Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice

Abstract

BackgroundUnderstanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS.ResultsHere we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters.ConclusionsIn summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0587-0) contains supplementary material, which is available to authorized users.

The Effect of Hops (Humulus lupulus L.) Extract Supplementation on Weight Gain, Adiposity and Intestinal Function in Ovariectomized Mice

“…However, we saw no significant differences in alpha or beta diversity across treatment groups and the community composition and size, inferred from a lack of differences in cecal weights, was similar, even at finer taxonomic scales. The lack of differences, particularly between OVX and SHAM groups was unexpected, particularly as OVX was accompanied by increased visceral adiposity and several previous studies have reported OVX-associated microbial shifts [52]. However, there are multiple environmental factors that can influence the microbiota, such as diet, age, and time post-OVX, that may account for differences between our study and previous reports.…”

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

“…E2 treatment may protect from HFD-induced metabolic disorders through blocking LPS activation [112]. Additionally, E2 upregulates intestinal alkaline phosphatase, a protein with protective role in the gut epithelium through attenuation of proinflammatory signals in the intestine [43]. Taken together with the present findings, estrogens can alter gut microbiota through multiple direct and indirect mechanisms to protect from metabolic disorders.…”

“…were negatively associated. The current and previous studies suggest that various gut microbial communities collectively exert E2-mediated protection against HFD-induced weight gain [38, 43].…”

“…Male mice exhibited higher abundances of Lachnospiraceae (phylum Firmicutes) and Parabacteroides spp. (phylum Bacteroidetes) and Proteobacteria than female mice [36, 43]. Additionally, testosterone administration to female neonatal rats decreased gut microbial diversity during adulthood, and increased the ratio of the two most abundant phyla, Firmicutes and Bacteroidetes [38].…”

“…The hormone-dependent changes in gut microbiota were more robust compared to the diet-induced changes in these rats [38]. Ovariectomy also alters gut microbial diversity in adult mice [36, 43, 44]. While obesity and ob/ob genotype are associated with a reduction in Bacteroidetes/Firmicutes ratio in humans and male mice, respectively [45-48], the effects of leptin on gut microbiota have not been studied in females.…”