{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:46:39Z","timestamp":1785415599365,"version":"3.56.0"},"reference-count":61,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2025M773939"],"award-info":[{"award-number":["2025M773939"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2025M773939"],"award-info":[{"award-number":["2025M773939"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Sichuan Science and Technology Program","award":["2025ZNSFSC1798"],"award-info":[{"award-number":["2025ZNSFSC1798"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Male infertility refers to the inability of a male partner to contribute to pregnancy after 12 months or more of regular unprotected intercourse. It is frequently associated with impaired spermatogenesis, and many cases cannot be completely explained by genetic, inflammatory, endocrine, or environmental factors. Trimethylamine N-oxide (TMAO) is generated when gut bacteria convert dietary choline, L-carnitine, and betaine into trimethylamine (TMA), which is oxidized in the liver mainly by flavin-containing monooxygenase 3 (FMO3). This focused review evaluates current evidence on TMAO and impaired spermatogenesis within the gut\u2013testis axis. The rationale is biologically plausible because sperm motility depends on coordinated glycolytic and mitochondrial energy metabolism, whereas Leydig cell steroidogenesis depends on mitochondrial cholesterol transport and redox balance. Human observational studies associate TMAO with asthenozoospermia and Leydig cell-related markers, particularly insulin-like peptide 3 (INSL3), while mouse studies suggest testicular injury and reduced spermatogenesis after TMAO-related exposure. The Hippo\/Yes-associated protein (YAP)\u2013mitochondria\u2013steroidogenic acute regulatory protein (StAR) axis has been proposed as one possible mechanism, but direct reproductive tract exposure, blood\u2013testis barrier kinetics, and human validation remain unresolved. Overall, TMAO should be considered as a candidate metabolic mediator and not a proven causal factor or therapeutic target in male infertility.<\/jats:p>","DOI":"10.3390\/biology15131078","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T08:05:38Z","timestamp":1783325138000},"page":"1078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trimethylamine N-Oxide and Impaired Spermatogenesis in the Gut\u2013Testis Axis: A Focused Review of Current Evidence"],"prefix":"10.3390","volume":"15","author":[{"given":"Xinyang","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Library, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujun","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). 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