Environmental factors such as diet contribute to the pathogenesis of inflammatory bowel disease (IBD). Epidemiological evidence suggests a robust linkage between IBD and the Western diet, which is often characterized by a high intake of food additives. These additives, including synthetic colourants, are widely used, leading to significant human exposure. Allura Red AC (AR) is one of the most popular synthetic colourants, yet little is known about its impact on human health and the role of AR in the pathogenesis of colitis remains elusive. Serotonin (5-hydroxytryptamine; 5-HT), which regulates various gut physiological processes, has been shown to modulate the gut microbiota and enhance susceptibility to colitis. In this thesis, it was discovered that chronic exposure to AR, at a dose found in commonly consumed dietary products, exacerbated dextran sulfate sodium (DSS)-induced colitis and triggered early onset of disease in the CD4+CD45RBhigh T cell-induced colitis model. AR also induced low grade colonic inflammation in naïve C57BL/6 mice. Exposure to AR was associated with increased colonic 5-HT levels and impaired intestinal barrier function via activation of the myosin light chain kinase (MLCK) pathway. However, AR did not promote colitis in mice lacking tryptophan hydroxylase 1 (Tph1), the rate-limiting enzyme responsible for colonic 5-HT synthesis. Further, AR increased colonic 5-HT levels in germ-free (GF) mice and perturbed the gut microbiota composition in specific pathogen-free (SPF) mice. Transfer of this altered microbiota from the dye-exposed SPF mice to GF mice conferred enhanced susceptibility to DSS-induced colitis. Mechanistically, AR induced reactive oxygen species (ROS) generation and promoted 5-HT secretion via the NF-κB pathway in BON cells. Data in this thesis indicate that the widely used synthetic colourant, AR, promotes colitis via colonic 5-HT in microbiota-dependent and -independent pathways. Collectively, these findings provide important information on enhancing public awareness of its detrimental effects on human health. / Thesis / Candidate in Philosophy / Epidemiological and experimental studies suggest a potential link between inflammatory bowel disease (IBD) and diet. The Western diet, often characterized by a high intake of processed foods, is associated with the growing incidence of IBD. Allura Red AC (AR) is a popular artificial food dye found in highly common processed foods, yet little is known about its impact on human health and disease. Serotonin, a key molecule in the gut, has been implicated in large bowel inflammation. Herein, the potential role of AR in the development of colitis was examined. Across multiple models, AR exposure heightened vulnerability to colitis in mice, an effect attenuated by reduced serotonin production in the gut. The effect of AR in enhancing colitis vulnerability occurred via gut microbiota-dependent and -independent pathways. These studies have identified how AR promotes colitis, findings that may advance public health awareness and impact the health of patients with IBD.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27688 |
| Date | January 2022 |
| Creators | Kwon, Yun Han |
| Contributors | Khan, Waliul I |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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