The Gut Microbiota and Developmental Programming of the Testis in Mice
Open accessAbstract
Nutrients and environmental chemicals, including endocrine disruptors, have been incriminated in the current increase in male reproductive dysfunction, but the underlying mechanisms remain unknown. The gastrointestinal tract represents the largest surface area exposed to our environment and thereby plays a key role in connection with exposure of internal organs to exogenous factors. In this context the gut microbiome (all bacteria and their metabolites) have been shown to be important contributors to body physiology including metabolism, cognitive functions and immunity. Pivotal to male reproduction is a proper development of the testis, including the formation of the blood-testis barrier (BTB) that encapsulates and protects germ cells from stress induced environmental cues, e.g. pathogenic organisms and xenobiotics. Here we used specific pathogen free (SPF) mice and germ-free (GF) mice to explore whether gut microbiota and/or their metabolites can influence testis development and regulation of BTB. Lumen formation in the seminiferous tubules, which coincides with the development of the BTB was delayed in the testes of GF mice at 16 days postpartum. In addition, perfusion experiments (Evans blue) demonstrated increased BTB permeability in these same mice. Reduced expressions of occludin, ZO-2 and E-cadherin in GF testis suggested that the microbiota modulated BTB permeability by regulation of cell-cell adhesion. Interestingly, exposure of GF mice to Clostridium Tyrobutyricum (CBUT), which secrete high levels of butyrate, restored the integrity of the BTB and normalized the levels of cell adhesion proteins. Moreover, the GF mice exhibited lower serum levels of gonadotropins (LH and FSH) than the SPF group. In addition, the intratesticular content of testosterone was lower in GF compared to SPF or CBUT animals. Thus, the gut microbiome can modulate the permeability of the BTB and might play a role in the regulation of endocrine functions of the testis.
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In mice, the microbiota can regulate testicular development and function, and androgen deficiency substantially alters the microbiome.
“In mice, the microbiota can regulate testicular development and function [251], while androgen deficiency has substantially altered the microbiome [252].”
From International Society of Sports Nutrition Position Stand: Probiotics (2019) · cites this paper as [251]
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Polyamine metabolism links gut microbiota and testicular dysfunction
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“Disruption of the gut microbiota by di-(2-ethylhexyl) phthalate was shown to alter the male reproductive system in rats [18], and the gut microbiota also modulated the permeability of the blood-testis barrier and performed a role in the regulation of endocrine functions of the testis in mice [19].”
BackgroundGut microbiota-gonadal axis: the impact of gut microbiota on reproductive functions
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“These defects in permeability persisted into adulthood, as demonstrated by leakage of Evans blue dye into the brain parenchyma(71) and seminiferous tubules of the testis of mature mice.(72) This leakiness was associated with reduced expression of TJ proteins(71,72): in the BBB, expression of claudin-5 and occludin was…”
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“Studies have demonstrated that the gut microbiome may modulate the permeability of the blood-testis barrier (BTB) and play a regulatory role in testicular function [37].”
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“This may have occurred through epigenetic modification in the form of enhanced histone acetylation stimulated by butyrate [2, 3].”
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“Compared with SPF male mice, GF male mice had lower serum levels of testosterone (T), LH, and FSH, however, colonizing their intestine with probiotics significantly increased the serum levels of these hormones (Al-Asmakh et al., 2014).”
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“Exposure of these mice to a strain of bacteria that secrete high levels of the short-chain fatty acid butyrate restored integrity of the blood-testis barrier (Al-Asmakh et al. 2014).”
BackgroundDietary exposure to endocrine disruptors in gut microbiota: A systematic review
Calero-Medina, L., Jiménez-Casquet, M. J., Heras-González, L., Conde-Pipó, J., López-Moro, A., Olea‐Serrano, F., & Mariscal‐Arcas, M. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.163991 · Cited by 41 · see citing works
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“An unrelated, but compelling study explored the interplay between the gut microbiome and the blood–testis barrier [79].”
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Immune System Modulations by Products of the Gut Microbiota
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“Similar effects were seen on the permeability of the blood–testis-barrier (BTB) in germ-free mice, after exposure to the bacteria Clostridium tyrobutylicum, which produces large amounts of butyrate [31].”
