Date of Award
Open Access Dissertation
Environmental Health Sciences
Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic with increased risks of chronic inflammation in obese and elderly population. It has become a major public health concern due to the unavailability of proper therapeutic approaches. NAFLD is a condition of the liver involving wide spectrum of events including accumulation of fat in the liver and inflammation, which can progress to a fibrotic and cirrhotic phenotype, often termed as non-alcoholic steatohepatitis (NASH). In this backdrop, exposure to environmental toxins from harmful algal blooms could prove detrimental to the overweight, obese or elderly population. NAFLD not only affects the liver but also can have ectopic manifestations to distal organs like kidney, intestines and the brain. In this study, I have examined the role of the toxin Microcystin-LR which is released by cyanobacterial blooms in the coastal waters, and the molecular mechanisms involved in exacerbating the conditions of NAFLD in an individual. I observed that exposure to microcystin in NAFLD mice altered the gut microbiome, induced intestinal inflammation, tight junction protein disruption and fibrosis. It was found that microcystin could lead to the formation of NLRP3 inflammasome through the activation of the NADPH oxidase 2 pathway and generation of reactive oxygen species leading to oxidative stress. Inflammasome activation and increased oxidative stress could lead to the disruption of tight junction proteins, gut leaching and portal endotoxemia. I also explored the effect of overproduction of lactate from pathogenic bacteria due to microcystin exposure on the NAFLD murine intestines. The lactate was found to induce TGFβ downstream signaling pathway involving SMAD proteins, which was again mediated by the NADPH oxidase enzyme. Increased collagen depositon and epithelial to mesenchymal transition was also observed on exposure to microcystin indicating formation of a fibrotic phenotype in the murine small intestine. The inflammation and fibrosis were greatly attenuated in the P47 Phox knockout mice suggesting an important role of the NADPH oxidase enzyme in the molecular mechanisms of the action of microcystin. Similar effects of microcystin exposure were observed on leptin primed transformed rat intestinal epithelial cells. The cells showed inflammatory and fibrotic phenotypes with tight junction protein disruption and extracellular matrix protein deposition as the end points. Also the use of specific inhibitors suggested the mechanism of NADPH oxidase 2 in exacerbating the inflammatory and fibrotic conditions of the intestines in vitro. Along with high inflammation, microcystin exposure in NAFLD also led to uncontrolled levels of IL-18 and IL-17A in murine small intestine which can promote tissue inflammation and also tumor growth. Also, the anti- inflammatory cytokines was observed to decrease in the microcystin exposed group. Thus, my research involves a novel mechanism of studying intestinal diseased pathology due to microcystin exposure and highlights the effects of the toxin under the conditions of non- alcoholic fatty liver disease.
Sarkar, S.(2019). Study of the Inflammatory and Fibrotic Pathology in the Gut Following Microcystin Exposure Under Conditions of Non-Alcoholic Fatty Liver Disease.. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5546