Project Details
Projekt
The connection between the gut microbiome and testicular immune cells: implications for testicular diseases
Subject Area
Reproductive Medicine, Urology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515636567
The gut microbiota has been suggested to influence male fertility and dysbiosis affects key testicular functions. Since testicular macrophages (TM) are the most dominant immune cell populations of testis and recent evidence suggest that TM s are key players in both pathological progression and resolution of the inflammation. This project aims to study how the gut microbiota, dependent on high fat diet (HFD) conditions, impacts on TM phenotypes in specific populations and testicular niches. Our preliminary results showed a significant reduction in TM density in germ-free (GF) mice as compared to conventionally raised SPF mice. Likewise, microbiota depletion by antibiotics reduced the proportion of TM. Interestingly, HFD feeding, resulting in a dysbiotic gut microbiota, reduced the proportion of TM relative to a chow diet control. By the use of germ-free mouse isolator technology (gnotobiotics), we will disentangle microbiome-dependent from diet-dependent effects on TM populations, affecting male fertility. To unveil how the gut microbiome impacts TM differentiation, we will analyse TM in GF mice and SPF mice during embryonal development, at weaning, and during adulthood, investigating expressional and epigenetic changes by RNA-seq and ATAC-seq technologies on FACS-purified TM. Since male infertility was linked to obesity, HFD-dependent effects on TM phenotype of GF and SPF mice will be analysed. To pinpoint how the microbiome shapes various TM populations, we will conduct scRNA-seq analysis, high-dimensional flow cytometry, and CO-detection by indEXing (CODEX) multiplexed imaging techniques. Furthermore, using high dimensional imaging (CODEX), the project will analyse how cell-to-cell interactions and the spatial localization of immune cells in the testis are influenced by the gut microbiota. By antibiotic depletion of the gut microbiome, we will study the dynamic nature of the identified TM phenotypes. To address the microbiota’s role in testicular inflammatory disease, we will perform a model of testicular antigen-induced experimental autoimmune orchitis (EAEO) under gnotobiotic conditions. Thus, taking advantage of gnotobiotic mouse models, the project will provide insights on how the gut microbiota dependent on diet shapes TM populations and functions and how this may contribute to male infertility.
DFG Programme
Research Units
