Thesis advisor: Babak Momeni / Diseases of the upper respiratory tract encompass a plethora of complex multifaceted etiologies ranging from acute viral and bacterial infections to chronic diseases of the lung and nasal cavity. Due to this inherent complexity, typical treatments often fail in the face of recalcitrant infections and/or severe forms of chronic disease, including asthma. Thus, in order to provide improved standard of care, the mechanisms at play in hard-to-treat etiologies must be better understood. More recently, research has demonstrated a significant association between microbiota and many URT diseases. Previous work has also identified species capable of directly inhibiting standard treatments used to control asthma exacerbations. Despite an exhaustive collection of data characterizing microbiota composition in states of both health and disease, our knowledge of what microbiota profiles are observed in what specific disease etiologies is severely lacking. Yet, gaining these insights is crucial for the translation of such data into application. In this thesis I sought to: 1) identify gut microbiota profiles associated with severe and treatment resistant forms of childhood asthma, and 2) formulate a predictive model to facilitate the restructuring of microbiota for desired therapeutic outcomes. To identify gut microbiota and metabolites enriched in severe and treatment resistant childhood asthma, I looked to an ongoing longitudinal human study on vitamin D and childhood asthma. In this study, I find several fecal bacterial taxa and metabolites associated with more severe (i.e., higher wheeze proportion) and treatment resistant asthma in children at age 3 years. Specifically, several Veillonella species were enriched in children with higher wheeze proportion and in children that responded poorly to inhaled corticosteroid treatment (ICS) (i.e., non-responders). Haemophilus parainfluenzae, a species previously identified as enriched in the airway of adults with ICS-resistant asthma, was also uniquely enriched in children considered ICS non-responders in this study. Several metabolic pathways were also distinctly enriched: histidine metabolism was enriched in children with higher wheeze proportion while sphingolipid metabolism was enriched in ICS non-responders. Both metabolic pathways have been previously identified in association with asthma, further corroborating their role in this disease. Yet, this study is the first to identify these taxa and metabolites in children with preexisting and treatment resistant asthma. In the pursuit of improved treatment outcomes for recalcitrant URT diseases, recent efforts have turned towards microbiota-based therapies. While such treatments have proven successful in the treatment of gastrointestinal infections, these methods have not yet been extended to other conditions. Considering this, I ask whether a predictive model describing microbial interactions can facilitate the restructuring of microbiota for desired therapeutic outcomes. For this, I use a community of nasal microbiota to determine when a simply Lotka-Volterra-like (LV) model is a suitable representation for microbial interactions. I then utilize our LV-like model to examine whether environmental fluctuations have a major influence on community assembly and composition. For this, I looked specifically at pH fluctuations. In this study, I found that LV-like models are most suitable for describing community dynamics in complex low nutrient conditions. I also identified simple in vitro experiments that can reliably predict the suitability of a LV-like model for describing outcomes of a two-species community. When our LV-like model was applied to an in silico community of nasal species to determine the impact of environmental fluctuations, I find that nasal communities are generally robust against pH fluctuations and that, in this condition, facilitative interactions are a stabilizing force, and thus, selected for in in silico enrichment experiments. Overall, this thesis further corroborates the association of microbiota with URT diseases and treatment outcomes while also providing unique insight into their association with specific etiologies in childhood asthma. This thesis also provides a framework for developing models able to facilitate the development of future microbiota-based therapies while also determining how, and when, environmental factors impact community assembly and composition. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_109223 |
| Date | January 2021 |
| Creators | Dedrick, Sandra |
| Publisher | Boston College |
| Source Sets | Boston College |
| Language | English |
| Detected Language | English |
| Type | Text, thesis |
| Format | electronic, application/pdf |
| Rights | Copyright is held by the author, with all rights reserved, unless otherwise noted. |
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