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Title: Investigating the effect of dietary cholesterol on the intestine in zebrafish larvae
Author: Charlwood, Kathryn
ISNI:       0000 0004 8504 3869
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The incidence of chronic inflammatory diseases has risen over the past few decades, particularly in Western societies. This increased incidence of disease has coincided with a number of lifestyle changes such as a shift in dietary habits to high lipid, high sugar diets and widespread use of antibiotics. High lipid diets specifically have been associated with intestinal disorders such as inflammatory bowel disease. A zebrafish model of a high cholesterol diet (HCD) has been found to cause inflammasome-dependent intestinal immune cell accumulation and peristalsis impairment. This PhD project used juvenile zebrafish larvae as a model organism to further investigate the effects of a 9-day HCD and antibiotic treatment on intestinal motility and inflammation. A 9-day HCD only induced peristalsis impairment and increased intestinal transit time in the presence of the antibiotic penicillin-streptomycin (PS). HCD-fed PS-treated (HCD+PS) larvae had increased levels of intestinal immune cell accumulation compared with control-fed PS-treated larvae, but similar levels of accumulation compared with untreated larvae. In untreated larvae, HCD did not increase immune cell accumulation compared with control-fed larvae. To investigate the role of antibiotic treatment on HCD-induced intestinal dysfunction, the effect of PS treatment on the microbiota was assessed. PS treatment reduced the diversity of the microbiota and altered the microbiota composition. Analysis of microbial metabolism indicated that PS-treatment may increase the production of pro-atherosclerotic compound trimethylamine N-oxide (TMAO). HCD+PS larvae showed greater gut microbiota compositional changes and showed indications of further TMAO production compared to PS-treated or HCD-fed larvae alone. These results demonstrate that antibiotic treatment can significantly affect the intestinal response to dietary cholesterol in a pathophysiologically relevant model of HCD-induced intestinal dysfunction. Overall, these findings highlight that antibiotic-induced alterations of the microbiota composition can lead to changes in nutrient handling and may contribute to the development of a pro-inflammatory state.
Supervisor: Dallman, Magaret ; Bugeon, Laurence ; Lamb, Jonathan Sponsor: National Centre for the Replacement, Refinement, and Reduction of Animals in Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral