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Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2021)

To further understand how the early life gut microbiota predisposes to food allergen sensitization, Tun et al (Gastroenterology 2021 Mar 16; https://doi.org/10.1053/j.gastro.2021.03.016) used sequential fecal 16S rRNA sequencing in the first year of life and skin prick testing at age 1 and 3 years to characterize changes in the fecal microbiome in infants and subsequent food allergen sensitization. Four distinct gut microbiota developmental trajectories were identified and were influenced by both ethnicity and birth mode. A higher rate of sensitization to food allergens was observed with the trajectory characterized by low Bacteroides and high Enterobacteriaceae, with a more dramatic effect occurring in infants born to Asian mothers. This trajectory also exhibited altered sphingolipid metabolism and Clostridium difficile colonization. Overall, this study shows how developmental trajectories of the gut microbiome early in life modulate the risk for food allergen sensitization. We asked first author Hein M. Tun, BVSc, MSc, PhD, of the School of Public Health, University of Hong Kong, Hong Kong, China, and corresponding author Anita L. Kozyrskyj, BScPhm, MSc, PhD, of the Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada, to comment on the study. Dr Tun writes, “Our study indicates the importance of early-life Bacteroides as a keystone foundation species in preventing food allergen sensitization and of cesarean birth in hindering their normal trajectory. We are the first to show a mediating role for the Bacteroides trajectory of development in the association between Asian ethnicity and food sensitization. The findings could be translated into various early-life interventions to prevent food allergy in children and associated diseases such as asthma and other types of allergies.” Dr Kozyrskyj writes, “These findings in 1422 infants build on our initial reports that a high Enterobacteriaceae/Bacteroidaceae (E/B) ratio in gut microbiota at age 3 months increased risk for food sensitization. Shown by statistical mediation analyses, they identify a gut microbiota trajectory of longitudinal development over infancy, characterized as persistently low Bacteroidaceae abundance, high E/B ratios and deficient sphingolipid metabolism as key pathways to food, specifically peanut, sensitization in infants of Asian mothers. Higher rates of atopic disease in offspring of new immigrants from Asian countries are a well-known but unexplained phenomenon.”Hein M. Tun and Anita L. KozyrskyView Large Image Figure ViewerDownload Hi-res image Download (PPT) In patients with mild asthma, as-needed budesonide-formoterol decreases the long-term risk for severe exacerbation similar to maintenance budesonide plus as-needed short-acting b-agonist (SABA). O’Byrne et al (Lancet Respir Med 2021;9:149-58; https://doi.org/10.1016/S2213-2600(20)30416-1) examined the risk of severe exacerbation in the 21 days following the first use of reliever medications through a post-hoc analysis of the placebo-controlled SYGMA 1 trial. Both as-needed budesonide-formoterol and maintenance budesonide plus as-needed SABA (terbutaline) reduced the short-term risk of severe exacerbations after a single day of increased use as compared to as-needed SABA alone. In addition to providing symptomatic relief, these results demonstrate that just a single day of repeated use of as-needed budesonide-formoterol protects against severe exacerbation to a similar degree as maintenance inhaled corticosteroids. We asked first author Paul M. O’Byrne, MB, FRCP(C), FRCS, of St Joseph’s Healthcare and Department of Medicine, McMaster University in Hamilton, Ontario, Canada, to comment on the study. He writes, “The study results support the hypothesis that the benefit achieved in reducing the risks of severe asthma exacerbations by using low doses of ICS together with a rapid onset long-acting b-agonist (LABA) as a reliever, compared to a SABA only as a reliever, is the timing of the administration of the ICS when both symptoms and airway inflammation are increasing as exacerbations develop.” The role of keratinocyte-derived signals in IgE production and progression of allergic disease is incompletely understood. Patrick et al (J Clin Invest 2021;131:e143334; https://doi.org/10.1172/JCI143334) identified a critical role of keratinocyte-derived IL-36a in an experimental murine model of atopic