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Title:Effects of diet and loss of ovarian hormone production on adiposity, inflammation, cecal integrity, and gut microbial communities of rodent models
Author(s):Liu, Tzu-Wen
Director of Research:Swanson, Kelly S
Doctoral Committee Chair(s):Miller, Michael J
Doctoral Committee Member(s):Fahey, George C; Cattai de Godoy, Maria Regina; Vieira-Potter, Victoria J
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Abstract:Menopause is an age-related loss of ovarian hormone production that has been linked with obesity-associated metabolic dysfunction, increased visceral adiposity, and inflammation, although the mechanisms remain unclear. Obesity has been strongly linked with profound shifts in the gastrointestinal (GI) microbiota, disrupted gut barrier function, and inflammation, but little is known regarding the involvement of the GI tract in obesity associated with loss of ovarian hormone production. Herein, we hypothesized that GI tract and the gut microbiota are involved in the weight gain and inflammation that occurs with the loss of ovarian hormone production and that dietary interventions may affect these responses. The objective of aim 1 was to evaluate the impact of soy on metabolic health, adipose tissue inflammation, and the cecal microbiota in ovariectomized (OVX) rats bred for low-running capacity (LCR), a model that has been previously shown to mimic human menopause. Forty 27-wk old LCR rats were either OVX or sham-operated (SHM) and fed either soy-rich (soy) or soy-free (control) diets for 28 wk. Soy consumption reduced (p<0.05) body weight gain, adiposity, circulating cholesterol concentrations, and improved insulin sensitivity of LCR rats. Principal coordinates analysis (PCoA) of weighted and unweighted UniFrac distances of cecal microbiota revealed a sharp separation (p<0.05) between soy- and control-fed groups. The soy-fed group had a lower (p<0.001) Firmicutes:Bacteroidetes ratio compared to control. The objective of aim 2 was to determine the energy metabolism, lipid accumulation, and inflammation in adipose and liver tissues of OVX female C57BL/6J mice in response to a high-fat diet (HFD). Forty 10-wk-old female C57BL/6J mice were fed either a high-fat diet (HFD; 60% kcal from fat) or a low-fat diet (LFD; 10% kcal from fat). After a 2-wk acclimation period, mice underwent surgical intervention (OVX or SHM). As expected, OVX mice fed HFD had substantially greater (p<0.05) body weight gain, adiposity, and hepatic triglyceride concentrations than OVX mice fed LFD. Compared to intact controls, ovariectomy led to greater (p<0.05) adipose and hepatic tissue inflammation, macrophage infiltration, oxidative stress, hindered insulin signaling and glucose uptake, and altered lipid and energy metabolism. Moreover, HFD feeding of OVX mice led to greater (p<0.05) inflammation and macrophage infiltration in gonadal adipose tissue. The degree of adiposity and inflammation resulting from HFD in OVX mice vs. SHM mice was dramatically greater than that observed in OVX mice vs. SHM control mice fed LFD. The objective of aim 3 was to examine the cecal microbial communities and barrier function in OVX or SHM mice fed a HFD or LFD for 12 wk. OVX/HFD mice had greater (p<0.05) serum lipopolysaccharide-binding protein than OVX/LFD mice. Cecal expression of inflammatory genes was not elevated due to ovariectomy, but the expression of B cell leukemia/lymphoma 2 (BCL2) was greater (p<0.05) in OVX mice than SHM mice, indicating greater apoptosis associated with loss of ovarian hormone production. Cecal permeability was not different among treatment groups. However, OVX mice had lower (p<0.05) cecal expression of occludin, claudin3, and AMP-activated protein kinase (AMPK) than SHM mice, suggesting that the cecal integrity was compromised due to loss of ovarian hormone production. Lower cecal expression of farnesoid X receptor (FXR) and fibroblast growth factor (FGF15) was observed in the OVX mice compared to SHM, suggesting an interaction between estrogen and the FXR-FGF15 pathway that is known to affect bile acid synthesis. PCoA of weighted and unweighted UniFrac distances of cecal microbiota revealed a distinct separation (p<0.05) between mice fed LFD and HFD. Despite the profound physiological changes of OVX/HFD vs. SHM/HFD mice, differential clustering of microbial communities was only observed between OVX/LFD and SHM/LFD mice. HFD promoted a greater (p<0.05) Firmicutes:Bacteroidetes ratio and lower (p<0.05) species richness of the cecal microbial community. Ovariectomy led to greater (p<0.05) abundance of Lactobacillus and lower (p<0.05) relative abundance of Oscillospira, Ruminococcus, and an undefined genus in the order Clostridiales. Differential clustering of the cecal microbial community was observed only between OVX and SHM mice fed a LFD, suggesting that the impact of ovariectomy on the cecal microbiota was masked by the HFD intervention. Thus, the objective of aim 4 was to determine the bacterial beta-glucuronidase activity level and the longitudinal shifts of the gut microbiota following the loss of ovarian function and progression of obesity in mice fed a HFD. Fecal pellets were collected at baseline (wk 0, prior to ovariectomy surgery but 2 wk after diet interventions were initiated) and 4-, 8-, and 12-wk post-surgerical intervention. Fecal beta-glucuronidase activity was elevated (p<0.05) in mice of the SHM/HFD group compared to those in the SHM/LFD group, but it was not different than mice in the OVX groups. PCoA of weighted UniFrac distances of fecal microbiota revealed a distinct separation (p<0.05) between diets. However, SHM and OVX mice only clustered differently in those fed a LFD. The Firmicutes:Bacteroidetes ratio was elevated at wk 8 and wk 12 of those fed the HFD, indicating that this elevation was due to increased adiposity instead of ovariectomy per se. The relative abundance of Clostridium and an undefined genus in the family Clostridiaceae was elevated in the OVX/HFD group at wk 4, but not SHM/HFD, indicating that this change may be due to the loss of ovarian hormone production. Our results indicate that ovariectomy impacts the composition of the gut microbial community, even though the signal was much weaker than that due to dietary intervention. However, ovariectomy promotes disrupted gut barrier function and the alteration of FXR and FGF15 in the cecum, suggesting that signaling and regulation of inflammation and bile acid metabolism in the GI tract were impacted by ovariectomy. Metagenomic, transcriptomic, and metabolomic analyses will need to be conducted to better examine the involvement of the gut microbiome and host-microbial interactions in ovariectomy- and menopausal-associated obesity.
Issue Date:2016-11-30
Rights Information:Copyright 2016 Tzu-Wen Liu
Date Available in IDEALS:2017-03-01
Date Deposited:2016-12

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