Metabolomics and allergy: Opening Pandora’s box
2020; Elsevier BV; Volume: 145; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2020.01.012
ISSN1097-6825
Autores Tópico(s)Allergic Rhinitis and Sensitization
ResumoUnderstanding disease pathogenic mechanisms is still the best way to improve diagnosis, prognosis, and therapeutic strategies. After decades of biased clinical observations or targeted disease models, where suspected mechanisms were essentially based on the demonstration of a rarely more than 1 ligand to receptor interaction, an unbiased approach based on the analysis of complex databases built on well-defined clinical expressions confronted to systems biology analyses (genomics, transcriptomics, metabolomics, proteomics, etc) has allowed the characterization of essential disease clusters. This has been the hallmark of the development of the field of severe asthma with the definition of essential asthma endotypes,1Wenzel S.E. Asthma phenotypes: the evolution from clinical to molecular approaches.Nat Med. 2012; 18: 716-725Crossref PubMed Scopus (1628) Google Scholar and more recently for atopic dermatitis.2Ghosh D. Bernstein J.A. Khurana Hershey G.K. Rothenberg M.E. Mersha T.B. Leveraging multilayered “omics” data for atopic dermatitis: a road map to precision medicine.Front Immunol. 2018; 9: 2727Crossref PubMed Scopus (50) Google Scholar Clusters are linked to potential disease markers, which may eventually become targets for therapeutic intervention. Asthma has been emblematic in this respect, and the current availability of powerful anti–IL-5 or IL-4/IL-13 biologicals is in large part derived from the creative work performed by several severe asthma networks over the recent few years. Therefore, applying this approach—an untargeted approach based on metabolomic analysis of patients’ serum—to allergy domains such as food allergy (FA), where progress in terms of disease markers, diagnosis, therapy, and prevention is largely unmet, represents a methodological breakthrough, which may feed novel, unsuspected pathogenic hypothesis and potential therapeutic strategies. This is the difficult path that Talal A. Chatila’s group has chosen to follow in a well-documented, substantial, and highly stimulating report in this issue.3Crestani E. Harb H. Charbonnier L.M. Leirer J. Motsinger-Reif A. Rachid R. et al.Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma.J Allergy Clin Immunol. 2020; 145: 897-906Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Serum metabolomic profiling by mass spectrometry of children with FA, children with asthma, and healthy controls was performed in an untargeted manner and analyzed by complex but now well-established biostatistical methodologies. The main conclusions indicate that pediatric FA metabolomic signature is associated with a decrease in serum level of sphingolipids and ceramides, lysophospholipids, lysoplasmalogens, diacylglycerol, and fatty acids as major lipid metabolite categories. Quite interestingly, FA appears to shape the metabolic landscape of these children, because the profile of children with FA and asthma was similar to the profile of children with FA alone, but radically different from the profile of children with asthma alone and of course from the profile of healthy children. Moreover, the metabolomic profile of food-allergic children without or with asthma was closely linked to the severity of allergic reactions to food, and even more so in children with multiple food allergies. In these cases, severe systemic reactions to food were closely associated with changes in tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids. The next point was to question the origin of such altered metabolomic signatures. Several observations pointed out the probable differentially regulated intervention of gut microbiota. Indeed, the specific comparison of children with FA with or without asthma with those with asthma alone showed significant alterations in the metabolism of secondary biliary acids as well as aromatic amino acids, products of microbiota-dependent enzymatic conversion in the gut. The natural killer (NK) T/NKTi (T invariant) cells’ role, highlighted in asthma,4An D. Na C. Bielawski J. Hannun Y.A. Kasper D.L. Membrane sphingolipids as essential molecular signals for Bacteroides survival in the intestine.Proc Natl Acad Sci U S A. 2011; 108: 4666-4671Crossref PubMed Scopus (91) Google Scholar was also examined, but NKT cells, at least in terms of frequencies and activation level, were found within the normal range. Taken together, without pinpointing definitive and specific pathogenic mechanisms, this study strongly suggests that the observed modulation in amino acid and lipid metabolites may be strongly dependent on immune cells’ interplay with the gut microbiota. Although this report has still the size of a pilot, cross-sectional study, its remarkable findings open the door to a number of sensitive questions around the pathogenesis of FA versus asthma, on the regulation of tolerance, and on the control of allergic reaction severity, and challenges the shaping of the immune programming by immune cell interactions with gut microbiota. Sphingolipids, present in all mammalian cell walls, but also issued from dietary sources, appear as potential key regulators of immune responses leading to specific allergic endotypes, here asthma versus FA. The link between sphingolipids, the microbiota, and specific immune-cell subsets such as NKTi cells is of particular interest. Indeed, Bacteroides species in the gut, frequently associated with protective antiallergic gut microflora, are able to metabolize food-derived sphingolipids, a known ligand of CD1d+ NKTi cells, and to produce them.4An D. Na C. Bielawski J. Hannun Y.A. Kasper D.L. Membrane sphingolipids as essential molecular signals for Bacteroides survival in the intestine.Proc Natl Acad Sci U S A. 2011; 108: 4666-4671Crossref PubMed Scopus (91) Google Scholar Interestingly, children with food sensitization presented with higher NKTi activation than did children with clinical FA, suggesting a protective role of sphingolipid-activated NKTi.5Lee-Sarwar K. Kelly R.S. Lasky-Su J. Moody D.B. Mola A.R. Cheng T.Y. et al.Intestinal microbial-derived sphingolipids are inversely associated with childhood food allergy.J Allergy Clin Immunol. 