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The Intestinal Physiology of Bariatric Surgery
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- Author / Creator
- Dang, Jerry
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BackgroundEvidence is emerging that the gut microbiome is an important contributor to the weight and metabolic effects of bariatric surgery. However, the microbial and intestinal physiological changes that occur with bariatric surgery are poorly understood. Developing this understanding potentially opens avenues for the development of targeted therapies to treat obesity and its metabolic diseases.AimsThe aims of this study were to perform a comprehensive analysis of the physiological intestinal changes after bariatric surgery including microbial, metabolomic, gut hormonal, and morphological changes.MethodsIn the first study, we developed a protocol to perform Roux-en-Y gastric bypass (RYGB) in rats that had similar weight loss and metabolic changes to human RYGB. Secondly, we performed RYGB in rats to study changes in the distal ileum. The distal ileum demonstrates the most significant bile acid changes and is also the location where important gut hormones, such as glucagon-like-peptide-1, are produced. Thirdly, we conducted a three-arm prospective clinical trial in humans undergoing RYGB, sleeve gastrectomy (SG) and non-operative controls (CTRL) to understand the microbial, metabolomic, and inflammatory changes that occur after bariatric surgery.ResultsIn the first study, we developed an excellent RYGB surgical model in rats that had an overall survival of 88.9%. This model had significantly greater weight loss and better glucose tolerance compared to the sham surgery cohort. It was also an easily reproducible procedure that required no formal surgical training or experience.In the second study, we performed RYGB and sham surgery in a cohort of rats and divided them into early (2 week) and late (14 week) cohorts. Ileal samples were comprehensively analyzed. At 14 weeks, there was increased L-cell density and increased villi height in the RYGB cohort. Bile acid analysis found lower concentrations of ileal bile acids following RYGB. Both early and late RYGB cohorts demonstrated higher abundances of Escherichia-Shigella and lower abundances of Lactobacillus. These shifts in microbial composition appeared to drive bile acid reductions as the loss of Lactobacillus and the increase in Escherichia-Shigella were both correlated with decreases in specific taurine and glycine conjugated bile acids.Our three-arm human trial found significant microbial and metabolic shifts after RYGB and SG. We conducted integrated microbial-metabolomic analysis and identified three unique pathways that contribute to weight loss and metabolic improvement. In the first pathway, the abundance of Romboutsia decreased after RYGB. This decrease was correlated to decreases in multiple different glycerophospholipids. This decrease in Romboutsia was correlated with lower weight and insulin resistance and appears to be a key pathway in RYGB.After SG, the aminoacyl-tRNA pathway was significantly enriched in both the microbiome and metabolome. This enrichment was linked to a decreased abundance of a cluster of Firmicutes bacteria consisting of Butyriciccocus, Eubacterium ventriosum and Monoglobus. This Firmicutes shift was correlated with an increase in five amino acids which consequently enriched the aminoacyl-tRNA pathway. This pathway appears to be a driver of metabolic change as the loss of this Firmicutes cluster was correlated with lower weight, decreased insulin resistance, and decreased systemic inflammation.When performing between group comparisons, SG demonstrated an enriched sphingolipid metabolism pathway at 9 months compared to RYGB. This pathway was enriched due to the loss of a cluster of Firmicutes bacteria (Monoglobus, Eubacterium ventriosum, Eubacterium hallii, Dorea, and Lachnospira) which correlated to increases in sphingomyelins and hydroxysphingomyelins and concurrently correlated to improved glucose tolerance. This appears to be a pathway in which SG, but not RYGB, improved glucose homeostasis.ConclusionsIn summary, this body of work identified pathways in which SG and RYGB induce weight loss and improved glucose metabolism. This occurred through various microbial-metabolomic pathways which included bile acids, glycerophospholipids, amino acids, and sphingolipids. Translational work building upon these findings by targeting and inducing shifts in microbial, metabolomic, or bile acid composition may lead to novel therapeutic options to treat obesity and its associated metabolic diseases.
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- Graduation date
- Spring 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.