Activation of aryl hydrocarbon receptor protein promotes testosterone synthesis to alleviate abnormal spermatogenesis...

Area of Science:

• Reproductive Biology
• Hepatology
• Microbiome Research

Background:

• Cholestasis, a condition of impaired bile flow, can affect systemic health.
• Male reproductive dysfunction is a complex issue with multifactorial causes.
• The gut microbiota's role in systemic diseases is increasingly recognized.

Purpose of the Study:

• To investigate the impact of cholestasis on spermatogenesis in a mouse model.
• To elucidate the molecular mechanisms linking cholestasis to male infertility.
• To identify potential therapeutic targets for cholestasis-associated male reproductive dysfunction.

Main Methods:

• Induction of cholestasis using a DDC diet in mice.
• Analysis of testicular gene expression related to androgen synthesis.
• Measurement of liver tryptophan metabolites and their correlation with AHR ligands.
• 16S rDNA sequencing to identify gut microbiota alterations.
• Supplementation with an Aryl Hydrocarbon Receptor (AHR) ligand (ITE).

Main Results:

• Cholestasis significantly disrupted testicular structure and function, downregulating androgen synthesis genes.
• Key tryptophan metabolites, acting as AHR ligands, were reduced in cholestatic mice.
• Reduced AHR ligand levels correlated with decreased androgen synthesis and AHR expression.
• Supplementation with ITE improved testosterone synthesis gene expression and spermatogenesis.
• A specific gut microbiota profile was associated with altered tryptophan metabolism and cholestasis.

Conclusions:

• Cholestasis induces male infertility through a gut microbiota-testis axis that disrupts tryptophan metabolism and androgen synthesis.
• Reduced endogenous AHR ligands play a crucial role in cholestasis-induced testicular dysfunction.
• Targeting this gut microbiota-testis axis and AHR signaling presents a potential therapeutic strategy for male infertility associated with cholestasis.