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Metabolomics connects aberrant bioenergetic, transmethylation, and gut microbiota in sarcoidosis

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Abstract

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Granulomatous inflammation in sarcoidosis may affect multiple organs, including the lungs, skin, CNS, and the eyes, leading to severe morbidity and mortality. The underlying mechanisms for sustained inflammation in sarcoidosis are unknown. We hypothesized that metabolic changes play a critical role in perpetuation of inflammation in sarcoidosis. 1H nuclear magnetic resonance (NMR)-based untargeted metabolomic analysis was used to identify circulating molecules in serum to discriminate sarcoidosis patients from healthy controls. Principal component analyses (PCA) were performed to identify different metabolic markers and explore the changes of associated biochemical pathways. Using Chenomx 7.6 NMR Suite software, we identified and quantified metabolites responsible for such separation in the PCA models. Quantitative analysis showed that the levels of metabolites, such as 3-hydroxybutyrate, acetoacetate, carnitine, cystine, homocysteine, pyruvate, and trimethylamine N-oxide were significantly increased in sarcoidosis patients. Interestingly, succinate, a major intermediate metabolite involved in the tricyclic acid cycle was significantly decreased in sarcoidosis patients. Application of integrative pathway analyses identified deregulation of butanoate, ketone bodies, citric cycle metabolisms, and transmethylation. This may be used for development of new drugs or nutritional modification.

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Abbreviations

ASCT2:

Amino acid transporter 2

BMI:

Body mass index

CD4+ :

Cluster of differentiation 4

D2O:

Deuterium oxide

DSS:

Disodium-2,2-dimethyl 2-silapentane-5-sulphonate

KEGG:

Kyoto Encyclopedia of Genes and Genomes

NMR:

Nuclear magnetic resonance

NOESY:

Nuclear Overhauser effect spectroscopy

PC:

Principal component

PCA:

Principal component analysis

PLS-DA:

Partial least square discriminant analysis

SIMCA:

Soft independent modeling of class analogy

TCA:

Tricarboxylic acid cycle

Th1:

T-helper type 1

TLR4:

Toll-like receptor 4

TMA:

Trimethylamine

TMAO:

Trimethylamine N-oxide

VIP:

Variable importance in the projection

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Acknowledgments

This work was supported by the Department of Medicine and the Center for Molecular Medicine and Genetics, Wayne State University School of Medicine (LS) and National Institute of Health R01HL113508 (LS).

Author contribution

AG contributed to the study design, participated in sample collection, conducted the analysis, interpreted the data and drafted the manuscript. SVG provided access and contributed to multivariate data analysis, as well as assisted with the preparation of the manuscript. CB participated in data interpretation and preparation of the manuscript. LS designed the study, and participated in all areas of the research, data analysis and writing of the manuscript. All authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine and Detroit Medical Center, 3990 John R., 3 Hudson, Detroit, MI, 48201, USA

    Andreea Geamanu & Lobelia Samavati

  2. Department of Nutrition and Food Science, Wayne State University, Detroit, MI, 48201, USA

    Smiti V. Gupta

  3. Division of Pediatric Critical Care, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, 48201, USA

    Christian Bauerfeld

  4. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Lobelia Samavati

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  1. Andreea Geamanu
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  2. Smiti V. Gupta
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  4. Lobelia Samavati
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Correspondence to Lobelia Samavati.

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AG, SVG, CB, and LS declare that they have no conflict of interest.

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Geamanu, A., Gupta, S.V., Bauerfeld, C. et al. Metabolomics connects aberrant bioenergetic, transmethylation, and gut microbiota in sarcoidosis. Metabolomics 12, 35 (2016). https://doi.org/10.1007/s11306-015-0932-2

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  • DOI: https://doi.org/10.1007/s11306-015-0932-2

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