Functional iron‐deficiency in women with allergic rhinitis is associated with symptoms after nasal provocation and lack of iron‐sequestering microbes
Authors: Lisa‐Marie Petje, Sebastian A. Jensen, Sebastian Szikora, Martin Sulzbacher, Tina Bartosik, Petra Pjevac, Bela Hausmann, Karin Hufnagl, Eva Untersmayr, Lisa Fischer, Erich Vyskocil, Julia Eckl‐Dorna, Erika Jensen‐Jarolim, Gerlinde Hofstetter, Sheriene Moussa Afify, Claus G. Krenn, Georg A. Roth, Elisa Rivelles, Stephan Hann, Franziska Roth‐Walter
Journal: Allergy (2021)

To the Editor, It is still unclear which underlying factors in atopic subjects contribute to their heightened immune response and lead to increased IgE production. Iron deficiency and anemia are clearly associated with the onset of allergic diseases with a poor iron status at birth increasing the risk of developing an atopic disease, whereas an improved iron status seems to prevent the onset of allergy.1 Importantly, in our preclinical studies, we were able to confirm that iron can be selectively delivered to immune cells with beta-lactoglobulin carrying iron complexes as ligands, resulting in immune resilience and allergy prevention.2 As a lack of iron is also a danger signal for immune cells leading to Th2 activation,2 we hypothesized that atopy may be linked with functional iron deficiency, in which the iron stores are not accessible, thus facilitating allergy development and amplifying the clinical symptom burden in allergy sufferers. As iron parameters and reference ranges differ between gender and with age, we eliminated confounding factors (Supplementary Materials, exclusion criteria) and this study focused only on premenopausal women with or without respiratory allergies. Here, we show for the first time that women with allergic rhinitis and without anemia—though having similar dietary habits as nonallergic ones (Table S1, Figure S1)—have decreased levels of metabolically active iron in the circulation with lower serum iron, transferrin saturation, and elevated ceruloplasmin levels compared with nonallergic women, while significantly more hepcidin is produced (Figure 1 A and more parameters on Table S2 and Figure S2; sensitization profile is listed in Table S3 and Table S4). Despite increased iron mobilization efforts by the copper-containing ferroxidase ceruloplasmin, which also acts as an acute-phase reactant, allergic women had lower serum iron. However, greater amount of urinary hepcidin, which blocks cellular iron release and mobilization, was present in our allergic rhinitis cohort and may point toward greater immune activity inherent in allergics compared with nonallergic individuals. The increased hepcidin excretion also suggests that in women with allergic rhinitis, dietary intestinal iron absorption and/or cellular iron release are inhibited to a greater degree than in nonallergic individuals. Furthermore, for the first time, ceruloplasmin levels in serum (r = 0.53, p=0.0007) and nasal secretions (r = 0.59, p=0.000089) were linked with symptoms after nasal provocation (Figure 1B, C and Table S5,S6,S7). Gut iron appeared to be beneficial and was associated with reduced symptom burden (r=−0.78, p= 0.000042) (Figure 1B,D) that even showed linearity in regression analysis in allergic rhinitis subjects that underwent graded nasal provocation. Gut iron also seemed to contribute to an improved iron status in women (Figure 1E). Indeed, elevated levels of ceruloplasmin have already been described in atopic dermatitis and asthma patients and were suggested as a sputum marker for plasma protein leakage in subjects suffering from asthma and chronic obstructive pulmonary disease.3 Our data also link ceruloplasmin with clinical reactivity and thus with the allergy effector cells, the mast cells. The presence of iron in stool extracts reflects the occurrence of commensal microbial communities relying on and solubilizing iron. Bacteria associated with gut iron (green), such as members of the genus Bacteroides—that also support immune iron repletion and resilience 4 —and Ruminococcus were associated with reduced symptom burden (amplicon sequence variants, ASV_qzd_als, r=−0.61, p= 0.00007; ASV_jhl_q2w, r=−0.51, p=0.0017) were negatively associated with serum ceruloplasmin (Figure 2). Importantly, the same ASV of the genus Ruminococcus was also relatively enriched in our nonallergic cohort (Figure 2E), emphasizing its relation to a healthy gut.5 Similar to a study with atopic dermatitis subjects,6 only one ASV of the genus Faecalibacterium (red, ASV_k3p_vr6, r=0.34 m p=0.04) showed an association with symptom severity and ceruloplasmin (r=0.3) and was negatively associated with gut iron (r=−0.45). In summary, in this association study, we linked the hyper-active state in allergic rhinitis subjects with decreased iron mobilization. Ceruloplasmin was the sole protein marker that was linked with clinical reactivity probably due to its increased release by mast cells, whereas gut iron levels seemed beneficial to reduce symptom burden. The microbial taxa Bacteroides, which contribute in immune iron repletion and resilience4 and Ruminococcus, which was also relatively enriched in nonallergics, were linked to gut iron and reduced clinical reactivity. Our findings underline the existence of functional iron deficiency in subjects with allergy. The knowledge may be exploited to combat the allergy epidemic by developing a new generation of therapeutic and prophylactic approaches. To replenish immune iron may thus become a way to achieve immune resilience. We thank Miroslawa Matz for assistance during sample processing and storage. EJJ declares shareholdership in Biomedical Int. R+D GmbH, Vienna, Austria. FRW and EJJ are inventors of EP2894478, owned by Biomedical International R+D GmbH, Vienna, Austria. The other authors declare no relevant conflict of interest in relation to this publication. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.