Probiotics to improve testicular function (Andrology 5:439–444, 2017) – a comment on mechanism of action and therapeutic potential of probiotics beyond reproduction

A recent study published in this journal (Maretti & Cavallini, 2017) reported significant improvements in sperm quality and testosterone levels in infertile men using a proprietary probiotic/prebiotic (Flortec) therapy. While previous animal studies had also reported similar improvements in testicular function with probiotic therapy (Poutahidis et al., 2014), this latest study is the first to confirm such a response in men in a well-conducted placebo-controlled setting. The authors hypothesized that these improvements may be mediated by normalization of subtle alterations in hypothalamic–pituitary function, an antioxidant effect and possibly even improvements in the prostatic microenvironment. However, the reported data only provide direct evidence for improvement in pituitary function (increase serum LH and FSH). The purpose of this letter is to inform the readership of an important alternative potential mechanism of action for Flortec-modulation of the gut microbiome and inflammation. Recently, we published the GELDING theory (Gut Endotoxin Leading Decline In Gonadal function) linking gut health with testicular function (Tremellen, 2016). Obesity, a Western diet, psychological stress and a lack of exercise, all common maladies of modern life, have been associated with impaired intestinal mucosa barrier function (‘leaky gut’), resulting in the passage of endotoxin-containing gut bacteria into the systemic circulation. Endotoxin is a powerful immune stimulant, with recent data from our own group linking endotoxin activation of the immune system with impaired Leydig and Sertoli cell function (Tremellen et al., 2017). Multiple studies have previously reported an association between male hypogonadism and inflammation, but the GELDING theory is the first to suggest that gut bacteria may be the trigger for inflammation and impaired testicular function. The Flortec RCT results provide additional support for this theory. Experimental administration of endotoxin to animals is known to directly inhibit Leydig cell steroidogenesis, while also impairing pituitary LH drive (Tremellen, 2016). Therefore, it is plausible that a breakdown in gut wall integrity caused by poor lifestyle will result in bacterial translocation, systemic inflammation and hypogonadism in these men. The consumption of Lactobacillus paracasei probiotic bacteria, and their preferred food source (FOS, fibre) present within the Flortec supplement, is known to enhance intestinal barrier function, thereby reducing levels of endotoxin exposure and inflammation. We believe that this is a likely mechanism behind the improvement in testicular function seen in these men, especially as earlier reports have shown that Lactobacillus probiotic primarily mediates its beneficial effect on testicular function via modulation of the immune system (Poutahidis et al., 2014). A better understanding of how probiotics/prebiotics may augment testicular function has importance beyond reproduction. Low testosterone is known to be associated with metabolic syndrome, inflammation and increased cardiovascular disease in older men (Foresta et al., 2017). Currently we supplement these hypogonadal men with testosterone, yet surprisingly this does not result in superior cardiovascular outcomes despite improvements in insulin sensitivity and lean muscle mass (Foresta et al., 2017). We believe that this perplexing observation occurs because the link between low testosterone and cardiovascular disease is not actually causational, but merely an epiphenomenon. Inflammation is the key, with inflammation known to drive insulin resistance, impaired endothelial function, plus precipitate acute atherosclerotic plaque rupture leading to myocardial infarction and stroke (Foresta et al., 2017). As such, we believe that reducing endotoxin-initiated inflammation by augmenting intestinal barrier function with probiotic/prebiotic therapy has superior therapeutic potential as it may resolve both