BackgroundDiet-induced microbiome shifts of sympatric overwintering birds
Li, C., Liu, Y., Gong, M., Zheng, C., Zhang, C., Li, H., Wen, W., Wang, Y., & Liu, G. (2021) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-021-11448-y · Cited by 39 · see citing works
Endocrine Disruptors and Gut Microbiome Interactions
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“Interestingly, exposing germ-free (GF) mice to Clostridium tyrobutyricum (CBUT), which secretes high levels of butyrate, increased their serum levels of gonadotropins [luteinising hormone (LH) and follicle-stimulating hormone (FSH)] (Al-Asmakh et al., 2014).”
BackgroundMechanism of testicular injury induced by Di-ethylhexyl phthalate and its protective agents
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Dysbiosis of Gut Microbiota and Short-Chain Fatty Acids in Encephalitis: A Chinese Pilot Study
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“Regulation of occludin expression by the intestinal microbiota has been reported in the intestinal epithelial barrier (59) and blood-testis barrier (60).”
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“Gut microbiota dysbiosis can lead to increased permeability of the bloodtestis barrier (BTB) and affect serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels in mice (Al-Asmakh et al., 2014).”
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The effect of testosterone on the gut microbiome in mice
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“A recent study found that the intra-testicular levels of testosterone in germ-free mice were signi fi cantly lower than in speci fi c pathogen-free mice 21 .”
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“Conversely, the exposure of germ-free mice to commensal bacteria such as Clostridium tyrobutyricum can restore the blood–testis barrier integrity [90].”
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Cornuside Alleviates Diabetes Mellitus-Induced Testicular Damage by Modulating the Gut Microbiota
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Taxifolin increased semen quality of Duroc boars by improving gut microbes and blood metabolites
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“Metabolic regulation plays a crucial role in spermatogenesis (Rato et al., 2012; Al-Asmakh et al., 2014; Dai et al., 2015), and gut microbiota can produce metabolites to modulate systemic”
Turning the tide on sex and the microbiota in aquatic animals
Bates, K. A., Higgins, C., Neiman, M., & King, K. C. (2022) · Hydrobiologia · doi:10.1007/s10750-022-04862-4 · Cited by 23 · see citing works
“Similar results have been demonstrated in a study of germ-free mice colonized with a microbial community (Al-Asmakh et al., 2014).”
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“IGF-1 levels, which are reduced in starvation or low protein intake 26 and obesity 27–29 , IBD, differences in BMI, progress of puberty 30 and sex hormone production 31 .”
BackgroundThe microbiota extends the reproductive lifespan of mice by safeguarding the ovarian reserve
Munyoki, S. K., Goff, J. P., Reshke, A., Wilderoter, E., Mafarachisi, N., Kolobaric, A., Sheng, Y., Mullett, S. J., King, G. E., DeSchepper, J. D., et al. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.09.006 · Cited by 21 · see citing works
“34,36 Additionally, GF males retain the ability to fertilize eggs and sire offspring at similar rates to conventional controls, despite reported abnormalities in the epididymis.”
Wang, M., Ren, C., Wang, P., Cheng, X. J., Chen, Y., Huang, Y., Chen, J., Sun, Z., Wang, Q., & Zhang, Z. (2023) · Animals · doi:10.3390/ani13060996 · Cited by 21 · see citing works
“When passing through other organs, blood metabolites can affect development or cause diseases [9].”
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“A previous study also demonstrated clearing the gut microbiota in pregnant mice resulted in delayed fetal semi-niferous tubule formation, which lasted until the mice reached adulthood [19].”
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Immune Microenvironment Dysregulation: A Contributing Factor to Obesity-Associated Male Infertility
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“…studies in germ-free mice have shown a downregulation of genes related to steroido-genesis and BTB formation—such as occludin, Zonula Occludens-2 (ZO-2), and E-cad-herin—highlighting the essential role of balanced gut microbiota in maintaining endocrine and barrier functions in the testes [110].”
Characterization of Non-Obstructive Azoospermia in Men Using Gut Microbial Profiling
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“Moreover, bacterial translocation may lead to chronic inflammation, endothelial damage, and disrupted blood–testis barrier (BTB) and thus result in impaired sperm production [27,28].”
