ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This translational study identifies significant shifts in bile acid composition associated with puberty in female adolescents and rats and identifies a new mechanism of GnRH secretion regulation by bile acid.

Metabolic cues regulate the reactivation of the GnRH system at puberty. The last few years have identified leptin, ghrelin and essential fatty acids as permissive or inhibitory cues regulating GnRH neuron activity^1-4. The effects of those signalling factors are mostly mediated by the kisspeptin-neurokinin-dynorphin neurons in the arcuate nucleus⁵. Recent studies have shown that the gut microbiome influences metabolic and reproductive health in humans and suggested that regulation of bile acid metabolism by the microbiome might be a mechanism through which environmental factors regulate reproduction⁶.

This study reported changes in bile acid composition in the serum of female adolescent and rats throughout puberty. This shift in bile composition was accompanied by a shift in gut microbial composition suggesting that the gut microbiome was the mediator linking bile acid isoforms to pubertal maturation. Authors also showed that the expression of tgr5, a gene coding for a bile acid receptor, increased in the female rat arcuate nucleus throughout puberty. The authors showed that TGR5 was expressed by kisspeptin neurons and that bile acids stimulate GnRH secretion from hypothalamic explants through a mechanism involving kisspeptin. Moreover, they showed that overexpression of tgr5 in the arcuate nucleus leads to early onset of puberty in female rats.

In summary, this study defines a new role for the hepatic-gut-neuroendocrine axis in the control of puberty. Bile acid might provide a key metabolic signal which modulates the timing of puberty and is influenced by the gut microbiome. This suggest a potential role of the microbiome in pathological situations associated with abnormal puberty such as chronic inflammatory bowel diseases or obesity.

References: 1. Smith SS, Neuringer M, Ojeda SR. Essential fatty acid deficiency delays the onset of puberty in the female rat. Endocrinology. 1989;125(3):1650-1659. 2. Cheung CC, Thornton JE, Nurani SD, Clifton DK, Steiner RA. A Reassessment of Leptin’s Role in Triggering the Onset of Puberty in the Rat and Mouse. Neuroendocrinology. 2001; 74(1):12-21. 3. Tena-Sempere M. Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology. 2007; 86(3):229-241. 4. Vazquez MJ, Toro CA, Castellano JM, et al. SIRT1 mediates obesity- and nutrient dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat Commun. 2018; 9(1):4194. 5. Manfredi-Lozano M, Roa J, Tena-Sempere M. Connecting metabolism and gonadal function: Novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Connecting metabolism and 25 gonadal function: Novel central neuropeptide pathways involved in the metabolic 26 control of puberty and fertility. Front Neuroendocrinol. 2018; 48:37-49. 6. Giampaolino P, Foreste V, Di Filippo C, Gallo A, Mercorio A, Serafino P, Improda FP, Verrazzo P, Zara G, Buonfantino C, Borgo M, Riemma G, Angelis C, Zizolfi B, Bifulco G, Della Corte L. Microbiome and PCOS: State-of-Art and Future Aspects. Int J Mol Sci. 2021; 22(4):2048.