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http://hdl.handle.net/11375/27650
Title: | Microbiota-derived D-lactate alters macrophage inflammation |
Authors: | Singh, Anita |
Advisor: | Schertzer, Jonathan |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2022 |
Abstract: | Obesity-induced inflammation is a factor involved in the risk and progression of type 2 diabetes and non-alcoholic fatty liver disease. These diseases are associated with changes in gut microbiota composition and bacterial metabolites. Bacterial components with known innate immune receptors can cooperate with non-immunogenic metabolites derived from the gut microbiota to alter host immunity. Gut bacteria produce almost all D-lactate in the host, whereas L-lactate is host-derived. It is known that microbial-derived D-lactate in the portal circulation programs liver-resident macrophages to help combat bacterial infections. It was unknown how D-lactate and L-lactate alter cell-autonomous inflammation in macrophages exposed to low levels of bacterial cell wall muropeptides or lipopolysaccharide (LPS). It was also unknown if macrophage co-stimulation altered inflammation in macrophages exposed to bacterial metabolites and cell wall components. In vitro models showed that D-lactate had no effect (or a very small effect) on multiple markers of inflammation in the absence of interferon-gamma (IFN-γ) co-stimulation. Nevertheless, initial experiments on clonal macrophages discovered that equimolar and physiological levels of D-lactate increased Nos2 expression compared to L-lactate. Bone marrow-derived macrophages (BMDMs) co-stimulated with IFN-γ revealed a larger effect of D-lactate on immunity. Compared to L-lactate, D-lactate increased nitric oxide (NO) production and increased activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in BMDMs co-stimulated with IFN-γ and exposed to LPS. Further, D-lactate prevented L-lactate-induced lowering of NO production and NLRP3 inflammasome-mediated release of IL-1β from BMDMs co-stimulated with IFN-γ and LPS. Identifying appropriate cell models and defining conditions that reveal the effect of D-lactate versus L-lactate on immune responses in isolated cells was a major contribution of this work. Future work should characterize the interaction of macrophages and hepatocytes. This research may lead to the identification of gut microbiota-based approaches to limit liver inflammation in obesity and metabolic disease. |
URI: | http://hdl.handle.net/11375/27650 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Singh_Anita_M_finalsubmission202206_MSc.pdf | 2.77 MB | Adobe PDF | View/Open |
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