Dissertation
A phytoestrogen diet alters autoimmune disease through modulation of the gut microbiome and host response
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.006043
Abstract
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS); the brain and spinal cord. The symptomology of MS includes pain, numbness, walking difficulty, and/or cognitive dysfunction. As of 2020, 2.8 million individuals worldwide are diagnosed with MS. While the exact cause of MS is unknown, the disease is thought to arise from a complex interaction of genetic and environmental factors. Interestingly, genetic variations account for 30% of disease risk while 70% of risk stems from environmental factors. Recent evidence suggests that the gut microbiome – the trillions of microorganisms that reside in the intestinal tract – is an environmental factor that contributes to disease pathogenesis. Several studies have demonstrated that the composition of the gut microbiome within MS patients is distinct from that of healthy individuals, including a loss of phytoestrogen metabolizing bacteria in MS patients. The pathogenic relevance of these bacterial differences remains elusive. My thesis work focuses on the influence of phytoestrogen-metabolizing bacteria on the immune system and its subsequent impact on a mouse model of MS.Utilizing mouse diets either containing or lacking dietary isoflavones (a type of phytoestrogen), I demonstrate that the gut microbiomes of mice on either diet is distinct. Interestingly, the gut microbiomes of mice on an isoflavone and isoflavone-free diet exhibit some parallels to the gut microbiomes of healthy individuals and MS patients, respectively. Dietary isoflavones do not alter the levels of broad immune cell populations in the spleen, blood, inguinal lymph nodes, and mesenteric lymph nodes. However, dietary isoflavones influence the levels of certain immune cell populations in the intestinal lamina propria, specifically CD8+ T cells. Moreover, isoflavones influence intestinal barrier permeability and cytokine production in mice and human cell lines, respectively.
Utilizing the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, I demonstrate that mice consuming an isoflavone diet exhibit an amelioration of EAE compared to mice on a diet lacking dietary isoflavones. Mice on an isoflavone diet exhibit less spinal cord pathology and pro-inflammatory cellular infiltration into the CNS compared to mice on an isoflavone-free diet. Importantly, the ability of an isoflavone diet to protect was dependent on isoflavone-metabolizing bacteria in the intestines. Strikingly, bacteria that do not metabolize isoflavones do not confer protection against disease in mice on an isoflavone diet. This suggests that isoflavone-metabolizing bacteria provide unique anti-inflammatory benefits to hosts consuming dietary isoflavones. However, treatment with exogenous equol, the end product of isoflavone metabolism, provides protection against EAE in mice on either diet. These results demonstrate that metabolism of isoflavones into equol, by intestinal gut bacteria, provides protection against EAE and possibly MS.
Cumulatively, my thesis demonstrates that dietary isoflavones influence the gut microbiome and intestinal immunity. An isoflavone diet enhances the abundance of bacteria that are depleted in MS patients compared to healthy individuals. Furthermore, the same bacteria that are enhanced as a result of dietary isoflavones can uniquely protect against EAE in hosts on an isoflavone diet. Overall, these results suggest that MS patients are lacking gut bacteria that provide anti-inflammatory benefits.
Details
- Title: Subtitle
- A phytoestrogen diet alters autoimmune disease through modulation of the gut microbiome and host response
- Creators
- Samantha N Jensen
- Contributors
- Ashutosh K Mangalam (Advisor)Nitin J Karandikar (Committee Member)Kevin L Legge (Committee Member)Jon C.D Houtman (Committee Member)Vladimir P Badovinac (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pathology
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.006043
- Publisher
- University of Iowa
- Number of pages
- xix, 197 pages
- Copyright
- Copyright 2021 Samantha N Jensen
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 179-197).
- Public Abstract (ETD)
The immune system’s primary job is to protect us from “harmful” pathogens including bacteria and viruses. Interestingly, humans harbor trillions of “healthy” bacteria in their intestines. The healthy bacteria serve important functions; they help us harvest energy from food and keep our immune system up and running. In the same way that humans need to exercise to stay fit, the immune system needs to “exercise” by constantly interacting with healthy bacteria, so they are ready to protect us from harmful pathogens.
Unfortunately, for some individuals, their immune system attacks their own organs. This is referred to as autoimmunity. Multiple sclerosis (MS), a type of autoimmune disease, results in an immune attack to the brain and spinal cord causing symptoms including numbness and pain.
Recent studies show that certain intestinal bacteria influence MS. My laboratory discovered that gut bacteria that break down phytoestrogens – plant compounds that we consume through our diet – are drastically reduced in MS patients compared to healthy individuals. Therefore, we hypothesized that phytoestrogen metabolizing bacteria are “healthy bacteria” that may protect individuals from MS.
My dissertation focuses on utilizing a mouse model of MS to understand how phytoestrogen metabolizing bacteria influence “MS” in mice. I found that a phytoestrogen diet reduces “MS” in mice and increases “healthy” phytoestrogen metabolizing intestinal bacteria. The “healthy” phytoestrogen metabolizing intestinal bacteria were required for the diet to reduce disease. Overall, my thesis work aims to harness the power of the gut microbiome for therapies and advance our understanding of how MS develops.
- Academic Unit
- Pathology
- Record Identifier
- 9984097277202771
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