Metabolic endotoxemia and male infertility Prebiotics and probiotics: new options in the treatment of idiopathic male infertility? Probiotics significant augmentation in testosterone level and A recent study by Dardmeh et al. [7] demonstrated sperm quality of infertile men after using a that probiotics could be an alternative solution in combination of prebiotic/probiotic therapy. Data eliminating obesity drawbacks on semen quality. The showed a direct impact of prebiotic/probiotic therapy study was performed on male mice to investigate the on the function of the pituitary gland in terms of effect of probiotics (Lactobacillus rhamnosus) on enhancing FSH and LH serum levels. sperm kinematic parameters, testicular weight, lipid profiles and reproductive hormones such as follicle Since many studies show that prebiotics and High fat or high calories stimulating hormone (FSH), luteinizing hormone (LH) probiotics are the key regulators of microbiota Animal experiments and human observational alekoxelaia@ and testosterone. Probiotics have a positive effect on improvement, they may have an influential studies have shown that consumption of diets gmail.com male fertility by either a direct or indirect influence. therapeutic impact on the above-mentioned containing either high fat or a high number of The direct effect improves spermatogenesis and disturbances (metabolic endotoxemia) and in this way calories leads to significant changes in gut bacterial maturation process whereas the indirect effect works may open a new avenue in the treatment of idiopathic Infertility is a global health problem which affects populations. It also increases the circulating levels out by eliminating the adverse effects of obesity and male infertility. 10–15% of couples in the reproductive age. There is of plasma endotoxin, implying a breakdown in gut elevating the total antioxidant capacity. In another growing evidence to support the theory that mucosal wall integrity and the passage of study, Amandine Everard et al. [8] demonstrated that References lifestyle factors affect male fertility through Gram-negative bacteria membrane potent immune 1. Nehal N Mehta et al. Experimental endotoxemia induces prebiotic (oligofructose) treatment restored alterations in endocrine profiles, spermatogenesis stimulant into the systemic circulation. Interestingly, adipose inflammation and insulin resistance in humans. Akkermansia muciniphila abundance and improved and sperm function. Thus, the identification of the magnitude of this ‘metabolic endotoxemia’ is Diabetes 2010 Jan 59 (1): 172 -81. gut barrier/gut permeability and metabolic factors contributing to infertility may be critical to reported to be more pronounced in mice placed on 2. Gomez-Elias et al. Association between high-fat diet parameters. A. muciniphila improved metabolic offer simpler and/or more effective therapeutic a high fat diet than on an isocaloric high feeding and male fertility in high reproductive disorders in diet-induced obese mice, normalised options than those currently available. The carbohydrate diet. This suggests that dietary fat is performance mice. Scientific Reports | (2019) 9:18546 | diet-induced metabolic endotoxemia, adiposity, and increasing worldwide prevalence of metabolic more efficient in transporting bacterial endotoxin https://doi.org/10.1038/s41598-019-54799-3 the adipose tissue marker CD11c. Similarly, A. syndrome (MetS), especially in younger from the gut lumen into the circulation, mediated 3. Ning Ding et al. Impairment of spermatogenesis and muciniphila treatment reduced body weight and populations, is a risk factor for fertility disorders. by transfer of endotoxin across the intestinal wall in sperm motility by the high-fat diet – induced dysbiosis of improved body composition (fat mass/lean mass However, it remains unclear whether there is a lipid laden chylomicrons. gut microbes. Gut 2020;69:1608–1619. doi:10.1136/ ratio) without changes in food intake. This study direct correlation between MetS and male gutjnl-2019-319127 clearly demonstrated the lack of a direct relationship infertility. Obesity and a diet high in fat or calories, Intestinal permeability 4. Tremellen et al. Gut endotoxin leading to a decline in between the abundance of Gram-negative bacteria which is typically consumed by obese individuals, Furthermore, there are reports that a high fat diet Gonadal function (GELDING) – a novel theory for the within the gut and metabolic endotoxemia (i.e. have been reported to cause a breakdown in the unfavourably alters the gut microbial composition, development