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Title:Characterizing cholecystectomy: metabolic and gastrointestinal health, gastrointestinal microbiota, and dietary fiber treatment in a mouse model of menopause
Author(s):Alexander, Celeste
Director of Research:Swanson, Kelly S
Doctoral Committee Chair(s):Donovan, Sharon M
Doctoral Committee Member(s):Nelson, Erik R; Ridlon, Jason M; Holscher, Hannah D
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):cholecystectomy
dietary fiber
menopause
microbiota
metabolism
bile acids
gastrointestinal health
Abstract:Cholecystectomy (XGB), the surgical removal of the gallbladder, is the most common abdominal surgery performed in the United States. Individuals can survive without a gallbladder, but have an increased risk and incidence of several metabolic and gastrointestinal (GI) diseases. Despite substantial research demonstrating a complex relationship between bile acids (BA), the GI microbiota, and host metabolic, GI, and immunological processes, few preclinical studies have attempted to elucidate the impact of XGB on this relationship and the direct connection with associated disease risk. Furthermore, while more than 70% of cholecystectomies are performed in women, predominantly of middle-age, this clinical population remains virtually unstudied. Therefore, investigation of the impact of XGB on host metabolic health and GI physiology in a clinically-representative female animal model is jusitified. Additionally, side-effects of leading therapeutic drugs, such as cholestyramine, highlight the need to identify alternative treatment strategies. Psyllium husk (PH), a soluble, minimally fermentable fiber, possesses BA-binding capacity and may have potential to limit negative systemic effects associated with XGB. Due to these reasons, we aimed to develop a novel rodent model to better represent the main clinical XGB population, identify the impact and potential microbe-mediated mechanisms of XGB on metabolic health and GI physiology, and explore the ability of a dietary fiber intervention to attenuate observed outcomes through four aims. Our first aim was to develop a novel model of XGB in ovariectomized (OVX, menopause model) mice to more closely represent the main XGB patient population, and characterize the resulting metabolic and GI phenotypes. Additionally, we aimed to identify relatively short-term effects of XGB on the same outcomes. We hypothesized that mice that underwent XGB followed by OVX procedure would exhibit a metabolic disease phenotype similar to that of previous studies in OVX-only mice. First, we developed and demonstrated the feasibility of our novel model of XGB and subsequent OVX. Furthermore, we demonstrated that in some ways, as in increased body weight and fat mass (p<0.05), OVX resulted in the expected phenotype in XGB mice. However, the lack of other previously reported changes in OVX-only mice may be due to small sample size or potential metabolic alterations due to XGB. In fact, within six-wk post-XGB, mice exhibited a dramatic increase in CYP7A1 relative expression (p<0.05) and a dramatic decrease in HMCGR relative expression (p<0.05) compared to baseline, suggesting a shift in cholesterol and BA biosynthesis. The results from this study demonstrate a potential masking effect of XGB on OVX, warranting future research utilizing our model to elucidate the independent effects of XGB in female mice. Therefore, our second aim was to determine the systemic impact of XGB on metabolic health in our novel model developed in aim 1, and to investigate if post-prandial PH consumption could limit negative systemic effects. Using a 2x2 factorial design, we hypothesized that XGB mice would develop a metabolic disease phenotype compared to non-XGB controls (SHM), and that would be attenuated or ameliorated by post-prandial PH intervention. XGB mice gained more weight over the course of the study compared to SHM groups, in the form of fat mass (p<0.05). XGB mice also had higher fasting plasma TG and LDL and total cholesterol (p<0.05) compared to SHM mice, and PH intervention lowered plasma TG and LDL concentrations (p<0.05), independent of surgery. XGB mice had greater (p<0.05) hepatic TG content compared to SHM, independent of diet. Finally, XGB altered hepatic immune cell composition, namely tending to increase CD11b+ myeloid cells (p=0.08) and CD4+  T-cells (p=0.03), the latter having a variable role in liver fibrosis and tumorigenesis. Our findings suggest that women who have undergone XGB may be at an increased risk for metabolic disease upon entering menopause, and that post-prandial PH intervention may attenuate the impact on blood lipids. Our third aim was to assess the impact of XGB and post-prandial PH intervention on GI physiology, BA, and microbiota in our novel model. We hypothesized that XGB would perturb normal GI physiology by altering gut morphology, increasing secondary BA production, and shifting microbial composition. XGB tended to increase goblet cell density in duodenal villi (p=0.08) and mitotic rate in the cecum (p<0.05), while PH increased mitotic rate in the ileum (p<0.05). Flow cytometry analysis revealed a reduced proportion (p<0.05) of CD8+  T cells in the colon of XGB mice compared to SHM, which has also been observed in individuals with inflammatory bowel disease. In the short-term, XGB shifted the BA pool toward increased secondary BA; however, this effect was not observed long-term (p>0.05). Microbiota analysis revealed that XGB had a more substantial impact on the cecal microbiota than fecal microbiota, whereas PH intervention influenced microbial composition in both cecal and fecal samples. In particular, XGB resulted in increased relative abundance of cecal Lactococcus and Ruminiclostridium 5 (p<0.05). Our results indicate that XGB elicits some alterations to GI physiology and microbial composition in a menopausal mouse model. These alterations were generally not attenuated by post-prandial PH intervention. To our knowledge, this is the first study to investigate the effect of XGB on GI physiology in detail. Future studies would benefit from a more in-depth analysis of small intestinal, rather than only cecal and fecal, microbial composition following XGB. Our final aim was to use correlative analysis to identify microbe-independent and potentially microbe-dependent mechanisms contributing to the observed phenotypes following XGB and PH intervention that would direct future gnotobiotic studies. We hypothesized that some metabolic and GI physiology-based outcomes, specifically BW, GI immune cell populations, and fecal BA, would be correlated with differentially abundant microbial taxa in cecal and fecal samples. Overall, XGB and PH-induced changes in the cecal microbiota were more strongly correlated with host outcomes than was the fecal microbiota. Cecal Lactococcus and Ruminiclostridium 5 relative abundances were elevated in XGB and strongly correlated (p<0.001) with multiple metabolic health outcomes, suggesting these taxa may promote metabolic dysfunction associated with XGB. Cecal GCA-90066575 and Lachnospiraceae UGC-006 relative abundances, elevated in XGB animals, were also positively correlated with metabolic outcomes (p<0.05). Identification of specific taxa that may contribute to metabolic dysfunction following XGB will aid in the development of microbiota-targeted therapeutic strategies. In the present work, we establish the feasibility of a novel dual-surgery model of XGB in OVX mice to more accurately study the main clinical population undergoing XGB. Additionally, our work demonstrates that XGB exacerbates post-menopausal metabolic dysfunction, and may disrupt normal GI physiology and microbial composition. These discoveries establish foundational knowledge regarding the impact of XGB on the physiological, immunological, and microbial responses of the GI tract, and will shape the design of future research aimed at identifying both mechanisms driving the XGB phenotype and novel therapeutic strategies.
Issue Date:2020-11-20
Type:Thesis
URI:http://hdl.handle.net/2142/109495
Rights Information:© 2020 Celeste Alexander
Date Available in IDEALS:2021-03-05
Date Deposited:2020-12


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