Investigating the Role of Puberty in the Sex-Specific Maturation of the Gut Microbiome

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Project Summary/Abstract In this NIH F31 NRSA Fellowship proposal, I present a research and training program that integrates reproductive endocrinology, microbiology, and bioinformatics. Dr. Varykina Thackray (Mentor at UC San Diego), an expert in reproductive endocrinology, and Dr. Scott Kelley (Co-Mentor at San Diego State University), an expert in microbial diversity and bioinformatics, will oversee my research and career development. My training will include an intensive research experience, didactic and informal instruction in scientific communication, ethics, and research design, and acquisition of career skills that will help me to become an independent biomedical researcher. My proposal focuses on elucidating the role of puberty in the maturation of the intestinal (gut) microbiome. While studies in humans and rodents have shown that the composition of the gut microbiome changes between pre-adolescence and adulthood in a sex-specific manner, the mechanisms through which puberty regulates the gut microbiome are unknown. Sex steroids are conjugated by the liver, and a subset of gut microbes are able to metabolize conjugated sex steroids. Therefore, puberty may directly regulate the growth and composition of the gut microbiome by providing an energy source (sex steroids) for specific microbes. My preliminary data demonstrates that the composition of pre-pubescent gut microbes and metabolites shifts after puberty in female mice, supporting the idea that puberty may drive maturation of the sex-specific gut microbiome. I hypothesize that puberty drives sex-specific maturation of the gut microbiome via sex steroid regulation of gut bacterial growth and metabolite production. In Aim 1, I will determine the effect of puberty on the development of the sex-specific gut microbiome using the Gnrh1hpg mouse model. Since this model does not undergo puberty, this will allow the identification of both pubertal- and sex-specific changes in gut microbiota and metabolome. I will also determine whether sex steroids drive sex-specific maturation of the gut microbiome during puberty using gonadectomy and steroid hormone replacement during puberty in C57BL/6 mice. In Aim 2, I will ascertain whether sex steroids can exert direct effects on gut microbes by determining whether fecal slurries from post- pubertal mice metabolize conjugated sex steroids. I will also test whether sex steroids are metabolized by specific microbes that I identify in Aim 1 as being associated with puberty. Additionally, I will determine whether the presence of sex steroids shifts the microbial community composition of fecal slurries from pre-pubertal mice to a post-pubertal-like state. Given that many gut microbiome-associated diseases, such as diabetes, polycystic ovary syndrome, and depression, manifest during puberty, understanding how puberty shapes the gut microbiome may be important in deciphering the etiology and pathology of these diseases.