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Adverse effects of early life dysbiosis on pulmonary and allergic asthma development

Wilburn, Adrienne
http://orcid.org/0000-0003-1035-0955
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1681229047691756

Abstract Details

2023, PhD, University of Cincinnati, Medicine: Immunology.
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.
Ian Lewkowich, Ph.D. (Committee Member)
Satish Madala, Ph.D. (Committee Member)
William Zacharias, M.D. Ph.D. (Committee Member)
Sing Sing Way, M.D. Ph.D. (Committee Member)
Joseph Qualls, Ph.D. (Committee Member)
148 p.
Immunology
asthma; dysbiosis; microbial maturation; Th17; lung development; postnatal

Recommended Citations

Citations

  • Wilburn, A. (2023). Adverse effects of early life dysbiosis on pulmonary and allergic asthma development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1681229047691756

    APA Style (7th edition)

  • Wilburn, Adrienne. Adverse effects of early life dysbiosis on pulmonary and allergic asthma development. 2023. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1681229047691756.

    MLA Style (8th edition)

  • Wilburn, Adrienne. "Adverse effects of early life dysbiosis on pulmonary and allergic asthma development." Doctoral dissertation, University of Cincinnati, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1681229047691756

    Chicago Manual of Style (17th edition)

ucin1681229047691756
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© 2023, some rights reserved.Creative Commons License Adverse effects of early life dysbiosis on pulmonary and allergic asthma development by Adrienne Wilburn is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.