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DC Field | Value | Language |
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dc.contributor.advisor | Schertzer, Jonathan | - |
dc.contributor.author | Singh, Anita | - |
dc.date.accessioned | 2022-06-21T20:32:46Z | - |
dc.date.available | 2022-06-21T20:32:46Z | - |
dc.date.issued | 2022 | - |
dc.identifier.uri | http://hdl.handle.net/11375/27650 | - |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.title | Microbiota-derived D-lactate alters macrophage inflammation | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Biochemistry and Biomedical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Master of Science (MSc) | en_US |
dc.description.layabstract | Gut bacteria can influence both immunity and metabolism in the liver. It is not clear how bacteria in the gut communicate to the liver. Lactate is a key metabolite that can fuel liver metabolism and alter immunity. There are 2 types of lactate. L-lactate is host-derived, whereas D-lactate is mainly produced by gut bacteria. Bacterial-derived D-lactate can alter immune responses mediated by immune cells in the liver, including macrophages. Bacterial metabolites such as D-lactate and bacterial components that cause inflammation are increased in the blood during obesity. Our findings show that D-lactate can increase inflammation in macrophages when combined with bacterial components and that D-lactate increases inflammation more than L-lactate. Understanding the role of D-lactate may help us understand how bacteria contribute to insulin resistance, higher blood glucose and the risk of type 2 diabetes and fatty liver disease. | en_US |
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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