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Chorioamnionitis, a potentially serious inflammatory complication of pregnancy, is associated with the development of an inflammatory milieu within the amniotic fluid surrounding the developing fetus. When chorioamnionitis occurs, the fetal lung finds itself in the unique position of being constantly exposed to the consequent inflammatory meditators and/or microbial products found in the amniotic fluid. This exposure results in significant changes to the fetal lung, such as increased leukocyte infiltration, altered cytokine, and surfactant production, and diminished alveolarization. These alterations can have potentially lasting impacts on lung development and function. However, studies to date have only begun to elucidate the association between such inflammatory exposures and lifelong consequences such as lung dysfunction. In this review, we discuss the pathogenesis of and fetal immune response to chorioamnionitis, detail the consequences of chorioamnionitis exposure on the developing fetal lung, highlighting the various animal models that have contributed to our current understanding and discuss the importance of fetal exposures in regard to the development of chronic respiratory disease. Finally, we focus on the clinical, basic, and therapeutic challenges in fetal inflammatory injury to the lung, and propose next steps and future directions to improve our therapeutic understanding of this important perinatal stress.

Early-life dysbiosis is associated with increased risk of asthma development but the underlying mechanisms remain unclear. Although eosinophils have been reported in the developing lung, their contributions to alveolar morphogenesis and lung mechanics have not been functionally interrogated. Maternal exposure to antibiotics (ABX) was used to induce early-life offspring dysbiosis, and the effects on lung function and development was assessed. Similar measurements were made in mice lacking eosinophils due to genetic modification, or administration of IL-5 blocking agents. ABX exposure between Embryonic Day 15 (E15) and post-natal day 28 (PN28), increased allergen-induced, and baseline airway hyperreactivity (AHR). Similar observations were made when maternal ABX exposure was limited to PN10 to PN20. Complete characterization of baseline lung mechanics demonstrated downward-shifted pulmonary PV loops, increased small airway resistance, decreased compliance, and reduced inspiratory capacity at weaning and 14 months of age. Consistent with observation of small airway dysfunction, offspring of ABX-exposed dams demonstrated significantly smaller alveoli at multiple stages of lung development. Examination of recruitment to developing lungs demonstrated an exaggerated recruitment of eosinophils at key developmental periods (PN14) in offspring of ABX-exposed dams. 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.

Changes in microbiome (dysbiosis) contribute to severity of allergic asthma. Preexisting epidemiological studies in humans correlate perinatal dysbiosis with increased long-term asthma severity. However, these studies cannot discriminate between prenatal and postnatal effects of dysbiosis and suffer from a high variability of dysbiotic causes ranging from antibiotic treatment, delivery by caesarian section to early-life breastfeeding practices. Given that maternal antibiotic exposure in mice increases the risk of newborn bacterial pneumonia in offspring, we hypothesized that prenatal maternal antibiotic-induced dysbiosis induces long-term immunological effects in the offspring that also increase long-term asthma severity. Therefore, dams were exposed to antibiotics (gentamycin, ampicillin, vancomycin) from embryonic day 15 until birth. Six weeks later, asthma was induced in the offspring by repeated applications of house dust mite extract. Airway function, cytokine production, pulmonary cell composition and distribution were assessed. Our study revealed that prenatally induced dysbiosis in mice led to an increase in pulmonary Th17 + non-conventional T cells with limited functional effect on airway resistance, pro-asthmatic Th2/Th17 cytokine production, pulmonary localization and cell-cell contacts. These data indicate that dysbiosis-related immune-modulation with long-term effects on asthma development occurs to a lesser extent prenatally and will allow to focus future studies on more decisive postnatal timeframes.

