Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Chu, Xiaojing; Jaeger, Martin; Beumer, Joep; Bakker, Olivier B.; Aguirre-Gamboa, Raúl; Oosting, Marije; Smeekens, Sanne P.; Moorlag, Simone J.C.F.M.; Mourits, Vera P.; Koeken, Valerie A C M; Bree, Charlotte de; Jansen, Trees; Mathews, Ian T.; Dao, Khoi; Najhawan, Mahan; Watrous, Jeramie D.; Joosten, Irma; Sharma, Sonia; Koenen, Hans J. P. M.; Withoff, Sebo; Jonkers, Iris; Netea‐Maier, Romana T.; Xavier, Ramnik J.; Franke, Lude; Xu, Cheng‐Jian; Joosten, Leo A. B.; Jain, Mohit; Kumar, Vinod; Wijmenga, Cisca; Netea, Mihai G.; Li, Yang

doi:10.1186/s13059-021-02413-z

Cited by 40 publications

(29 citation statements)

References 76 publications

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“…While cellular metabolism is important for both innate and adaptive immune responses, it seems that the baseline abundance of metabolites more strongly affects variation in innate rather than adaptive immune responses induced by BCG. These results are in line with a recent study that observed a stronger effect of baseline metabolites on interindividual variation of monocyte-derived cytokines (TNF-α, IL-1β, IL-6) compared to T cell-derived cytokines (IL-17, IL-22, IFN-γ) [ 28 ]. Various metabolites influence the activity of epigenetic modifying enzymes, for example, acetyl-CoA, which acts as an acetyl group donor for histone acetyltransferases [ 29 ].…”

Section: Discussionsupporting

confidence: 92%

Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination

Koeken

Mourits

et al. 2022

PLoS Biol

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The antituberculosis vaccine Bacillus Calmette–Guérin (BCG) induces nonspecific protection against heterologous infections, at least partly through induction of innate immune memory (trained immunity). The amplitude of the response to BCG is variable, but the factors that influence this response are poorly understood. Metabolites, either released by cells or absorbed from the gut, are known to influence immune responses, but whether they impact BCG responses is not known. We vaccinated 325 healthy individuals with BCG, and collected blood before, 2 weeks and 3 months after vaccination, to assess the influence of circulating metabolites on the immune responses induced by BCG. Circulating metabolite concentrations after BCG vaccination were found to have a more pronounced impact on trained immunity responses, such as the increase in IL-1β and TNF-α production upon Staphylococcus aureus stimulation, than on specific adaptive immune memory, assessed as IFN-γ production in response to Mycobacterium tuberculosis. Circulating metabolites at baseline were able to predict trained immunity responses at 3 months after vaccination and enrichment analysis based on the metabolites positively associated with trained immunity revealed enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both of which were previously found to be important for trained immunity. Several new metabolic pathways that influence trained immunity were identified, among which taurine metabolism associated with BCG-induced trained immunity, a finding validated in functional experiments. In conclusion, circulating metabolites are important factors influencing BCG-induced trained immunity in humans. Modulation of metabolic pathways may be a novel strategy to improve vaccine and trained immunity responses.

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Section: Discussionsupporting

confidence: 92%

Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination

Koeken

Mourits

et al. 2022

PLoS Biol

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“…We acquired summary statistics of cytokine QTLs ( 17 ), cell proportion QTLs ( 19 ) and circulating mediators and metabolite QTLs ( 23 ) from our previous studies performed with 500FG. Metabolites were measured on the Brainshake Metabolomics/Nightingale Health metabolic platform.…”

Section: Methodsmentioning

confidence: 99%

The Genetic Risk for COVID-19 Severity Is Associated With Defective Immune Responses

Kuijpers

Chu

Jaeger³

et al. 2022

Front. Immunol.

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Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.

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“…Compared with transcriptomics, large-scale metabolomics data have become widely available only more recently and have been integrated with disease GWASs in only a few studies. 9 , 10 , 11 , 12 The extent to which metabolomics data in large cohorts improve our understanding of disease molecular mechanisms beyond the integration of transcriptomics and GWAS results has not been systematically investigated.…”

Section: Introductionmentioning

confidence: 99%

Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Yin¹,

Bose²,

Kwon³

et al. 2022

The American Journal of Human Genetics

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Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Cited by 40 publications

References 76 publications

Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination

Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination

The Genetic Risk for COVID-19 Severity Is Associated With Defective Immune Responses

Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

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