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The prevalence of obesity and obesity-related disorders have increased world-wide. In the last decade, the intestinal microbiome has become a major indicator of metabolic and gastrointestinal health. Previous research has shown that high-fat diet (HFD) consumption can alter the microbial composition of the gut by increasing the abundance of gram-positive bacteria associated with the onset of obesity and type 2 diabetes. Although, the most common form of obesity and metabolic syndrome intervention is exercise and diet, these recommendations may not improve severe cases of obesity. Thus, an important relevance of my project was to investigate whether the intake of an organometallic complex (OMC) would prevent the onset of metabolic and gastrointestinal complications associated with high-fat diet intake. I hypothesized that the consumption of a HFD for 6 weeks would promote the development of metabolic and gastrointestinal disease risk factors. Next, it was hypothesized that OMC treatment would decrease metabolic risk factors by improving insulin sensitivity and decreasing weight gain. Finally, I hypothesized that HFD-intake would increase the abundance of gram-positive bacteria associated with gastrointestinal disease. My preliminary data investigated the effects of a 6-week HFD on the development of hepatic steatosis, intestinal permeability and inflammation in male Sprague Dawley rats. I found that a 6-week HFD increases hepatic triglyceride concentrations, plasma endotoxins and promotes the production of pro-inflammatory cytokines in the cecum wall. I then investigated whether OMC treatment could prevent metabolic risk factors in male Sprague-Dawley rats fed a HFD for 10 weeks and found that OMC can mitigate risk factors such hyperglycemia, liver disease, impaired endothelial function, and inflammation. Lastly, I investigated the effects of a 10-week HFD on the gastrointestinal system and found an increase in liver triglycerides and free glycerol and alterations of the distal gut microbiome. My results support the hypothesis that a HFD can promote metabolic risk factors, alter the gut microbiome and increase systemic inflammation and that OMC treatment may help mitigate some of these effects. Together, these studies are among the first to demonstrate the effects of a soil-derived compound on metabolic complications. Additionally, these conclusions also provide an essential basis for future gastrointestinal and microbiome studies of OMC treatment.
ContributorsCrawford, Meli'sa Shaunte (Author) / Sweazea, Karen L (Thesis advisor) / Deviche, Pierre (Thesis advisor) / Al-Nakkash, Layla (Committee member) / Whisner, Corrie (Committee member) / Hyatt, Jon-Philippe (Committee member) / Arizona State University (Publisher)
Created2019
Description
Introduction: Cystic fibrosis (CF) is the most common life-shortening autosomal recessive genetic disease affecting Caucasians. The disease is characterized by a dysfunctional cystic fibrosis transmembrane regulator (CFTR) protein and aberrant mucus accumulation that subsequently alters the physicochemical environment in numerous organ systems. These mucosal perturbations have been associated with inflammation and microbial dysbiosis, most notably in the lungs and gastrointestinal (GI) tract. Genistein, a soy isoflavone and dietary polyphenol, has been shown to modulate CFTR function in cell cultures and murine models, as well exert sex-dependent improvement of survival rates in a CF mouse model. However, it is unknown whether dietary genistein affects gut microbiome diversity and community structure in cystic fibrosis. This study sought to examine associations between dietary genistein treatment and gut microbiome diversity and community structure in a murine model of CF. Methods: Twenty-four male and female mice homozygous for the DF508 CFTR gene mutation were maintained on one of three diet regimens for a 45-day period (n=11, standard chow; n=7, Colyte-treated water and standard chow; n=6, 600 mg dietary genistein per kg body weight). One fecal pellet was collected per mouse post-treatment, and microbial genomic DNA was extracted from the fecal samples, quantified, amplified, and sequenced on the Illumina MiSeq platform. QIIME 2 was used to conduct alpha- and beta-diversity analyses on all samples. Results: Measures of alpha-diversity were significantly decreased in the dietary genistein group as compared to either standard chow or Colyte groups. Measures of beta-diversity showed that community structure differed significantly between dietary treatment groups; these differences were further illustrated by distinct clustering of taxa as shown by principal coordinates analysis plots. Conclusion: This 3-arm parallel experimental study showed that dietary genistein treatment was associated with decreased microbial diversity and differences in microbial community structure in DF508 mice.
ContributorsArgo, Katy Bryana (Author) / Whisner, Corrie M (Thesis advisor) / Al-Nakkash, Layla (Committee member) / Sweazea, Karen L (Committee member) / Arizona State University (Publisher)
Created2019
Description
Morbid obesity is associated with cardiovascular and metabolic disorders. A major contributor to the pathogenesis of these diseases is impaired vasodilation resulting from elevated reactive oxygen species (ROS). This is because certain ROS such as superoxide are raised with obesity and scavenge the endogenous vasorelaxant nitric oxide, resulting in hypertension. The objective of this study was to measure the ability of genistein to quench superoxide in the vasculature of ob/ob mice, an animal model of obesity and type 2 diabetes. Genistein is an isoflavonic phytoestrogen naturally found in soy products. While genistein has documented antioxidant and anti-inflammatory properties, it is not known whether this protects the vasculature from oxidative stress. Genistein was hypothesized to reduce superoxide in arteries from female ob/ob mice. The superoxide indicator dihydroethidium (DHE) [2µL/mL HEPES buffer] was added to isolated aortae and mesenteric arteries from mice fed either a control (standard rodent chow containing 200-300 mg genistein/kg) or genistein-enriched (600mg genistein/kg rodent chow) diets for 4 weeks. Frozen tissues sections were collected onto glass microscope slides and examined using confocal microscopy. Contrary to the hypothesis, a diet containing twice the amount of genistein found in standard chow did not significantly reduce superoxide concentrations in aortae (p=0.287) or mesenteric arteries (p=0.352). Superoxide dismutase, an antioxidant enzyme that breaks down superoxide, was significantly upregulated in the genistein-enriched diet group (p=0.004), although this elevation did not promote the breakdown of superoxide. In addition, the inflammatory marker iNOS was not downregulated in the genistein-enriched diet group (p>0.05). The results indicate that high amounts of isoflavones, like genistein, may not exhibit the purported antioxidant effects in the vasculature of obese or diabetic subjects. Further studies examining arteries from ob/ob mice fed a genistein-free diet are needed to elucidate the true effects of genistein on oxidative stress.