2018; 142: 335-338.e9Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Conversely, lower levels of sphingolipids in stools were found in subjects with clinical FA as compared with food-sensitized subjects,5Lee-Sarwar K. Kelly R.S. Lasky-Su J. Moody D.B. Mola A.R. Cheng T.Y. et al.Intestinal microbial-derived sphingolipids are inversely associated with childhood food allergy.J Allergy Clin Immunol. 2018; 142: 335-338.e9Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar whereas NKTi cells were found in reduced frequency in children allergic to cow milk.6Jyonouchi S. Abraham V. Orange J.S. Spergel J.M. Gober L. Dudek E. et al.Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin.J Allergy Clin Immunol. 2011; 128: 102-109.e13Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Alterations in plasma sphingolipids (enhancement of sphingosine-1-phosphate) were associated with severe allergic respiratory reactions.7Obeso D. Mera-Berriatua L. Rodriguez-Coira J. Rosace D. Fernandez P. Martin-Antoniano I.A. et al.Multi-omics analysis points to altered platelet functions in severe food-associated respiratory allergy.Allergy. 2018; 73: 2137-2149Crossref PubMed Scopus (52) Google Scholar Nonetheless, the role of NKTi cells remains undefined in the current report because no differences were observed in terms of frequency at least in children with FA versus controls, whereas their frequency was increased as expected from previous studies in those with asthma.8Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (604) Google Scholar Other findings point out the potential relationship between microbiota differential regulation in FA, such as the association of decreased levels of tryptophan metabolites from the kinurenine and serotonin pathways in children with sensitization to more than 1 food, as well as the association of higher levels of indole tryptophan metabolites with severe food-induced anaphylactic reactions. Both the kinurenine pathway and the indolepropionate pathway are key controllers of mucosal barriers and intestinal homeostasis via microbiota-dependent tryptophan metabolism. Sphingolipid metabolism was also strongly affected in children with FA with severe anaphylaxis. This observation fits well with the fact that sphingomyelins and ceramide metabolites may act as negative regulators of mast cells.9Izawa K. Isobe M. Matsukawa T. Ito S. Maehara A. Takahashi M. et al.Sphingomyelin and ceramide are physiological ligands for human LMIR3/CD300f, inhibiting FcepsilonRI-mediated mast cell activation.J Allergy Clin Immunol. 2014; 133: 270-273.e1-7Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Furthermore, metabolomic differences between children with FA and children with asthma without FA identified significant differences in secondary bile acid ratios, themselves also strongly dependent on gut microbiota composition and function. This suggested, as underlined by Crestani et al, a potential role for intestinal dysbiosis in distinctly contributing to FA or asthma phenotypes, and possibly in generating specific microbiota-induced metabolite signatures, which may serve as disease markers. These metabolic findings open a quite innovative field of potential nonclassical allergic markers. A better understanding of the interplay between immune system and the microbiota with identification of specific lipid or amino acid metabolite fluctuation may help to better define not only specific pathologic conditions but possibly even to better evaluate in defined phenotypes their risk of developing allergy. Such information, still largely lacking, will be key to better master the follow-up of our young patients in their march to allergy. There is certainly still a long way to such a goal. At that stage Crestani et al’s study is still a relatively small pilot study, but based on high-quality recruitment bases with clinically and biologically well-defined cohorts of patients with FA and asthma. It will need confirmation in longitudinal observations. Long-term, prospective cohorts are needed to firmly establish the metabolomics findings presented here as the expression of basic mechanisms of FA, and not the trivial results of FA itself, in particular, as mentioned by authors, the consequence of restrictive diets. Furthermore, confirmation of these data in a replication cohort should ensure that these novel metabolomics findings can be validated. Anyhow, several exciting observations of this seminal article may shed new light on the field of tolerance regulation, as suggested by the alteration of tryptophan metabolism with possible impact on the breakdown of oral tolerance. The mechanisms leading from sphingolipid metabolism to TH2 expression will have to be further explored. The observation that the ORMDL3 gene, strongly associated with allergic asthma, may contribute to the modulation of sphingolipid levels in the lung10James B. Milstien S. Spiegel S. ORMDL3 and allergic asthma: from physiology to pathology.J Allergy Clin Immunol. 2019; 144: 634-640Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar supports the data presented here, and suggests that similar alterations of sphingolipid metabolism may play a role in the pathogenesis of not only asthma but possibly also FA. From these demonstrations may derive the long-term perspective of therapeutic interventions on sphingolipid metabolites. Dream or not, Crestani et al have here nicely attempted to reconcile the immune system and the microbiota via crosstalks between immune cells and bacteria-dependent food metabolites, a domain that we will need to become more familiar with (Fig 1). They opened the doors to novel concepts of allergy pathogenesis, and we can bet that further work will lead to other unsuspected boxes and doors. Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthmaJournal of Allergy and Clinical ImmunologyVol. 145Issue 3PreviewFood allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Novel disease biomarkers and curative treatment options are strongly needed. Full-Text PDF
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