of late onset hypogonadism in obese men. caused by serum LPS) because gut colonisation by A. normal gut mucosal barrier function, leading to the leading to an increase in intestinal permeability due Basic Clin Androl 2016 26:7 muciniphila decreased metabolic endotoxemia passage of gut bacteria membrane remnants into to disordered tight junction proteins (zonulin, 5. Linn B. Hakonsen et al. Does weight loss improve semen arising on an HF diet. An explanation for this the systemic circulation, initiating a chronic state of occludin) and a reduction in the colonic mucous quality and reproductive hormones? results from a counterintuitive result may be that A. muciniphila systemic inflammation. Inflammation, particularly barrier. In his study, Kelton Tremellen postulated for cohort of severely obese men. Reproductive health 2011; regulates gut barrier function at various levels. So, in adipose tissue, has been implicated in diet and the first time that in the gut transmucosal passage of 8:24 obesity-related insulin resistance in experimental bacterial lipopolysaccharide (LPS) from the lumen into according to previous data, gut microbiota contribute 6. Karma L. Pearce et al. Obesity related metabolic to gut barrier alterations during obesity and are the models. [1] the circulation is a key inflammatory trigger endotoxemia is associated with oxidative stress and underlying male hypogonadism. [4] High-fat diet has reason of metabolic endotoxemia. impaired sperm DNA integrity. Basic Clin Andrology 2019 High-fat diet a prominent role in increasing oxidative stress and May 13;29:6. Anti-oxidant probiotic strains Gómez-Elías et al [2] induced a metabolic syndrome- lowering antioxidant effect. A recent study was carried out by Valcarce et al. [9] to 7. Dardmeh F. Lactobacillus rhamnosus PB01 (DSM 14870) like condition in experimental models. supplementation affects markers of sperm kinematic evaluate the effect of two selected anti-oxidant (C57BL/6xBALB/c) F1 male mice were fed a high-fat “The increasing worldwide parameters in a diet-induced obesity mice model. 2017, probiotic strains (Lactobacillus rhamnosus CECT8361 diet (HFD, 30% fat) for 19 weeks, while controls PLoS One 12(10):1–17 and Bifidobacterium longum CECT7347) on sperm received a normal-fat diet (NFD, 6% fat). HFD-fed prevalence of metabolic syndrome 8. Amandine Everard. Cross-talk between Akkermansia criteria of asthenozoospermic men. Four parameters animals exhibited increased body weight, (MetS), especially in younger muciniphila and intestinal epithelium controls were evaluated: sperm motility, sperm viability, DNA hypercholesterolemia, hyperglycaemia and glucose diet-induced obesity. Proc Natl Acad Sci 2013 May 28; 110 fragmentation, and level of ROS. Viability was not intolerance. HFD-fed males exhibited a higher populations, is a risk factor for (22). affected while the other three tested parameters amount of gonadal fat, proposed to increase testicular fertility disorders.” 9. Valcarce. Probiotic administration improves sperm demonstrated a significant improvement after and epididymal temperature, thus affecting sperm quality in asthenozoospermic human donors. Benificial probiotic treatment. These findings support the production, maturation and storage. However, Diet composition and obesity Microbes 2017 8:2 importance of using probiotics to improve fertility of HFD-fed mice exhibited a decrease in epididymal There is mounting evidence that obesity has negative human males. 10. Maretti C, Cavallini G The association of probiotic with a weight, consistent with the lower epididymal sperm repercussions for reproductive physiology in males. prebiotic (Flortec, Bracco) to improve the quality/quantity count. Also, sperm analysis showed significant A large part of this evidence has accumulated from of spermatozoa in infertile patients with idiopathic Placebo-controlled study differences between HFD and NFD-fed mice in cauda oligoasthenoteratospermia: a pilot study. Andrology 2017 Finally the first placebo-controlled study was epididymal sperm count, sperm viability, morphology animal studies employing diets high in fat and sugar (‘high fat’ or ‘western’ diets). While excessive fats and conducted by Maretti and Cavallini10 and reported a 5:439–444 and progressive motility. carbohydrates are supposed to be major determinants of diet-induced obesity, a growing body of research Impairment of sperm motility suggests that the relationships between diet Ning Ding et al. [3] investigate if HFD-induced gut composition and obesity are more complex than microbiota