Objective High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.
Design Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.
Results Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus Bacteroides and Prevotella, both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of Bacteroides-Prevotella and sperm motility, and a positive correlation between blood endotoxin and Bacteroides abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.
Conclusion We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.
Trial registration number NCT03634644.
- intestinal microbiology
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Contributors XZ and ND performed the whole experiments. XYB, YJY, LLP, GMX and XZ performed some experiments and analysed the data. SSL and XZ provided technical guidance. ND, YPM, BY and JJ collected and analysed human semen and faecal samples. HC, ND and AZZ wrote the manuscript. FHL and AZZ conceived and designed the experiments.
Funding This work was supported by grants from the National Key R&D Program of China (2018YFA0800600 to AZZ); the National Natural Science Foundation of China (81630021 to AZZ); Key research and development program of Guangdong Province for "Innovative drug creation" (2019B020201015 to FHL); the Guangdong Innovative Research Team Program (2016ZT06Y432 to AZZ and FHL); the National Key Research and Development Program of China (2018YFC1004700 to BY); the National Natural Science Foundation of China (81701431 to JJ, 81871202 and 81671432 to HC, 81700690 to XYB); the National Program on Key Basic Research Project of China (2013CB945202 to AZZ and FHL); the China Postdoctoral Science Foundation (2018T110852 to XYB) and the Startup R&D Funding of Guangdong University of Technology (50010102 to AZZ and FHL).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by Experimental Animal Ethics Committee of Guangdong Pharmaceutical University, Guangzhou, China. All clinical samples were collected under informed consent and approved by the Research Ethics Committee of Jinling Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open-access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All raw sequences have been deposited in the NCBI Sequence Read Archive (SRA) database (https://www.ncbi.nlm.nih.gov/). Accession number: SRP167405 (mRNA sequencing of testes in the FMT group), SRP221703 (16S-rDNA sequencing of clinical faecal samples), SRP168312 (16S-rDNA sequencing of FMT faeces). Data sets generated and analysed during this study are available from the corresponding author on reasonable request.
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