This is pretty cut up with the cliff notes, but you see what might be possible, and again im not looking at this as a drug specific issue, but a life issue.
we observed a feminization of gene expression (i.e., downregulation of male-biased and upregulation of female-biased genes) in the liver and WAT of GF male mice. In females, our analysis confirmed an attenuation of sexually dimorphic rhythmic gene expression and metabolic activities in GF mice. This was a consequence of altered sex-hormone and growth hormone (GH) signaling, likely due to the defective sexual maturation of GF (germ free) mice. These results highlight the key role of the microbiota on the establishment of sexually dimorphic liver metabolism and tentatively elucidate several unexplained phenotypes of GF mice that are also known to be sexually dimorphic, such as resistance to liver cancer (Grant and Roe, 1969), xenobiotic detoxification (Carmody and Turnbaugh, 2014), metabolic differences (Nieuwdorp et al., 2014), and poor reproduction
Global Alteration of Gene Expression in the Digestive Tract of GF Mice
To study the impact of microbiota on host gene expression, we compared temporal gene expression in the liver, duodenum, ileum, and WAT of GF and ConvR male mice (Figure S1A). The transcriptomes of GF and ConvR could be distinguished in the liver, duodenum, and ileum but less so in WAT (Figure S1B). We first analyzed constitutive changes between GF and ConvR mice in the different tissues. In the duodenum and ileum of GF mice, most affected genes displayed a significant decrease in expression (Figure S1C and Table S1). Specifically, genes associated with immune response and immune cell mobility were downregulated in the intestine of GF mice (Figure S1D). In the liver, we detected a significant alteration for genes involved in lipid and cholesterol metabolism, confirming the role of microbiota in these pathways (Joyce et al., 2014). In WAT, genes related to immune response were downregulated, consistent with previous reports
Sex-Specific Gene Expression Is Damped in GF Mice
male GF animals showed a feminized expression pattern
it is likely that the complete lack of gut microbiota, rather than sex difference in microbiota, alters sex-dimorphic gene expression.
impact of Microbiota on the Sexually Dimorphic Metabolome
We next analyzed the impact of microbiota on sex-dimorphic metabolomes in liver and serum from ConvR and GF male and female mice. The observed sexual dimorphism in metabolite levels was markedly decreased in GF conditions (Figures 5A and 5B); notably, female-biased metabolites were upregulated in GF males and male-biased metabolites downregulated in both liver and serum (Figures 5C and S4A). Sexual dimorphism was also diminished in GF females, albeit to a lower extent
Microbiota-Derived Metabolites Affect Sexual Maturation
What causes attenuated sexual dimorphism and altered action of testosterone, E2, and GH in GF animals? Sexual dimorphism in the liver appears during puberty (Conforto and Waxman, 2012) when sex hormones imprint sex-specific and pulsatile GH secretion patterns (Jansson et al., 1985). Given the significant impact of the microbiome on sexual dimorphism of liver gene expression, microbiota-derived metabolites appear attractive agents to interfere with sexual development and the imprinting of GH secretion.
the absence of microbiota leads to alterations in sex-dimorphic gene expression and metabolism.
We found that the absence of microbiota perturbed hepatic gene expression in rhythmic and sexually dimorphic pathways such as lipid and xenobiotic metabolism. Although the signals responsible for this phenomenon are not well characterized, a role of microbiome-derived signals has been suggested (Leone et al., 2015, Montagner et al., 2016, Sayin et al., 2013, Thaiss et al., 2016, Venkatesh et al., 2014, Zelante et al., 2013). Here, we showed that sexual dimorphic gene expression and metabolism are altered in GF mice. Indeed, several metabolic characteristics of GF mice, such as reduced growth (Yan et al., 2016), reduced body fat, liver lipogenesis, increased mitochondrial activity, insulin sensitivity (Bäckhed et al., 2004), increased brown adipose tissue (Suarez-Zamorano et al., 2015), and resistance to HFD-induced obesity (Bäckhed et al., 2007, Rabot et al., 2010) are all hallmarks of feminized metabolism
We also identified other microbiota-activated pathways, besides GH signaling, which play crucial roles in sexual development.
We found that the mouse microbiome plays a critical role in sexual dimorphism through the regulation of GH secretion and sexual maturation. While we provide evidence that microbiota-derived metabolites are likely involved in sustaining sexual dimorphism through the activation of the xenobiotic receptors AHR and PXR, the exact mechanism of their action remains elusive. Moreover, the implication of deficient ghrelin secretion in attenuated sexually dimorphic expression patterns that we describe for several conditions will be a topic for future studies. Despite the described limitations of our study, the importance of microbiota in sustaining sexual dimorphism is unexpected and might bear relevance for human perturbation of microbiota diversity at an early age.