| In recent decades,obesity has become a serious public health problem worldwide.Female obesity patients are often accompanied by ovarian dysfunction and infertility.An increasing body of evidence suggests that obesity brings an increased risk for abnormalities in oocyte maturation and embryonic developmentin.At the same time,obesity is intricately linked to dysregulation of the gut microbiota and the host metabolome.In addition,more and more studies have shown that there is a causal relationship between fertility disorders and gut microbiota,which is mainly verified by Fecal Microbiota Transplantation(FMT).There is therefore a need to explore the relationship between female fertility disorders and gut microbiota dysbiosis in obesity.In this study,we first established a high fat diet-induced model of obesity and a genetic mouse model of obesity(leptin(ob/ob)mice),these mice were defined as‘ND(normal diet),HFD(high-fat diet),and OB’,respectively.Glucose tolerance test(GTT)and insulin tolerance test(ITT)clearly showed that HFD and OB groups became glucose intolerant and insulin resistant,whereas the ND groups did not.Furthermore,immunofluorescence staining of MII stage oocytes and in vitro fertilization(IVF)experiments showed that the meiosis process and early embryonic development potential of HFD mice oocytes were affected.To confirm whether obesity led to gut microbiota dysbiosis,16s-rDNA sequencing analysis was performed.We found that the HFD and OB groups had similar bacterial composition at the phylum level,including Bacteriodetes and Firmicutes.As expected,OB group and HFD group showed a significant difference compared with ND groups.Next,we set out to explore the relationship between gut microbiota dysbiosis and oocyte quality following FMT;these recipient mice were named as ‘ND-FMT,HFD-FMT,and OB-FMT’,respectively.After 8 weeks of colonization,the HFD and OB recipient mice did not exhibit glucose intolerance and insulin resistance.Moreover,a high frequency of aberrant spindles and misaligned chromosomes in MII oocytes were observed in HFD-FMT and OB-FMT mice,which was consistent with the HFD mice.Meanwhile,a total of 558 transcripts were identified to be significantly changed in the HFD-FMT group as compared with the ND-FMT group,suggesting that maternal m RNA was severely impaired.As expected,the percentage of normal blastocysts was significantly lower in the HFD-FMT groups,along with more blastocysts showing severe developmental delay or cytoplasmic fragmentation.These data indicated that gut microbes were responsible for the regulation of oocyte quality,thus affecting embryonic development in HFD-FMT mice.To explore the underlying mechanism by which a qualitative reduction in HFD-FMT oocytes.We performed metabolomics profiling assays to reveal that pyrimidine metabolism in ovaries was disturbed,which was concomitant with a sharp decline in the abundance of cytosine and cytidine in the HFD-FMT group compared to that in the ND-FMT group.Moreover,cytosine and cytidine are closely related with gut microbiota dysbiosis,accompanied by a notable reduction of abundance of Christensenellaceae R-7 group.Additionally,the abundance of Christensenellaceae R-7 group was also significantly decreased in HFD and OB mice.In conclusion,we found abnormal meiosis process of oocytes,impaired maternal m RNA,and abnormal early embryonic development ability in recipient mice after microflora transplantation.We also found that the pyrimidine metabolic pathway was disrupted,which may be responsible for the decreased oocyte quality in HFD recipient mice.Moreover,dysregulation of gut microbiota was closely related to cytosine and cytosine nucleoside,especially the abundance of Christensenellaceae R-7 group in HFD recipient mice was significantly reduced.These results not only provide a potential diagnostic mechanism and marker for obesity-induced female fertility disorders,but also reveal that gut microbiota intervention may be a potential treatment for obese infertile women. |
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