College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113235. doi: 10.1016/j.intimp.2024.113235. Epub 2024 Sep 26.
The disorder of gut microbiota has negative impact on male reproductive, and testicular damage is associated with obesity. However, the detailed mechanism of gut microbiota on the obesity-induced testis injury are still unknown. Therefore, we constructed a mouse model to investigate the effects of obesity on testis injury. In this study, we found that HFD-induced obesity could disorder gut microbiota homeostasis, which increased the abundance of Brevundimonas, Desulfovibrionaceae_unclassified and Ralstonia, ultimately leading to the overproduction of lipopolysaccharides (LPS). Meanwhile, HFD-feeding promoted intestinal permeability via inhibiting expression of tight junction proteins (ZO-1, Occludin and Claudin) and reducing excretion of mucus, leading to translocation of LPS. The over-accumulation of LPS in the bloodstream triggered an inflammatory response by activating TLR4/NF-κB pathway in testis. On the other hand, the gut microbiota produced-LPS also could induce ferroptosis in testis, as reflected by enhancing iron content and lipid peroxidation (MDA), as well as decreasing ferroptosis-related proteins, including GPX4, FTH1 and SLC1A11. Moreover, inhibition of LPS ligand (TLR4) with Resatorvid (TAK-242) alleviated obesity-induced testis injury through suppression of inflammation and ferroptosis. In conclusion, this study provides novel insights into the underlying mechanisms of obesity-related testis injury induced by gut microbiota disorder via the gut-testis axis, thus offering potential targets to counteract obesity-induced male reproductive disorder.
肠道微生物群紊乱对男性生殖功能有负面影响，睾丸损伤与肥胖有关。然而，肠道微生物群对肥胖引起的睾丸损伤的详细机制尚不清楚。因此，我们构建了一个小鼠模型来研究肥胖对睾丸损伤的影响。在这项研究中，我们发现 HFD 诱导的肥胖会破坏肠道微生物群的平衡，增加 Brevundimonas、Desulfovibrionaceae_unclassified 和 Ralstonia 的丰度，最终导致内毒素（LPS）的过度产生。同时，HFD 喂养通过抑制紧密连接蛋白（ZO-1、Occludin 和 Claudin）的表达和减少黏液排泄来促进肠道通透性，导致 LPS 的易位。LPS 在血液中的过度积累通过激活睾丸中的 TLR4/NF-κB 途径引发炎症反应。另一方面，肠道微生物群产生的 LPS 也可以通过增加铁含量和脂质过氧化（MDA），以及降低与铁死亡相关的蛋白质，包括 GPX4、FTH1 和 SLC1A11，来诱导睾丸中的铁死亡。此外，用 Resatorvid（TAK-242）抑制 LPS 配体（TLR4）通过抑制炎症和铁死亡来减轻肥胖引起的睾丸损伤。总之，本研究通过肠-睾丸轴提供了关于肠道微生物群紊乱引起的肥胖相关睾丸损伤的潜在机制的新见解，从而为对抗肥胖引起的男性生殖障碍提供了潜在的靶点。
