Trimethylamine N-Oxide Linked to Impaired Spermatogenesis and Leydig Cell Dysfunction in Gut-Testis Axis

Male infertility, often stemming from impaired spermatogenesis, affects many couples, with a significant portion of cases lacking clear genetic, inflammatory, endocrine, or environmental explanations. Current diagnostic and therapeutic approaches are often insufficient, highlighting a need for novel insights into contributing factors. Trimethylamine N-oxide (TMAO), a metabolite derived from gut bacterial processing of dietary choline, L-carnitine, and betaine, has emerged as a candidate mediator. Its biological plausibility in male reproductive health stems from sperm motility's reliance on glycolytic and mitochondrial energy metabolism, and Leydig cell steroidogenesis' dependence on mitochondrial cholesterol transport and redox balance.

This focused review systematically evaluated current evidence on the association between trimethylamine N-oxide (TMAO) and impaired spermatogenesis within the gut-testis axis. Researchers synthesized findings from human observational studies and preclinical mouse models, examining the proposed mechanisms. The review considered the biological plausibility of TMAO's impact on sperm motility and Leydig cell steroidogenesis, which rely on mitochondrial function and redox balance, to identify gaps and future research directions.

The review found consistent associations between TMAO and markers of impaired male fertility across different study types. Human observational studies linked TMAO levels with asthenozoospermia (reduced sperm motility) and specific Leydig cell-related markers, most notably insulin-like peptide 3 (INSL3). Preclinical mouse studies further supported these observations, indicating that TMAO-related exposure can lead to testicular injury and reduced spermatogenesis. A potential mechanistic pathway, the Hippo/Yes-associated protein (YAP)-mitochondria-steroidogenic acute regulatory protein (StAR) axis, has been proposed to mediate these effects, suggesting an impact on mitochondrial function and steroidogenesis. However, the review emphasizes that TMAO should be viewed as a candidate metabolic mediator rather than a proven causal factor or therapeutic target.

TMAO is consistently associated with asthenozoospermia and reduced INSL3 in human studies, and testicular injury in mouse models.