dysbiosis can functionally influence spermatogenesis and sperm motility. Faecal microbes originally thought, involving interactions between derived from the HFD-fed or NFD-fed male mice were dietary macronutrients. Elevation of reactive oxygen transplanted to the mice maintained on NFD. The gut species (ROS) may have a detrimental effect on sperm quality and hence fertilisation potential. This is microbes, sperm count and motility were analysed. undoubtedly an important finding, given the clear Transplantation of the HFD gut microbes into the negative impact of obesity on male reproduction and NFD-maintained (HFD-FMT) mice resulted in a the strong relationship between diet and obesity risk. significant decrease in spermatogenesis and sperm Send your application to become member of one of the eleven motility, whereas similar transplantation with the YAU Groups now! Healthy reproduction diet microbes from the NFD-fed mice failed to do so. However, there is no clear definition of what a Transplantation with HFD microbes also led to ‘healthy diet’ for reproduction is. For most men, intestinal infiltration of T-cells and macrophages as Submission deadlines: 1 March - 1 July - 1 November switching to a ‘healthy diet’ means reducing the well as a significant increase of pro-inflammatory intake of food containing saturated fat and added cytokines in the epididymis, suggesting that Please check our website for details regarding the eligibility criteria epididymal inflammation has likely contributed to the salt and sugars and eating a wider variety of and application procedure: www.uroweb.org/education/youngunprocessed food (as recommended by nutritional impairment of sperm motility. RNA-sequencing dietary guidelines). There is a clear need to further revealed significant reduction in the expression of urologists-office-yuo/yau or contact the office via yau@uroweb.org those genes involved in gamete meiosis and testicular explore how diet impacts male reproductive function in order to develop evidence-based mitochondrial functions in the HFD-FMT mice. Ning preconception nutritional guidance for men. In their Ding et al. revealed an intimate linkage between cohort study, Linn B. Hakonsen et al. observed that HFD-induced microbiota dysbiosis and defects in the altered androgen profile tends to improve spermatogenesis with elevated endotoxin, following weight loss and that weight loss may dysregulation of testicular gene expression and potentially lead to improvement in semen quality. localised epididymal inflammation as potential [5] In a pilot study of 37 infertile men, Karma L. causes. [3] Pearce et al. confirmed a significant positive correlation between body mass index (BMI), Metabolic endotoxemia European Urological Scholarship Programme (EUSP) increased intestinal permeability (serum zonulin), Obesity and a high fat/high calorie diet are both metabolic endotoxemia (LBP), sperm DNA oxidative reported to result in changes in gut bacteria and Don't forget to submit your online applications for Short Visit, intestinal wall permeability, leading to the passage of damage (seminal 8 OHdG) and increasing levels of Clinical Visit, Clinical and Lab Scholarship, and Visiting Professor bacterial endotoxin (lipopolysaccharide-LPS) from the sperm DNA fragmentation. Metabolic endotoxemia was positively correlated with increasing levels of gut lumen into the circulation (metabolic Programme before 1 May. sperm DNA oxidative damage. This relationship endotoxemia), where it initiates systemic remained significant, even after adjustment for inflammation. Endotoxin is known to reduce For more information and application, please contact relevant confounders such as age, BMI and days of testosterone production by the testis, both by direct abstinence. These observations suggest that inhibition of Leydig cell steroidogenic pathways and the EUSP Office – eusp@uroweb.org or check our website metabolic endotoxemia and its associated oxidative www.uroweb.org/education/scholarship/ stress may be a key driver of sperm DNA damage in EAU Section for Urologists in Office (ESUO) obese men. [6] Dr. Alekzander Khelaia ESUO, Board Member National Centre of Urology European University Tbilisi (GE)
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indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production. Gramnegative bacteria, which comprise 70% of the total bacterial load in the human gut, contain a potent immune stimulant in their cell wall, referred to as lipopolysaccharide (LPS) or endotoxin.
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