boring beetle, Agrilus biguttatus, represent the primary symptoms. It is known that complex interactions between the plant host and its microbiome, i.e. the holobiont, significantly influence the health status of the plant. In AOD, necrotic lesions are caused by a microbiome shift to a pathobiome consisting predominantly of Brenneria goodwinii, Gibbsiella quercinecans, Rahnella victoriana and potentially other bacteria. However, the specific mechanistic processes of the microbiota causing tissue necrosis, and the host response, have not been established and represent a barrier to understanding and managing this decline.ResultsWe profiled the metagenome, metatranscriptome and metaproteome of inner bark tissue from AOD symptomatic and non-symptomatic trees to characterise microbiota-host interactions. Active bacterial virulence factors such as plant cell wall-degrading enzymes, reactive oxygen species defence and flagella in AOD lesions, along with host defence responses including reactive oxygen species, cell wall modification and defence regulators were identified. B. goodwinii dominated the lesion microbiome, with significant expression of virulence factors such as the phytopathogen effector avrE. A smaller proportion of microbiome activity was attributed to G. quercinecans and R. victoriana. In addition, we describe for the first time the potential role of two previously uncharacterised Gram-positive bacteria predicted from metagenomic binning and identified as active in the AOD lesion metatranscriptome and metaproteome, implicating them in lesion formation.ConclusionsThis multi-omic study provides novel functional insights into microbiota-host interactions in AOD, a complex arboreal decline disease where polymicrobial-host interactions result in lesion formation on tree stems. We present the first descriptions of holobiont function in oak health and disease, specifically, the relative lesion activity of B. goodwinii, G. quercinecans, Rahnella victoriana and other bacteria. Thus, the research presented here provides evidence of some of the mechanisms used by members of the lesion microbiome and a template for future multi-omic research into holobiont characterisation, plant polymicrobial diseases and pathogen defence in trees.

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Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.

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