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Stephanie Peterson Thesis - Revised Final for Grad College3.81 MB
Embargoed Access, Embargo ends: 01/26/2028
Dissertation
A tale of two diets: divergent effects of fructose and isoflavones in an animal model of Multiple Sclerosis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2023
DOI: 10.25820/etd.006860
Abstract
Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) with debilitating effects for those affected by it. Both genetic and environmental factors are thought to be involved in disease predisposition and propagation. However, the presence of only 30% concordance for MS incidence in monozygotic twins points towards a major effect of environmental factors in the pathobiology of MS. One emerging environmental factor linked to MS is diet, which can have wide-ranging effects on health through potential systemic circulation or interaction between nutrients found in the diet and the gut microbiome. However, food can have both beneficial as well as detrimental effects in MS depending on dietary composition.
MS incidence is highest in Western/”developed” countries where the diet is often high in fat and processed foods while being low in fiber. Fructose is a monosaccharide that is often an additive in Western-style diet foods, leading to increased sugar consumption. However, the effects of fructose alone on the host microbiome, immune response, and MS disease are not well studied.
Therefore, in this dissertation, we wanted to investigate the effects of fructose on the composition and functional capacity of the gut microbiome, the immune system, and disease outcomes in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). We observed that a fructose-rich diet (FRD) was able to alter the gut microbiome’s composition and functional capacity. Additionally, FRD also modulated local (intestine) and systemic immune responses. Interestingly, despite modulating gut microbiota and immune response, FRD did not affect EAE disease severity. We also investigated whether giving FRD in water (to mimic sugary drinks), for a longer duration, or combining it with other components of the Western diet, such as high fat diet (HFD), can increase disease severity. However, no matter the duration of the FRD, method of ingestion (diet or water), or combination with a HFD, there was no significant effect of high fructose intake on EAE disease severity.
Conversely to the western-style diet, other diet patterns with higher fiber and plant content are often associated with better outcomes and lower incidence of MS. One class of dietary compounds that can be found in many of these diets is isoflavones, a type of phytoestrogen. Previous work from our lab showed that isoflavones are protective in the context of EAE, leading to lower disease severity than controls. This protection is dependent on the presence of phytoestrogen metabolizing gut bacteria and requires CD8 T cells. Thus, we wanted to determine potential mechanisms of protection mediated by isoflavones. We hypothesized that because isoflavones are estrogenic, they exert their protective effects through estrogen receptor signaling, specifically in CD8+ T-cells in the intestinal lamina propria. We observed that isoflavone-fed mice had increased expression of estrogen receptor alpha (ERα) in the colon and that blockade of estrogen receptor (ER) signaling led to loss of isoflavone-mediated protection in EAE. Loss of disease protection in ovariectomized mice suggested that isoflavone-mediated protection required endogenous estrogens as well. Furthermore, we observed that CD8+T-cells in the colonic lamina propria have altered phenotype and function in isoflavone-fed mice, with increased expression of markers linked with exhaustion and/or immunomodulation. Overall, between fructose and isoflavones, the data in my thesis suggest that different dietary components can have very different effects on the host immune response and disease itself in the context of MS. Future studies will help both in understanding the precise mechanism through which isoflavones protect from disease and in the development of diet-based therapies to treat MS.
Details
- Title: Subtitle
- A tale of two diets: divergent effects of fructose and isoflavones in an animal model of Multiple Sclerosis
- Creators
- Stephanie Peterson
- Contributors
- Ashutosh K Mangalam (Advisor)Kevin L Legge (Committee Member)Scott M Lieberman (Committee Member)Ali Jabbari (Committee Member)Sukirth M Ganesan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Autumn 2023
- DOI
- 10.25820/etd.006860
- Publisher
- University of Iowa
- Number of pages
- xiii, 173 pages
- Copyright
- Copyright 2023 Stephanie Peterson
- Language
- English
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 146-173).
- Public Abstract (ETD)
- Multiple Sclerosis is a debilitating disease of the brain and spinal cord affecting an estimated 2.8 million people worldwide. Both genetic and environmental factors influence the initiation and progression of the disease. These environmental factors include diet, the gut microbiome, infections, and more. However, diet has emerged as a major player because compounds in food can interact with the gut microbiome, changing the bacteria and their functions to either benefit or harm the host. Dietary compounds may also reach the bloodstream and have effects throughout the body that, again, can be helpful or harmful. Previous research has shown that Western-style diets high in fat, sugar, and processed foods are associated with various negative health outcomes, while diets rich in plants and fiber are generally more beneficial. Furthermore, “developed” countries such as the USA, Canada, and many areas of Europe where a Western diet is the norm are also the areas with the most people diagnosed with MS. However, how various diets can influence MS disease is unknown. Thus, we wanted to investigate the effects of two dietary components with potentially opposite effects: fructose and isoflavones. Fructose is a sugar found in high quantities in the Western-style diet and we hypothesized that it would negatively affect the gut microbiome and disease outcomes in an animal model of MS. Conversely, isoflavones are plant-based estrogenic compounds with the ability to reduce symptom severity in an MS animal model, but the mechanism of that protection is not well understood. We hypothesized that isoflavones reduce MS severity through estrogen receptor signaling, especially on CD8+ T-cells. In my studies, I found that fructose can alter the gut microbiome and its’ function, as well as the immune response. Despite these changes, a fructose rich diet did not translate to worse clinical outcomes in the animal model of MS. Furthermore, even when fructose was given in combination with a high fat diet, making it closer to the Western diet, it had no significant effect on disease outcome. Additionally, when investigating how isoflavones provide protection in MS, I found that loss of estrogen receptor signaling does lead to loss of isoflavone-mediated protection from MS-like disease. I also found that CD8+ T-cells in the colons of isoflavone-fed mice had altered properties compared to isoflavone-free fed mice. Overall, my data show that fructose and isoflavones have different effects on the host immune response and disease. Better understanding of these varied effects will help us identify targets for future therapies or find compounds that people with MS should potentially avoid to slow or stop disease progression.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984546849102771
Metrics
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