Food protein induced enterocolitis syndrome (FPIES) induced by cow’s milk traduces in local cellular response and in a specific metabolic signature in plasma

Abstract

[Background] Protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy of increasing prevalence for which immune mechanisms are not elucidated and no biomarkers are available.

[Objectives] We aimed 1) to further characterize immune response and 2) to carry complementary and innovative approaches using metabolomics to go deeper in pathogenesis and to identify specific biomarkers of cow’s milk induced-FPIES (CM-FPIES)

[Methods] Children with active CM-FPIES (n=9) or active IgE-mediated CM allergy (IgE-CMA, n=6; also avoiding CM consumption) were recruited in Hospital Necker day care Unit when visiting to perform an oral food challenge (OFC). Blood samples were collected before the OFC. Plasma from age-matched patients tolerant to CM but presenting an IgE-mediated peanut allergy (n=6) were used as controls. The total and CM-allergens specific IgE, IgG1-4, IgA, IgM and IgD were assessed in all plasma, as the same as IgE and IgG4 specific to digestats obtained after in vitro gastric and gastro-duodenal digestion of CM. Specific ex-vivo stimulation of PBMC from CM-FPIES and IgE-CMA children were performed and cytokine secretion and cellular proliferation induced analyzed. Additionally, T cells and innate lymphoid cells (ILC) were analyzed in intestinal biopsies obtained from children with active (n=2) vs non active (n=2) FPIES. Finally, individual metabolic profiles were obtained using two complementary LC-MS methods analysis on plasma from CM-FPIES patients and compared to that obtained from patients suffering from active or resolved IgE-CMA (negative OFC, n=3).

[Results] Systemic antigen-specific T-cells and humoral responses were evidenced in IgE-CMA patients whereas they were weak or even absent in CM-FPIES patients, an absence of response that cannot then be restricted to a lower exposure to cow’s milk. Preliminary data evidenced activated Th1, Th2 and Th17 cells and activated innate lymphoid cells showing a mixed ILC1/2 phenotype within the intestinal mucosa of active FPIES. Moreover, discriminant statistical analysis of metabolic profiles clearly separated CM-FPIES versus IgE-CMA patients. Further univariate analysis allowed the identification of discriminant metabolites, demonstrating notably dysregulation of fatty acids metabolism in CM-FPIES children.

[Conclusions] Children with CM-FPIES have a weak or absent systemic specific immune responses. Our preliminary data suggest that new studies analysing innate and adaptive cells in the mucosa may help to delineate the pathophysiology of FPIES. Metabolomics could further help to identify biomarkers for FPIES, by highlighting altered metabolic pathways.