Investigating the regulatory role of indole-3-aldehyde in intestinal homeostasis during inflammatory conditions
File(s)
Author(s)
Wang, Mu
Type
Thesis
Abstract
Indole-3-aldehyde (IAld) is a bacterial metabolite of tryptophan, and its overall role in regulating intestinal homeostasis is not yet fully understood.
In this study, male C57BL/6J mice were orally administered IAld, IAld with an AhR inhibitor (CH-223191), or olive oil as a control, followed by the introduction of 2.5% dextran sulfate sodium (DSS) in their drinking water to induce colitis. Macrophage (RAW264.7 and THP-1) and intestinal epithelial (Caco-2) cell lines were used to study the role of IAld in intestinal homeostasis in vitro. These cells were treated with lipopolysaccharide (LPS), IAld, IAld and CH-223191, or DMSO as a control. Biomarkers related to the inflammatory response (e.g., IL-6, IL-1β, and TNF-α) and the intestinal epithelial barrier (e.g., tight junction protein expression) were assessed both in vivo and in vitro. Additionally, the effects of IAld and AhR activation on the inflammatory response in the brain and on the faecal microbial composition in colitis-induced mice were investigated.
Key findings showed that IAld reduced the protein levels of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α in the colonic tissues of mice with colitis, compared to DSS-treated mice, with the IL-6 reduction mediated by AhR activation. Furthermore, IAld-mediated AhR activation specifically decreased IL-6 levels in the prefrontal cortex and striatum of the brain in mice with colitis. Improved intestinal integrity was attributed to the downregulation of phosphorylated myosin light chain through IAld-mediated AhR activation. Additionally, IAld-mediated AhR activation inhibited the Nuclear Factor-κB pathway in both in vivo and in vitro models. However, IAld had minimal impact on reshaping the microbial community to alleviate colitis symptoms in mice. This study highlights the role of IAld in regulating intestinal homeostasis and suggests potential treatment strategies for patients with colitis.
In this study, male C57BL/6J mice were orally administered IAld, IAld with an AhR inhibitor (CH-223191), or olive oil as a control, followed by the introduction of 2.5% dextran sulfate sodium (DSS) in their drinking water to induce colitis. Macrophage (RAW264.7 and THP-1) and intestinal epithelial (Caco-2) cell lines were used to study the role of IAld in intestinal homeostasis in vitro. These cells were treated with lipopolysaccharide (LPS), IAld, IAld and CH-223191, or DMSO as a control. Biomarkers related to the inflammatory response (e.g., IL-6, IL-1β, and TNF-α) and the intestinal epithelial barrier (e.g., tight junction protein expression) were assessed both in vivo and in vitro. Additionally, the effects of IAld and AhR activation on the inflammatory response in the brain and on the faecal microbial composition in colitis-induced mice were investigated.
Key findings showed that IAld reduced the protein levels of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α in the colonic tissues of mice with colitis, compared to DSS-treated mice, with the IL-6 reduction mediated by AhR activation. Furthermore, IAld-mediated AhR activation specifically decreased IL-6 levels in the prefrontal cortex and striatum of the brain in mice with colitis. Improved intestinal integrity was attributed to the downregulation of phosphorylated myosin light chain through IAld-mediated AhR activation. Additionally, IAld-mediated AhR activation inhibited the Nuclear Factor-κB pathway in both in vivo and in vitro models. However, IAld had minimal impact on reshaping the microbial community to alleviate colitis symptoms in mice. This study highlights the role of IAld in regulating intestinal homeostasis and suggests potential treatment strategies for patients with colitis.
Version
Open Access
Date Issued
2024-05
Date Awarded
2024-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Li, Jia
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)