Multi-Omics Analysis of Lung Tissue Demonstrates Changes to Lipid Metabolism during Allergic Sensitization in Mice

Abstract

Allergy and asthma pathogenesis are associated with the dysregulation of metabolic pathways. To understand the effects of allergen sensitization on metabolic pathways, we conducted a multi-omics study using BALB/cJ mice sensitized to house dust mite (HDM) extract or saline. Lung tissue was used to perform untargeted metabolomics and transcriptomics while both lung tissue and plasma were used for targeted lipidomics. Following statistical comparisons, an integrated pathway analysis was conducted. Histopathological changes demonstrated an allergic response in HDM-sensitized mice. Untargeted metabolomics showed 391 lung tissue compounds were significantly different between HDM and control mice (adjusted p < 0.05); with most compounds mapping to glycerophospholipid and sphingolipid pathways. Several lung oxylipins, including 14-HDHA, 8-HETE, 15-HETE, 6-keto-PGF1α, and PGE2 were significantly elevated in HDM-sensitized mice (p < 0.05). Global gene expression analysis showed upregulated calcium channel, G protein–signaling, and mTORC1 signaling pathways. Genes related to oxylipin metabolism such as Cox, Cyp450s, and cPla2 trended upwards. Joint analysis of metabolomics and transcriptomics supported a role for glycerophospholipid and sphingolipid metabolism following HDM sensitization. Collectively, our multi-omics results linked decreased glycerophospholipid and sphingolipid compounds and increased oxylipins with allergic sensitization; concurrent upregulation of associated gene pathways supports a role for bioactive lipids in the pathogenesis of allergy and asthma.

Metabolomics Applied to Pediatric Asthma: What Have We Learnt in the Past 10 Years?

“…Based on their data, the authors suggest that an integrated microbiome and metabolome analysis can help understand the role of host–microbial interactions in IgE-mediated childhood asthma [ 37 ]. Recently, Turi et al [ 38 ] applied a multi-omics analysis (untargeted metabolomics, targeted analysis of oxylipins, and transcriptomics of lung tissue) to understand the molecular processes underlying allergic asthma etiology in house dust mite (HDM)-induced allergic mice. In these mice, this integrated analysis showed a downregulation of glycerophosphatidylcholines, glycerophosphatidylethanolamines, phosphosphingolipids, and glycerophosphoinositols, whereas there was an upregulation of several diacylglicerols, phosphatidylserines and glycerophosphate, providing additional insight into novel links between metabolic, immune, and neuronal signaling pathways triggered by HDM sensitization.…”

Metabolomics in Animal Models of Bronchial Asthma and Its Translational Importance for Clinics

“…As regulation of the TCA cycle depends on the availability of substrates, alteration of energy metabolism in asthma leads to changes in glucose, pyruvate, citrate, succinate, malate, etc. [ 59 , 65 , 67 , 74 , 75 ]. Under stress and in anaerobic conditions, pyruvate may change to lactate, representing an alternative source of energy.…”

“…In HDM-sensitized mice, several lung oxylipins were significantly elevated and calcium channel, G protein-signaling, and mTORC1 signaling pathways were upregulated. Association of allergic sensitization with decreased glycerophospholipid and sphingolipid compounds and increased oxylipins confirmed a role for bioactive lipids in the pathogenesis of allergy and asthma [ 75 ].…”

“…More detailed information is provided in the text and in Table 1 and Table 2 . Alterations in lipid metabolism have been demonstrated in both human [ 29 , 39 , 41 , 43 , 44 , 45 , 51 , 52 , 54 , 55 ] and animal [ 75 , 79 , 80 , 81 , 82 , 83 , 85 , 86 , 87 , 93 ] studies. Alterations in amino acid metabolism have been shown in both human [ 41 , 54 , 58 , 59 , 60 , 61 , 62 , 64 , 65 , 66 , 69 , 72 ] and animal [ 79 , 80 , 81 , 82 , 83 , 85 , 87 , 92 , 93 , 94 ] studies.…”

“…Alterations in purine metabolism have been confirmed in both human [ 71 , 72 , 73 ] and animal [ 79 , 80 , 83 , 92 ] studies. Alterations in glycolysis and TCA cycle have been demonstrated in both human [ 55 , 59 , 65 , 67 , 74 , 75 , 76 , 77 ] and animal [ 78 , 81 , 87 , 92 , 93 , 94 ] studies.…”