Abstract
Non-communicable diseases (NCDs) are chronic diseases including cardiovascular diseases, chronic respiratory diseases, diabetes and immune disorders such as inflammatory and allergic diseases. These diseases kill over 41 million people each year and are accountable for 74% of all deaths worldwide. NCDs are associated with dysbiosis of the gut microbiome and
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impaired gut barrier function, leading to increased permeability to macromolecules like lipopolysaccharides (LPS) and low-grade inflammation, both locally and systemically within the intestine. The altered composition of the gut microbiome in NCDs may lead to changes in the presence and activity of bacteria producing butyrate, potentially resulting in reduced butyrate concentrations in the intestine. Butyrate, known for its anti-inflammatory and barrier-protective effects, plays a crucial role in maintaining gut homeostasis and integrity. Consequently, supplementation of butyrate via medication could be beneficial for NCD patients. This thesis aimed to explore the therapeutic potential of butyrate for chronic diseases, both in laboratory settings and in a clinical study. It investigated the pharmacodynamics and pharmacokinetics of butyrate and tested a sustained release tablet containing butyrate as the active ingredient in a randomized, double-blind, placebo-controlled clinical trial involving patients with hand osteoarthritis. In examining the pharmacodynamics of butyrate, experiments focused on its effects on HT-29 intestinal epithelial cells activated with interferon-gamma (IFN-γ) or a combination of IFN-γ and tumor necrosis factor-alpha (TNF-α). Butyrate demonstrated potent anti-inflammatory effects by blocking the release of CXCL10, primarily through the non-canonical STAT1 pathway. This inhibition of CXCL10 release was comparable to the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), suggesting a potential mechanism of action for butyrate involving HDAC inhibition. Pharmacodynamics of butyrate were also studied in a co-culture model using Caco-2 intestinal epithelial cells and activated peripheral blood mononuclear cells (PBMCs) to mimic the interaction between intestinal epithelial cells and immune cells in the lamina propria. Butyrate was found to inhibit the release of serveral cytokines in the model with LPS-activated and αCD3/CD28-activated PBMCs and reduced the activation of T-helper cell phenotypes. Butyrate also effectively preserved the barrier function of Caco-2 cells against cytokine-induced disruption, indicating its protective role in inflammation-induced intestinal barrier dysfunction. Based on the pharmacodynamics and pharmacokinetics of butyrate, a sustained release tablet was developed. This tablet formulaton was tested in a randomized, double-blind, placebo-controlled clinical trial involving patients with hand osteoarthritis. The sustained release butyrate tablets did not significantly impact markers of systemic inflammation or LPS leakage. However, they did affect the activation of T helper (Th) cells and shifted the Th17/Treg balance in favor of Treg cells. This modulation of Th cell activation was not accompanied by changes in cytokine release. In conclusion, while butyrate shows potential as a therapeutic agent for NCDs based on in vitro experiments, further research into the pharmacokinetics of butyrate tablets is necessary to optimize their effectiveness for NCD patients.
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