dermatitis involving epicutaneous Staphylococcus aureus exposure. In combination with IL-4, IL-36a increased serum IgE levels by inducing IgE class-switching and plasma cell differentiation. Notably, blockade of the IL-36/IL-36R axis prevented allergen-specific lung inflammation. Finally, these findings appear generalizable as IL-36 cytokine levels were increased in the skin of patients with atopic dermatitis and increased serum IgE levels were observed in IL-36 receptor antagonist-deficient subjects. On the basis of these results, the authors propose IL-36 signaling as a potential therapeutic target for the treatment of atopic dermatitis and allergic diseases. We asked co-corresponding authors Nathan K. Archer, PhD, and Lloyd S. Miller, MD, PhD, of the Department of Dermatology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, to comment on the study. They write, “Our work uncovers an immune pathway initiated by S aureus skin exposure that explains the increased likelihood of atopic dermatitis patients to progress to allergic diseases, including asthma, allergic rhinitis, and food allergy. Importantly, our findings suggest that targeting IL-36 may provide a novel therapeutic approach in the treatment of atopic dermatitis and allergic diseases.” The oral Janus kinase 1 (JAK1) selective inhibitor abrocitinib is a promising emerging therapeutic for the treatment of atopic dermatitis because of its ability to inhibit both IL-4 and IL-13 signaling and other cytokines implicated in the pathogenesis of AD. Bieber et al (N Engl J Med 2021;384:1101-12; https://doi.org/10.1056/NEJMoa2019380) performed a phase 3 double-blind, double-dummy, randomized controlled trial comparing oral abrocitinib (200 mg and 100 mg), subcutaneous dupilumab (300 mg), and placebo in patients with moderate-to-severe atopic dermatitis. As compared with placebo, abrocitinib improved both symptomatic control and disease status after 12 weeks of use. Additionally, abrocitinib 200 mg was superior to dupilumab at reducing itch by 2 weeks. There were no significant differences between abrocitinib and dupilumab on other outcomes at week 16, although the study was not designed to assess superiority at other timepoints other than week 2. While this study provides insights about the differences between abrocitinib and dupilumab in the short-term, longer-term studies are required to gain a deeper understanding of the effect of abrocitinib on outcomes, relative to dupilumab. Image attribution Wikimedia by user Edgar181, public domain, via Wikimedia Commons, https://commons.wikimedia.org/wiki/File:Abrocitinib.svg. We asked first author Thomas Bieber, MD, PhD, of the University Hospital of Bonn, Bonn, and University of Lübeck, both in Germany, to comment on the study. He writes, “This study confirms the impressive efficacy of abrocitinib in combination with topical therapies and appears to show distinct advantages in terms of the rapidity of itch relief compared to standard of care.” Direct interactions between the immune and peripheral nervous systems are increasingly implicated in the itching responses present in atopic dermatitis. Voisin et al (Proc Natl Acad Sci U S A 2021;118:e2022087118; https://doi.org/10.1073/pnas.2022087118) identified that cysteinyl leukotriene LTC4 potently induces itch in an experimental murine model of atopic dermatitis through its receptor CysLT2R present on peripheral sensory neurons. Notably, this signaling pathway did not contribute to nonallergic chronic itch experimental models such as dry skin. Collectively, these results demonstrate a critical role for the LTC4/CysLT2R pathway in atopic dermatitis–related chronic itch. We asked co-corresponding authors K. Frank Austen, MD, of the Division of Allergy and Clinical Immunology at Brigham & Women’s Hospital in Boston, Massachusetts, and Isaac M. Chiu, PhD, of the Department of Immunology at Harvard Medical School in Boston, Massachusetts, to comment on the study. Dr Austen writes “The finding that leukotriene C4, the initial biosynthetically generated cysteinyl leukotriene, interacts with its receptor, CysLT2R, to initiate itch presents a new pathway for this response. Of note, mast cells were not required in a model of chronic itch involving CysLT2R.” Dr Chiu writes, “Itch is a burdensome symptom of skin diseases including atopic dermatitis (AD). We found that sensory neurons express the CysLT2R receptor, which mediates acute itch caused by the leukotriene LTC4 and chronic itch in a mouse model of AD.”