Author ORCID Identifier
Date Available
4-11-2023
Year of Publication
2022
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Arts and Sciences
Department/School/Program
Chemistry
First Advisor
Dr. Christopher I. Richards
Abstract
The consumption of tobacco products is a known contributor to a variety of health conditions and disease pathologies including cardiovascular and lung diseases. In addition to these well-known pathological effects of tobacco use, it has been established recently that tobacco consumption as well as nicotine consumption alone results in distinct, dysbiotic perturbations to the enteric microflora of the gastrointestinal tract. Previous research into the intestinal microbiome has demonstrated that these microbes are active contributors to the maintenance of a homeostatic and tolerogenic environment within the host. In fact, the presence of our enteric microflora is necessary for the proper development of a variety of critical internal systems, namely the immune and nervous systems. It is well known in literature that nicotine/tobacco consumption alters the intestinal microbiome in a dysbiotic fashion resulting in the development of inflammatory conditions, diseases of the digestive tract, and the development of stress- related disorders and depression. However, what has yet to be elucidated are the mechanisms by which nicotine/tobacco use alters the composition of the microflora to these dysbiotic states. In this dissertation, our research efforts focused on elucidating the mechanisms by which nicotine use alters the microbial composition of the gastrointestinal tract and what effect these compositional changes have on immune function.
In order to accomplish our experimental goals we studied 1) the inhibitory properties of nicotine alongside other similar phytochemicals. This work revealed that nicotine does possess antimicrobial properties however, the concentrations at which nicotine was inhibitory were not physiologically relevant. Thus, we were able to dismiss inhibition by nicotine exposure as an explanation for the compositional changes seen in the literature. We next studied 2) bacterial products produced under nicotine stress and evaluated the impact these products had on innate immune cells to gauge the immune response under nicotine-exposed conditions. Here we found that exposure to nicotine and its primary metabolite, cotinine, resulted in differential protein packaging into extracellular vesicles in addition to hypervesiculation and an altered metabolic profile by the microbes studied. We also found that the plasticity of anti-inflammatory macrophages to a pro-inflammatory phenotype was impaired by nicotine in the presence of vesicles as a bacterial stimulus. Lastly, we studied 3) whether use of electronic nicotine delivery systems (ENDS) resulted in compositional changes similar to those seen in tobacco and nicotine use. We demonstrated that ENDS use appears to instigate compositional changes to the intestinal microflora similar to tobacco use and that these compositional changes are accompanied by inflammation of the gastrointestinal tract in murine models. In this manner, we were able to determine that nicotine/tobacco use likely alters microbial composition through a multifaceted approach, namely, through shifts in microbial metabolism thereby altering the pantry of available nutrients for consumption by other microbes and through shifts in immune response to a dominantly tolerogenic environment allowing for the growth and spread of a multitude of microbes without immune intervention.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2022.366
Funding Information
This study was supported by the National Institute on Drug Abuse T32
DA016176 Pre-doctoral Fellowship from 2018 - 2021.
Recommended Citation
Lakes, Jourdan, "Nicotine and Cotinine: Microbial Modulators of the Immune Response" (2022). Theses and Dissertations--Chemistry. 169.
https://uknowledge.uky.edu/chemistry_etds/169
