title: A tale of two diets
title: divergent effects of fructose and isoflavones in an animal model of Multiple Sclerosis
titleType: Subtitle
Creators: name: Peterson, Stephanie
Publisher: name: University of Iowa
Year: 2026
Subjects: subject: Diet
subject: EAE
subject: Gut Microbiome
subject: Metagenomics
subject: public abstract
subject: Immunology
subject: FOS: Clinical medicine
subject: Multiple Sclerosis

description: 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.
description: 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.
description: 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.
description: 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.