UC San Diego

The gut microbiome, a complex set of communities within the intestinal tract, interacts with the host to impact health and disease. Many sex-specific diseases, including reproductive, metabolic, and auto-immune diseases, have been linked to the composition of the gut microbiome. Studies have also shown that sex differences in the gut microbiome develop in adulthood. Given this, understanding how sex differences in the gut microbiome develop is necessary to understand how sex-specific, gut microbiome-linked diseases develop and can be treated. In Chapter 1, I describe what was previously known about the timing of when sex differences develop in the gut microbiome, the effect of sex steroids on the gut microbiome, and propose mechanisms through which sex steroids could affect gut microbiome composition. To investigate the role of reproductive development on sexual maturation of the gut microbiota in this, I used a hypogonadal mouse model, in which the hypothalamic-pituitary-gonadal (HPG) axis is not activated, to determine the impact of the HPG axis on sexual maturation of the gut microbiota. In Chapter 2, I use 16S sequencing of intestinal samples to show that activation of the HPG axis during development leads to niche- specific sexual maturation of the intestinal microbiome. Results from Chapter 2 also indicate that sex chromosomes may cause sex differences in the gut microbiome in some parts of the intestine. In Chapter 3, I show that HPG axis activation during the pubertal period specifically is necessary for sexual differentiation of the gut microbiota, but that some aspects of gut microbiome maturation during puberty are independent of the HPG axis. Overall, these results indicate that HPG axis activation is critical for both general maturation and sexual differentiation of the gut microbiota, but that the HPG axis may not be the only factor contributing to this maturation. This suggests that microbiome-based therapeutics, especially for sex-specific disorders, should consider patient sex, age, and hormonal status.