Surrogate fostering of mice prevents prenatal estradiol-induced insulin resistance via modulation of the microbiota-gut-brain axis

Huihui Wang; Chengliang Zhou; Shuping Gu; Yun Sun

doi:10.3389/fmicb.2022.1050352

Surrogate fostering of mice prevents prenatal estradiol-induced insulin resistance via modulation of the microbiota-gut-brain axis

Front Microbiol. 2023 Jan 9:13:1050352. doi: 10.3389/fmicb.2022.1050352. eCollection 2022.

Authors

Huihui Wang^{1

2

3}, Chengliang Zhou^{4

5}, Shuping Gu⁶, Yun Sun^{1

2

3}

Affiliations

¹ Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
³ Animal Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁵ Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
⁶ Department of Science and Technology Research, Shanghai Model Organisms, Shanghai, China.

Abstract

Introduction: Prenatal and early postnatal development are known to influence future health. We previously reported that prenatal high estradiol (HE) exposure induces insulin resistance in male mice by disrupting hypothalamus development. Because a foster dam can modify a pup's gut microbiota and affect its health later in life, we explored whether surrogate fostering could also influence glucose metabolism in HE offspring and examined mechanisms that might be involved.

Methods: We performed a surrogate fostering experiment in mice and examined the relationship between the metabolic markers associated to insulin resistance and the composition of the gut microbiota.

Results: HE pups raised by HE foster dams (HE-HE) developed insulin resistance, but HE pups fostered by negative control dams (NC-HE) did not. The gut microbiota composition of HE-HE mice differed from that of NC mice raised by NC foster dams (NC-NC), whereas the composition in NC-HE mice was similar to that of NC-NC mice. Compared with NC-NC mice, HE-HE mice had decreased levels of fecal short-chain fatty acids and serum intestinal hormones, increased food intake, and increased hypothalamic neuropeptide Y expression. In contrast, none of these indices differed between NC-HE and NC-NC mice. Spearman correlation analysis revealed a significant correlation between the altered gut microbiota composition and the insulin resistance-related metabolic indicators, indicating involvement of the microbiota-gut-brain axis.

Discussion: Our findings suggest that alterations in the early growth environment may prevent fetal-programmed glucose metabolic disorder via modulation of the microbiota-gut-brain axis. These findings offer direction for development of translational solutions for adult diseases associated with aberrant microbial communities in early life.

Keywords: estradiol; insulin resistance; microbiota-gut-brain axis; prenatal exposure; surrogate fostering.