Maternal Antibiotic Exposure-Mediated Alterations in Basal, and Allergen-Induced Lung Function Are Associated with Altered Recruitment of Eosinophils to the Developing Lung

Adrienne N. Wilburn^1,2Rabia Ülkü Korkmaz^3,4Jaclyn W McAlees⁵Julie M Hargis¹Schmaiel Shirdel^4,6Imke Lingel^4,6Miki Watanabe-Chailland⁷Lindsey Elizabeth Romick-Rosendale⁷Inken Schmudde^4,6,8James Bridges^10,9Claire Anne Chougnet^1,11HITESH DESHMUKH^11,12William Zacharias^11,12Joerg Koehl^13,4Peter König^4,6Yves Laumonnier¹⁴Marc Rothenberg^11,15Ian Paul Lewkowich^1,11*

• ¹Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
• ²Immunology Graduate Program, University of Cincinnati, Cincinnati, United States
• ³Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Asthma and Allergy Prevention, Neuherberg, Germany
• ⁴Airway Research Center North (ARCN), Lubeck, Germany
• ⁵Division of Immunobiology, Cincinnati CHildren's Hospital Medical Center, Cincinnati, United States
• ⁶Universitat zu Lubeck Institut fur Anatomie, Lübeck, Germany
• ⁷Translational Metabolimcs Facility, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
• ⁸Institute of Nutritional Medicine, University of Lubeck, Lubeck, Germany
• ⁹Division of Pulmonary, Critical Care Medicine, National Jewish Hospital, Denver, United States
• ¹⁰University of Colorado Anschutz Medical Campus Division of Pulmonary Sciences and Critical Care Medicine, Aurora, United States
• ¹¹Department of Pediatrics, University of Cincinnati, Cincinnati, United States
• ¹²Division of Neonatology and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
• ¹³Institute for Systemic Inflammation Research, University of Lübeck, Lubeck, Germany
• ¹⁴Institute for Nutritional Medicine, University of Lubeck, Lubeck, Germany
• ¹⁵Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnait, United States

Although early-life dysbiosis is associated with increased risk of asthma development, the underlying mechanisms remain unclear. We report herein that maternal exposure to antibiotics (ABX) between post-natal day 10 (PN10) and PN20, but not pre-natal, or earlier post-natal periods results in increased allergen-induced, and baseline airway hyperreactivity (AHR). Assessment of lung mechanics in allergen-naïve offspring of ABX-exposed dams demonstrate specific changes in lung function (downward-shifted pulmonary PV loops, increased small airway resistance, decreased compliance, reduced inspiratory capacity) at both weaning and 14 months of age. As the PN10-PN20 is a period of intensive alveolar development, we examined alveolar structure in offspring of ABX-exposed dams. Consistent with observation of small airway dysfunction, offspring of ABX-exposed dams demonstrated significantly smaller alveoli at multiple stages of lung development, suggesting underlying developmental processes were accelerated in offspring of ABX-exposed dams. Examination of cellular profiles in the developing lungs demonstrated an exaggerated recruitment of eosinophils at key developmental periods (PN14) in offspring of ABX-exposed dams. Although eosinophils have been reported in the developing lung, their contributions to alveolar morphogenesis and lung mechanics have not been functionally interrogated. We report here that mice with fewer eosinophils (through genetic knockout, or treatment with anti-IL-5) display altered patterns of lung mechanics opposite to that seen in offspring of ABX-exposed dams. These data underscore an underappreciated role of eosinophils in homeostatic lung development and suggest that early life modulation of pulmonary eosinophil activity has long-term effects on susceptibility to the development of chronic lung diseases such as asthma.