Date of Completion
2023
Document Type
Honors College Thesis
Department
Biology, Biomedical and Health Sciences
Thesis Type
Honors College, College of Arts and Science Honors
First Advisor
Dimitry Krementsov
Second Advisor
Brent Lockwood
Keywords
Microbiome, Immunology, Multiple Sclerosis, Lactobacillus reuteri, Molecular Biology, Autoimmunity
Abstract
Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). The causes of MS are extremely complex; however, it’s becoming increasingly apparent that disease risk is highly associated with environmental factors and consequent gene-environmental interactions. As such, this study focuses on the connection between the gut microbiome and CNS as an arising risk factor and potential mediator of CNS autoimmune disease. The present research examines the capacity of a gut commensal species, Lactobacillus reuteri (L. reuteri), to modulate effector function of immune cells in the peripheral immune system and along the GI tract, before these cells go on to invade the CNS and initiate breakdown of the blood brain barrier (BBB). One proposed mechanism by which L. reuteri impacts immune cells is through the production of tryptophan-derived indole metabolites. We hypothesize that these metabolites act as agonists for the aryl hydrocarbon receptor (AhR), and through modulating the AhR, enhance pathogenic immune responses by means of cytokine production to mediate and sustain an inflammatory autoimmune phenotype across the BBB. To test specifically if L. reuteri can modulate the immune system through the production of unique metabolites, we treated cultured cell lines and primary T cells with bacterial-produced tryptophan metabolites and monitored the levels of AhR activity directly through a luciferase reporter system or resulting cytokine production through flow cytometry and ELISA. Through these methods, we found that L. reuteri-derived metabolites activate the AhR in a ligand-specific manner, with some acting as agonists while others could function as antagonists of the receptor. We also found that an increase in AhR activity correlated with an increase in pro-inflammatory interleukin-17 (IL-17) and interferon-gamma (IFN-γ) cytokines produced by T cells, hinting at a potential mechanistic pathway of enhanced autoimmunity through microbiota-induced AhR activity.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Recommended Citation
Heney, Eamonn Ray, "Unique Lactobacillus Produced Metabolites Modulate T-Cell Response through the Aryl Hydrocarbon Receptor: Implications for CNS Autoimmunity" (2023). UVM Honors College Senior Theses. 552.
https://scholarworks.uvm.edu/hcoltheses/552