Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis

Jensen, Samantha N.; Cady, Nicole; Shahi, Shailesh K.; Peterson, Stephanie R; Gupta, Arnav; Gibson‐Corley, Katherine N.; Mangalam, Ashutosh K.

doi:10.1126/sciadv.abd4595

Cited by 49 publications

(41 citation statements)

References 56 publications

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“…However, a few studies speculate that phytoestrogen intake must be high during prepubescent stages of development to achieve the protective benefits of phytoestrogens. In addition, another indirect impact of phytoestrogens is the alteration in the intestinal microbiota [ 154 ] that are known to regulate immune response and inflammation. Overall, findings from the epidemiological studies have been inconclusive, and as such, the chemoprotective role of phytoestrogens remains ambiguous.…”

Section: Xenoestrogens In Inflammation and Breast Cancermentioning

confidence: 99%

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Maharjan

Wang

et al. 2021

Cancers

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The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen’s pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.

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Section: Xenoestrogens In Inflammation and Breast Cancermentioning

confidence: 99%

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Maharjan

Wang

et al. 2021

Cancers

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“…To determine if the effect of IL-17A on EAE disease was universal or limited to the HLA class II transgenic mouse model, we assessed the effects of depleting IL-17A in wild-type C57BL/6J (B6) mice. In this mouse strain, EAE was induced with MOG 35-55 as described previously (31). B6 mice treated with anti-IL-17A antibody after the onset of EAE (i.e., at days 5, 8, 11, 14, 17, 20, 23, 26, 29, and 32 post disease induction) showed significantly lower average clinical scores over time compared to mice treated with PBS or IgG1a (Fig.…”

Section: Resultsmentioning

confidence: 99%

IL-17A-mediated alterations in gut microbiota composition, particularly changes in Prevotella abundance, impact Treg function in CNS Autoimmunity

Shahi

Ghimire

Jensen

et al. 2022

Preprint

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A disrupted equilibrium between IL-17A-producing CD4 T-cells (Th17) and CD4+CD25+FoxP3+ regulatory T cells (Tregs) play an important role in the pathobiology of Multiple sclerosis (MS). Gut bacteria help in maintaining immune homeostasis by regulating the balance between anti-inflammatory Tregs and pro-inflammatory Th17 cells. Although, both gut bacteria and Tregs can regulate Th17 cells, the impact of IL-17A on gut microbiota and Tregs is unclear. Utilizing HLA-DR3 transgenic mouse model of MS, we show that IL-17A deficiency (HLA-DR3.IL17A-/- mice) expands Treg-inducing gut bacteria such as Prevotella, Parabacteroides, and Bacteroides and consequently Tregs, resulting in a milder disease in an animal model of MS. Notably, IL-17A sufficient DR3 mice develop milder disease on cohousing with IL-17A-deficient mice, highlighting a dominant role for gut microbiota in inducing Treg and reducing disease severity. Further, we observed an enrichment of bacterial-specific Treg promoting short-chain-fatty-acid metabolic pathways and induction of tolerogenic dendritic cells in HLA-DR3.IL17A-/- mice. Thus, our study shows a novel role of IL-17A in immune homeostasis and inflammation through regulation of the gut microbiota-Treg axis which can be used for the development of gut bacteria as therapeutics for MS.Significance of our workIL-17A a pro-inflammatory cytokine, is linked with pathobiology of multiple inflammatory diseases including multiple sclerosis (MS) and regulated by both gut microbiota and regulatory CD4 T cells (Tregs). However, the importance of IL-17A in the regulation of gut microbiota and Treg is unknown. Here we show that IL-17A can regulate Treg and disease phenotype by modulating gut microbiota and provide a novel mechanism by which immune-mediators such as IL-17A impact the gut microbiota to alter immune cell function and ultimately disease outcomes. Transfer of milder disease phenotype from IL-17A deficient mice to IL-17A sufficient mice on cohousing indicate a dominant role of gut microbiota in disease suppression. Thus, our study lays the foundation for future studies to unravel the interplay between immunological responses and the gut microbiota which will result in the development of microbiota-based therapeutics to treat autoimmune diseases.

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“…Similarly, in a double-blind randomized controlled study, a high-dose biotin supplement reduced the proportion of patients that progressed in their disability scores [ 62 ]. Moreover, an isoflavone diet attenuated EAE through the presence of isoflavone-metabolizing bacteria [ 63 ]. Furthermore, in patients with low vitamin D levels, vitamin D supplementation was associated with a lower annual relapse rate, a reduction in brain lesions and a slower progression of disability [ 64 ].…”

Section: Diet the Microbiota And Msmentioning

confidence: 99%

Multiple sclerosis and the microbiota

Engelenburg

Lucassen

Sarafian

et al. 2022

Evolution, Medicine, and Public Health

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Multiple sclerosis (MS), a neurological autoimmune disorder, has recently been linked to neuro-inflammatory influences from the gut. In this review, we address the idea that evolutionary mismatches could affect the pathogenesis of MS via the gut microbiota. The evolution of symbiosis as well as the recent introduction of evolutionary mismatches is considered, and evidence regarding the impact of diet on the MS-associated microbiota is evaluated. Distinctive microbial community compositions associated with the gut microbiota of MS patients are difficult to identify, and substantial study-to-study variation and even larger variations between individual profiles of MS patients are observed. Furthermore, although some dietary changes impact the progression of MS, MS-associated features of microbiota were found to be not necessarily associated with diet per se. In addition, immune function in MS patients potentially drives changes in microbial composition directly, in at least some individuals. Finally, assessment of evolutionary histories of animals with their gut symbionts suggests that the impact of evolutionary mismatch on the microbiota is less concerning than mismatches affecting helminths and protists. These observations suggest that the benefits of an anti-inflammatory diet for patients with MS may not be mediated by the microbiota per se. Further, any alteration of the microbiota found in association with MS may be an effect rather than a cause. This conclusion is consistent with other studies indicating that a loss of complex eukaryotic symbionts, including helminths and protists, is a pivotal evolutionary mismatch that potentiates the increased prevalence of autoimmunity within a population. Lay Summary Multiple sclerosis (MS) is associated with the microbiota in some experimental models, and diets that modulate the microbiota may help treat MS. However, available data suggest that, the beneficial effects of healthy diets for MS may be mediated directly by decreasing inflammation rather than by altering the gut microbiota composition

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Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis

Cited by 49 publications

References 56 publications

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

IL-17A-mediated alterations in gut microbiota composition, particularly changes in Prevotella abundance, impact Treg function in CNS Autoimmunity

Multiple sclerosis and the microbiota

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