Abstract Microbial maturation disrupted by early-life dysbiosis has been linked with increased asthma risk and severity; however, the immunological mechanisms underpinning this connection are poorly understood. We sought to understand how delaying microbial maturation drives worsened asthma outcomes later in life and its long-term durability. Drinking water was supplemented with antibiotics on Postnatal Days 10–20. To assess the immediate and long-term effects of delaying microbial maturation on experimental asthma, we initiated house dust mite exposure when bacterial diversity was either at a minimum or had recovered. Airway hyperresponsiveness, histology, pulmonary leukocyte recruitment, flow cytometric analysis of cytokine-producing lymphocytes, and assessment of serum IgG1 (Immunoglobulin G1) and IgE (Immunoglobulin E) concentrations were performed. RT-PCR was used to measure IL-13 (Interleukin 13)–induced gene expression in sequentially sorted mesenchymal, epithelial, endothelial, and leukocyte cell populations from the lung. Delayed microbial maturation increased allergen-driven airway hyperresponsiveness and Th17 frequency compared with allergen-exposed control mice, even when allergen exposure began after bacterial diversity recovered. Blockade of IL-17A (Interleukin 17A) reversed the airway hyperresponsiveness phenotype. In addition, allergen exposure in animals that experienced delayed microbial maturation showed signs of synergistic signaling between IL-13 and IL-17A in the pulmonary mesenchymal compartment. Delaying microbial maturation in neonates promotes the development of more severe asthma by increasing Th17 frequency, even if allergen exposure is initiated weeks after microbial diversity is normalized. In addition, IL-17A–aggravated asthma is associated with increased expression of IL-13–induced genes in mesenchymal, but not epithelial cells.

Asthma has been on the rise globally for decades, but the underlying causes are still unclear. The rapidity of the rise in asthma argues against a solely genetic etiology. Instead, changes in our surrounding environment alter our daily exposures, altering our gut microbiota, also known as dysbiosis. A well-established risk factor for asthma, dysbiosis is a side effect of many asthma risk factors; air pollution, diet, cesarean birth, farm upbringing. The mechanisms underlying dysbiosis driven asthma development however are not well understood, particularly in the context of severe asthma. Despite studies observing distinct gut microbiota between non-asthmatic and mild/moderate asthmatics, very little work has been done to understand the dysbiosis mechanisms underlying the development of severe asthma.In this dissertation, we have developed a model of a transient early neonatal dysbiosis that delays the progression of gut microbial maturation, which we have termed “delayed microbial maturation” or DMM. We demonstrate that DMM mice sensitized to house dust mite (HDM) allergen develop a more severe form of asthma with increased airway hyperresponsiveness (AHR), as well as a more pronounced frequency of Th17 cells, phenotypes consistent with the presentation of severe asthma patients. These effects were durable, manifesting whether allergen sensitization occurred during or following resolution of the dysbiotic period, suggesting epigenetic factors may underlie DMM aggravation of allergic asthma development. Interestingly, while the lung epithelial response is usually considered the primary driver in asthma pathogenesis, we found evidence suggesting the effects of IL-17 were most pronounced in the mesenchymal compartment of the lung. Thus, these data provide novel insight into a previously observed, but mechanistically undefined, connection between dysbiosis and severe asthma.From these studies exploring DMM and allergic asthma it was observed that even in the absence of allergen exposure, DMM animals had a modest but persistent increase in AHR compared to control animals. This led us to explore the question of whether DMM not only influenced the development of disease, but also postnatal development of the lungs. We found that DMM worsened airway functionality parameters like AHR and PV loops. The smaller airways in particular were affected, and closer inspection revealed changes in the epithelial compartment, particularly a decrease in the activity of epithelial histone deacetylase (HDAC), a class of enzymes that can produce epigenetic changes through de-acetylation of histones. Strangely, many of these findings were transient, however it is unclear if lungs from DMM animals may retain an increased susceptibility to later life pulmonary insults given these pulmonary changes experienced early in life. These findings present compelling evidence that the gut microbiota may influence the development programs of structural cells in the lung in addition to the inflammatory capacity of immune cells.Altogether this body of work provides evidence of how early life dysbiosis may influence pulmonary health by not only inducing changes in the immune cell compartment but also pulmonary epithelial cells. These changes are capable of reducing overall lung performance, whether in a pathogenic state like asthma, or during normal developmental periods.