Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Benedek, Gil; Zhang, Jun; Nguyen, Ha Nam; Kent, Gail; Seifert, Hilary; Davin, Sean; Stauffer, Patrick; Vandenbark, Arthur A.; Karstens, Lisa; Asquith, Mark; Offner, Halina

doi:10.1016/j.jneuroim.2017.06.007

Cited by 50 publications

(37 citation statements)

References 60 publications

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“…134 Treatment with pregnancy levels of estrogen induces changes in the composition and diversity of the gut microbiota, associated with protection against EAE. 135 It was shown that while EAE led to dysbiosis in mice, pretreatment with estrogen reduced these changes and increased regulatory B-cell and anti-inflammatory macrophage numbers in mesenteric lymph nodes and in the spinal cord. 135 Vitamin D (D3) is an environmental factor that may be involved in the development of autoimmunity.…”

Section: Interaction Between Hormonal and Environmental Factorsmentioning

confidence: 99%

“…135 It was shown that while EAE led to dysbiosis in mice, pretreatment with estrogen reduced these changes and increased regulatory B-cell and anti-inflammatory macrophage numbers in mesenteric lymph nodes and in the spinal cord. 135 Vitamin D (D3) is an environmental factor that may be involved in the development of autoimmunity. Sun protection behavior, which has increased in recent decades, has significantly reduced the hours of light exposure in the population at large.…”

Section: Interaction Between Hormonal and Environmental Factorsmentioning

confidence: 99%

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Impact of sex hormones on immune function and multiple sclerosis development

2018

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women, in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiological conditions in women such as puberty, pregnancy, puerperium, and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clinical evidence for the impact of sex hormones (estrogens, progesterone, prolactin, and testosterone) on MS and attempt to elucidate the hormonal and immunological mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells and provide new insights in the context of MS. Understanding these molecular mechanisms may contribute to the development of new and safer treatments for both men and women.

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Section: Interaction Between Hormonal and Environmental Factorsmentioning

confidence: 99%

Section: Interaction Between Hormonal and Environmental Factorsmentioning

confidence: 99%

Impact of sex hormones on immune function and multiple sclerosis development

2018

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“…Many mechanisms remain undefined or even unidentified. Estrogen prevents changes in gut microbiota associated with EAE [81]. Such mechanisms may include the promotion of specific gut microbiota, and the cross talk between the gut microbiota and sex hormones may help immune-regulation resulting in neuroprotection.…”

Section: Role Of Sex Hormones In Remyelinationmentioning

confidence: 99%

The Role of Sex Hormones in Multiple Sclerosis

et al. 2018

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Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.

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“…The present findings provide evidence that the modulation of gut microbiota is another mechanism by which E2 mediates energy homeostasis. While E2 was associated with a decrease in the gut microbial evenness in the current study, an increase in microbial diversity has been reported in cycling rats and E2-treated female mice [38, 73]. These differences across studies could be due to fluctuating estrogens and other ovarian hormones in the cycling rats and/or species differences [38], and a much higher dose of estradiol (2.5 mg/day, consistent with levels at pregnancy) used in the mice [73].…”

Section: Discussionmentioning

confidence: 48%

“…While E2 was associated with a decrease in the gut microbial evenness in the current study, an increase in microbial diversity has been reported in cycling rats and E2-treated female mice [38, 73]. These differences across studies could be due to fluctuating estrogens and other ovarian hormones in the cycling rats and/or species differences [38], and a much higher dose of estradiol (2.5 mg/day, consistent with levels at pregnancy) used in the mice [73]. Alternatively, while a lower microbial diversity is usually associated with obesity and metabolic disorders [74, 75], a change in relative abundance without any changes in microbial richness or evenness can also alter microbial homeostasis [45].…”

Section: Discussionmentioning

confidence: 48%

Estradiol modulates gut microbiota in femaleob/obmice fed a high fat diet

Gao

et al. 2019

Preprint

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0Estrogens protect against diet-induced obesity in women and female rodents. In support of these 2 1 anorectic effects, lack of estrogens in postmenopausal women is associated with weight gain, 2 2 increasing their risk for cardiovascular diseases and cancer. Estrogens act with leptin, a satiety 2 3 2 hormone encoded by the ob gene, to regulate energy homeostasis in females. Leptin-deficient 1 mice (ob/ob) exhibit morbid obesity and insulin resistance. In addition to estrogens and leptin, 2 the gut microbiome (gut microbes and their metabolites), is critical in regulating energy 3 metabolism. The present study investigates whether estrogens and leptin modulate gut 4 microbiota in ovariectomized ob/ob (obese) or heterozygote (lean) control mice fed a high-fat 5 diet (HFD) that received either 17β-Estradiol (E2) or vehicle implants. E2 attenuated weight gain 6 in both genotypes compared to vehicle counterparts. Moreover, both obesity (ob/ob mice) and 7 E2 reduced gut microbial diversity. ob/ob mice exhibited lower species richness than control 8 mice, while E2-treated mice had reduced evenness compared to vehicle mice. Regarding taxa, 9 E2 treatment was associated with higher abundances of the family S24-7. Leptin was associated targeting the gut microbiome for hormone-dependent metabolic disorders in women. 1 6 1 7 1 8 1 9 2 1and behavior [4][5][6]. Estrogens reduce food intake, attenuate body weight gain and adiposity, and 2 2 increase physical activity in both humans and rodents [1, 2]. Postmenopausal women have lower 2 3 3 levels of circulating estrogens and an increased tendency to gain fat weight, which increases their 1 risk for obesity, cardiovascular disease, stroke, and type 2 diabetes [7][8][9]. Similarly, in mice on a 2 high-fat diet (HFD), ovariectomy increases energy intake and the development of obesity, while 3 estradiol (E2) treatment prevents weight gain [2,[10][11][12][13], indicating that estrogens protect against 4 HFD-induced obesity. 6Leptin is a peptide hormone secreted primarily by adipocytes, which acts in the brain to stimulate 7 metabolism, promote satiety, and regulate fat storage [14][15][16]. A mutation in the ob gene that 8 encodes leptin results in mice lacking the hormone (ob/ob) [17]. While phenotypically normal at 9 birth, ob/ob mice quickly develop obesity and diabetes [18]. Additionally, ob/ob mice exhibit 1 0 increased food intake and decreased physical activity, energy metabolism, and body temperature 1 1 compared to lean controls, making ob/ob mice an excellent genetic model of obesity [19][20][21]. 2Administering leptin to adult ob/ob mice reverses these effects by decreasing food intake, 1 3 increasing energy output and decreasing circulating levels of glucose and insulin [22, 23]. 1 4 1 5Leptin and estrogen signaling pathways interact to influence reproduction and energy 1 6 metabolism. High levels of E2 are associated with increased leptin sensitivity in both male and 1 7 female rodents [24]. In mice, ovariectomy decreases leptin sensitivity, but can be restored by E2 1 ...

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Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Cited by 50 publications

References 60 publications

Impact of sex hormones on immune function and multiple sclerosis development

Impact of sex hormones on immune function and multiple sclerosis development

The Role of Sex Hormones in Multiple Sclerosis

Estradiol modulates gut microbiota in femaleob/obmice fed a high fat diet

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