ContributorsSimperova, Anna Marie (Co-author) / Al-Nakkash, Layla (Co-author) / Ricklefs, Kristin (Co-author) / Faust, James J. (Co-author) / Sweazea, Karen L. (Co-author) / Sweazea, Karen (Thesis director) / Gonzales, Rayna (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / T. Denny Sanford School of Social and Family Dynamics (Contributor)
Created2014-05
Description
Obesity is one of the most challenging health conditions of our time, characterized by complex interactions between behavioral, environmental, and genetic factors. These interactions lead to a distinctive obese phenotype. Twenty years ago, the gut microbiota (GM) was postulated as a significant factor contributing to the obese phenotype and associated metabolic disturbances. Exercise had shown to improve and revert the metabolic abnormalities in obese individuals. Also, genistein has a suggested potential anti-obesogenic effect. Studying the dynamic interaction of the GM with relevant organs in metabolic homeostasis is crucial for the design of new long-term therapies to treat obesity. The purpose of this experimental study is to examine exercise (Exe), genistein (Gen), and their combined intervention (Exe + Gen) effects on GM composition and musculoskeletal mitochondrial oxidative function in diet-induced obese mice. Also, this study aims to explore the association between gut microbial diversity and mitochondrial oxidative capacity. 132 adult male (n=63) and female (n= 69) C57BL/6 mice were randomized to one of five interventions for twelve weeks: control (n= 27), high fat diet (HFD; n=26), HFD + Exe (n=28), HFD + Gen (n=27), or HFD + Exe + Gen (n=24). All HFD drinking water was supplemented with 42g sugar/L. Fecal pellets were collected, DNA extracted, and measured the microbial composition by sequencing the V4 of the 16S rRNA gene with Illumina. The mitochondrial oxidative capacity was assessed by measuring the enzymatic kinetic activity of the citrate synthase (CS) of forty-nine mice. This study found that Exe groups had a significantly higher bacterial richness compared to HFD + Gen or HFD group. Exe + Gen showed the synergistic effect to drive the GM towards the control group´s GM composition as we found Ruminococcus significantly more abundant in the HFD + Exe + Gen than the rest of the HFD groups. The study did not find preventive capacity in either of the interventions on the CS activity. Therefore, further research is needed to confirm the synergistic effect of Exe, Exe, and Gen on the gut bacterial richness and the capacity to prevent HFD-induced deleterious effect on GM and mitochondrial oxidative capacity.
ContributorsOrtega Santos, Carmen Patricia (Author) / Whisner, Corrie M (Thesis advisor) / Dickinson, Jared M (Committee member) / Katsanos, Christos (Committee member) / Gu, Haiwei (Committee member) / Liu, Li (Committee member) / Al-Nakkash, Layla (Committee member) / Arizona State University (Publisher)
Created2021
Description
As the 7th leading cause of death in the world, with over 1.6 millions deaths attributed to it in 2016 alone, diabetes mellitus has been a rising global health concern. Type 1 diabetes is caused by lack of insulin production whereas type 2 diabetes is caused by insulin resistance. Both types of diabetes lead to increased glucose levels in the body if left untreated. This, in turn, leads to the development of a host of complications, one of which is ischemic heart disease. Accounting for the death of 16% of the world’s population, ischemic heart disease has been the leading cause of death since 2000. As of 2019, deaths from this disease have risen from 2 million to over 8.9 million globally. While medicine exists to counter the negative outcomes of diabetes mellitus, lower income nations suffer from the lack of availability and high costs of these medications. Therefore, this systematic review was performed to determine whether a non-medicinal treatment could provide similar therapeutic benefits for individuals with diabetes. Genistein is a phytoestrogen found in soy-based products, which has been potentially linked with preventing diabetes and improving diabetes-related symptoms such as hyperglycemia and abnormal insulin levels. We searched PubMed and SCOPUS using the terms ‘genistein’, ‘diabetes’, and ‘glucose’ and identified 32 peer-reviewed articles. In general, preclinical studies demonstrate that genistein decreases body weight as well as circulating glucose and triglycerides concentrations while increasing insulin levels and insulin sensitivity. It also delayed the onset of type 1 and type 2 diabetes. In contrast, clinical studies of genistein in general reported no significant relationship between genistein and body mass, circulating glucose, serum insulin, A1C concentrations, or onset of type 1 diabetes. However, genistein was found to improve insulin sensitivity, delay type 2 diabetes onset and improve serum triglyceride levels. In summary, preclinical and clinical studies suggest that genistein may help delay onset of type 2 diabetes and improve several symptoms associated with the disease. By translating these findings into clinical settings, genistein may offer a cost effective natural approach at mitigating complications associated with diabetes, although additional research is required to confirm these findings.
ContributorsJain, Rijul (Author) / Sweazea, Karen (Thesis director) / Al-Nakkash, Layla (Committee member) / Bolch, Charlotte (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-04-16