BackgroundThe emerging role of the gut-testis axis in male reproductive health and infertility
Leelani, N., Bajic, P., Parekh, N. V., Vij, S. C., & Lundy, S. D. (2023) · F&S Reviews · doi:10.1016/j.xfnr.2023.01.001 · Cited by 19 · see citing works
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“Products of the microbiota also affect the development and maturation of Sertoli cells in experimental animals [87].”
Obesity Causes Abrupt Changes in the Testicular Microbiota and Sperm Motility of Zebrafish
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Male infertility risk and gut microbiota: a Mendelian randomization study
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“tyrobutyricum has been revealed to protect barrier function in different tissues, including the gut (8), testis (9), and endometrium (10).”
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“The gut microbiota affects the testispituitary axis, regulates lumen formation of the seminiferous tubules and the permeability of the blood-testis barrier (26).”
BackgroundReappraising the exteriorization of the mammalian testes through evolutionary physiology
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“testis barrier permeability and endocrine function [144,145].”
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“…has demonstrated that several antidiabetic drugs can protect male reproduction through various mechanism 14–17 , and GM dysbiosis is known to contribute to male reproductive dysfunction by influencing the process of spermatogenesis and the permeability of the blood-testis barrier 25–27 , 43 .”
BackgroundEvaluation of probiotic properties of a Brevibacillus laterosporus strain
Cao, Y., Wang, Z., Dai, X., Zhang, D., Zeng, Y., Ni, X., & Pan, K. (2024) · The FASEB Journal · doi:10.1096/fj.202302408r · Cited by 14 · see citing works
“92 Reactive oxygen species (ROS) is a general term for chemical substances formed by incomplete reduction of oxygen molecules, 93 which is associated with many conditions such as cancer, 94 neurodegenerative disease, 95 cardiovascular disease, 96 and so on.”
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“A lack of normal gut microbiota leads to abnormal formation of the blood–testis barrier (BTB) in male mice [16].”
BackgroundAdvances in the study of the relationship between gut microbiota and erectile dysfunction
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Gut Microbiota Dysbiosis: A Neglected Risk Factor for Male and Female Fertility
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“Thus, the investigation suggested the importance of gut microbiota composition in testis development and consequently male reproductive behavior [92].”
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“Research also indicates that the gut microbiome can enhance the blood-testis barrier and maintain normal testosterone levels, thereby preserving male fertility (40).”
BackgroundTestis–Gut‐Reproduction Axis: The Key to Reproductive Health
Zou, H., Chen, W., Hu, B., Liu, H., & Zhao, J. (2024) · Andrologia · doi:10.1155/2024/5020917 · Cited by 10 · see citing works
Strontium Chloride Improves Reproductive Function and Alters Gut Microbiota in Male Rats
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“In addition, the gut microbiota can also regulate the permeability of the blood–testis barrier (BTB), which is important in testicular endocrine function [35].”
BackgroundLi, Z., Duan, T., Wang, L., Wu, J., Meng, Y., Bao, D., Gao, L., & Liu, L. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1341512 · Cited by 10 · see citing works
- Authors
- Al-Asmakh, M., Stukenborg, J.-B., Reda, A., Anuar, F., Strand, M.-L., Hedin, L., Pettersson, S., & Söder, O.
- Affiliations
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Sidra Medical and Research Center (QA)
- Nanyang Technological University (SG)
- Corresponding author
- Söder, Olle
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-13
- Volume
- 9
- Issue
- 8
- Pages
- e103809
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4132106
- OpenAlex
- W2112346304
- Cited by
- 173
- References
- 46
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 25 · 2023: 23 · 2022: 14 · 2021: 29 · 2020: 12 · 2019: 15 · 2018: 1 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 1
- FWCI
- 6.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Qatar University QSpace (Qatar University) (submittedVersion)
- Funders
- Agency for Science, Technology and Research
- Qatar University
- Vetenskapsrådet
- Barncancerfonden
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- gut microbiota, testicular development, blood-testis barrier, germ-free mice, butyrate, cell-cell adhesion, occludin, ZO-2, E-cadherin, gonadotropins, testosterone, male reproductive disorders, endocrine disruptors, postpartum period
- MeSH terms
- Animals, Blood-Testis Barrier, Cell Adhesion, Fertility, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Permeability, Specific Pathogen-Free Organisms, Testis, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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