PDF(Pubmed)
Abstract：
Men with prediabetes often exhibit concomitant low-quality sperm production or even infertility, problems which urgently require improved therapeutic options. In this study, we have established a sheep model of diet-induced prediabetes that is associated with spermatogenic defects and have explored the possible underlying metabolic causes.
We compared male sheep fed a normal diet with those in which prediabetes was induced by a rich diet and with a third group in which the rich diet was supplemented by melatonin. Only the rich diet group had symptoms of prediabetes, and in these sheep, we found impaired spermatogenesis characterized by a block in the development of round spermatids and an increased quantity of testicular apoptotic cells. Comparing the gut microbiomes and intestinal digest metabolomes of the three groups revealed a distinctive difference in the taxonomic composition of the microbiota in prediabetic sheep, and an altered metabolome, whose most significant feature was altered sphingosine metabolism; elevated sphingosine was also found in blood and testes. Administration of melatonin alleviated the symptoms of prediabetes, including those of impaired spermatogenesis, while restoring a more normal microbiota and metabolic levels of sphingosine. Fecal microbiota transplantation from prediabetic sheep induced elevated sphingosine levels and impaired spermatogenesis in recipient mice, indicating a causal role of gut microbiota in these phenotypes.
Our results point to a key role of sphingosine in the disruption of spermatogenesis in prediabetic sheep and suggest it could be a useful disease marker; furthermore, melatonin represents a potential prebiotic agent for the treatment of male infertility caused by prediabetes.
We compared male sheep fed a normal diet with those in which prediabetes was induced by a rich diet and with a third group in which the rich diet was supplemented by melatonin. Only the rich diet group had symptoms of prediabetes, and in these sheep, we found impaired spermatogenesis characterized by a block in the development of round spermatids and an increased quantity of testicular apoptotic cells. Comparing the gut microbiomes and intestinal digest metabolomes of the three groups revealed a distinctive difference in the taxonomic composition of the microbiota in prediabetic sheep, and an altered metabolome, whose most significant feature was altered sphingosine metabolism; elevated sphingosine was also found in blood and testes. Administration of melatonin alleviated the symptoms of prediabetes, including those of impaired spermatogenesis, while restoring a more normal microbiota and metabolic levels of sphingosine. Fecal microbiota transplantation from prediabetic sheep induced elevated sphingosine levels and impaired spermatogenesis in recipient mice, indicating a causal role of gut microbiota in these phenotypes.
Our results point to a key role of sphingosine in the disruption of spermatogenesis in prediabetic sheep and suggest it could be a useful disease marker; furthermore, melatonin represents a potential prebiotic agent for the treatment of male infertility caused by prediabetes.
摘要：
患有糖尿病前期的男性通常表现出伴随的低质量精子产生甚至不育，迫切需要改进治疗方案的问题。在这项研究中,我们建立了一个与生精缺陷相关的饮食诱导的前期糖尿病绵羊模型,并探索了可能的潜在代谢原因.
我们比较了饲喂正常饮食的雄性绵羊与那些由丰富饮食诱发前驱糖尿病的绵羊，以及第三组由褪黑激素补充丰富饮食的绵羊。只有丰富的饮食组有糖尿病前期的症状，在这些羊身上，我们发现精子发生受损，其特征是圆形精子细胞发育受阻，睾丸凋亡细胞数量增加。比较三组的肠道微生物组和肠道消化代谢组，发现糖尿病前期绵羊的微生物群的分类组成存在显着差异，和改变的代谢组，其最重要的特征是鞘氨醇代谢改变；在血液和睾丸中也发现了鞘氨醇升高。褪黑素的给药减轻了糖尿病前期的症状，包括精子发生受损的精子发生，同时恢复更正常的微生物群和鞘氨醇的代谢水平。糖尿病前期绵羊的粪便微生物移植诱导受体小鼠鞘氨醇水平升高和精子发生受损，表明肠道微生物群在这些表型中的因果作用。
我们的研究结果指出鞘氨醇在糖尿病前期绵羊精子发生破坏中的关键作用，并表明它可能是一个有用的疾病标志物；此外，褪黑激素是治疗前驱糖尿病引起的男性不育的潜在益生元。
我们比较了饲喂正常饮食的雄性绵羊与那些由丰富饮食诱发前驱糖尿病的绵羊，以及第三组由褪黑激素补充丰富饮食的绵羊。只有丰富的饮食组有糖尿病前期的症状，在这些羊身上，我们发现精子发生受损，其特征是圆形精子细胞发育受阻，睾丸凋亡细胞数量增加。比较三组的肠道微生物组和肠道消化代谢组，发现糖尿病前期绵羊的微生物群的分类组成存在显着差异，和改变的代谢组，其最重要的特征是鞘氨醇代谢改变；在血液和睾丸中也发现了鞘氨醇升高。褪黑素的给药减轻了糖尿病前期的症状，包括精子发生受损的精子发生，同时恢复更正常的微生物群和鞘氨醇的代谢水平。糖尿病前期绵羊的粪便微生物移植诱导受体小鼠鞘氨醇水平升高和精子发生受损，表明肠道微生物群在这些表型中的因果作用。
我们的研究结果指出鞘氨醇在糖尿病前期绵羊精子发生破坏中的关键作用，并表明它可能是一个有用的疾病标志物；此外，褪黑激素是治疗前驱糖尿病引起的男性不育的潜在益生元。
