Browsing by Subject "Inhibition"
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Item Investigating the Effects of Antidepressants on Intestinal Bacteria(2024-04-16) Lebakken, Sophia; Basting, Christopher M; Bailey, Melisa; Schroeder, Ty; Broedlow, Courtney A; Guerrero, Candace; Hemmila, Charlotte; Klatt, Nichole RIntroduction: The gut-brain axis (GBA) involves bidirectional communication between the gastrointestinal tract and brain, which contains many species of bacteria that play an important role in this communication. Major depressive disorder is often treated with antidepressant medications (ADMs) that pass through the gastrointestinal tract; however, the possible adverse effects of ADMs on the gut microbiome are not well characterized. Methods: This project investigates the impact of three selective serotonin reuptake inhibitors, sertraline, fluoxetine, citalopram; one norepinephrine and dopamine reuptake inhibitor, bupropion; and one tetracyclic antidepressant, mirtazapine, on the growth of eight species of gut bacteria, Bacteroides fragilis, Bifidobacterium longum, Bacteroides uniformis, Collinsella aerofaciens, Prevotella copri, Escherichia coli, Akkermansia muciniphila, and Lactobacillus plantarum. Bacteria were treated with various concentrations of each ADM to determine potential impact on growth. We calculated the concentration of drug needed to inhibit growth by 50% (IC50) using spectrophotometry. Results Several ADMs inhibited gut bacterial growth. At 50% bacterial growth inhibition, the most prominent was sertraline (28.742 μM), followed by bupropion (43.976 μM), then fluoxetine (76.449 μM). Citalopram (244.738 μM) and mirtazapine (294.316 μM) exhibited far less inhibition. Discussion These findings suggest ADMs have antibiotic effects that disturb the microbiome resulting in potential consequences for microbiota-GBA interactions. Building on these results, future experimentation will measure uptake and metabolism of ADMs by exposing bacteria to each drug longitudinally. Metabolites will be characterized using liquid chromatography-mass spectrometry. Conclusion Given the profound impact of the gut microbiome on the gut-brain axis, these data provide novel insights into potential mechanisms by which ADMs could have unintended consequences on the gut that may perpetuate, instead of treat, mood disorders thus the microbiome should be further investigated in relation to ADMs.Item The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation(2013-04) Zumwalde, Nicholas AlanCD8+ T cells are vital components to the immune system and serve as crucial effectors in the elimination of infected cells and pathogens. During the course of an immune response many interactions occur among antigen presenting cells and T cells, as well as, eventual contacts between activated T cells and target cells. However, during the stimulation of T cells, interactions exist among T cells themselves. These adhesion molecule mediated T cell activation clusters occur both in vitro and in vivo. Here we demonstrate the role of CD8+ T cell clusters on the eventual effector function and differentiation of CD8+ T cells. Our findings reveal that T cell clusters mediated via ICAM-1:LFA-1 interactions, help to dampen the immune response by regulating expression levels of the effector markers interferon-gamma and granzyme B, as well as, cytotoxicity. Understanding the mechanisms by which this effector regulation occurs is complex. Our data suggest that unclustered T cells sense an increased amount of antigen as shown through Nur77-GFP studies. In addition, our findings demonstrate a dependence on T cell cluster formation and contact in general for the upregulation of the immune inhibitory protein CTLA-4. CTLA-4 suppresses CD8+ T cell immunity via the downregulation of the transcription factor eomesodermin and thereby regulates the production of both interferon-gamma and granzyme B. Similar effector function studies, under certain conditions, are indeed shown in vivo as well. Thus, T cell clusters regulate the tuning of CD8+ T cell function and terminal differentiation. These studies contribute to our knowledge of the necessity of T cell interactions and crosstalk during priming and potentially, via cluster manipulation, we hope to augment vaccine efficacy and anti-tumor immunotherapeutics.