In recent studies, 48.5 million couples worldwide were identified as being infertile, and 50% of these were found to be due to a male infertility problem (Agarwal et al., 2015). Multiplefactors may be contributing to male infertility such as high caloric intake, reduced physical activity, high use of electronic devices, alcohol consumption, smoking, and stressful environment. It is suggested that these factors lead to the alteration in the gut microbiota, which directly or indirectly affects male sexual health (Oliva et al., 2001).
The adult human gut contains approximate 1014 microbes, which is 10-fold higher than the number of human body cells (Hooper LV, Gordon JI 2001). In the entire gut microbiota, there are three major types of bacterial phyla predominantly found: Firmicutes, Bacteroidetes, and Actinobacteria. Among them, the genera Lactobacillus and Bifidobacterium are the most common groups that are characterized as probiotics (Tap et al.,2009). Reports are available on beneficial effects of probiotics in human health conditions such as diarrhea (Chouraqui et al.,2008; Gaon et al.,2003), and more recently food allergies (Pohjavuori et al.,2004), inflammatory bowel disease (Peril et al.,2011), colorectal cancer, and even male sexual health (Lenoir et al.,2016; Poutahidis et al., 2014). Therefore, probiotic therapy may open new avenues for addressing male infertility and could be considered as a safe candidate treatment for improving male sexual health. The following sections describe evidence for different potential effects of probiotics in male sexual health.
Rationale for probiotics eradicating pathogenic microbes and increasing hypothalamic-pituitary-gonadal axis activity:
Lifestyle and infection-related factors disturb the community of microorganisms in the gut, potentially causing permeability in the gut barrier (Pickard et al., 2017). The ‘leaky gut’ is associated with a number of metabolic, immunological, inflammatory and neurological problems, suppressing the hypothalamic-pituitary-gonadal axis activity, and in turn, affecting male sexual health either directly or indirectly (Gerard et al.,2009). In this context, probiotics are the beneficial microbes that have potential for eradicating pathogenic bacteria and preventing leakiness of the gut to improve health through following mechanisms: (1) By augmentation in the growth of the epithelial wall; (2) By improving the intestinal mucosa; (3) By competitive replacement of pathogenic microbes and reduction of their adhesion; (4) By generation of antimicrobial bodies; and (5) By altering immunological molecules (Plaza et al., 2019). Generally, the healthy gut harbours beneficial microbes which release metabolites like short-chain fatty acids (such as acetate, propionate, and butyrate) that bind to cell surface receptors and send the signals with the help of the enteric nervous system to enhance the level of reproductive hormones (e.g. Testosterone, Luteinizing Hormone), ultimately helping restore male sexual health (Asmakh et al.,2014).
Rationale for probiotics reversing the antioxidative potential and protecting spermatozoa from oxidative stress:
The mature spermatozoa contain abundant polyunsaturated fatty acids and are therefore highly susceptible to oxidative stress due to lipid peroxidation processes (Agarwal et al.,2017). This leads to the disruption of membrane permeability, and changes the ATP efflux, while also impairing flagellar movement, resulting in the loss of sperm motility (Linus C. and Saalu 2010). Hence the detrimental impact of oxidative stress on sperm viability, motility, and fertilization potential—requiring the treatment of male infertility (Agarwal et al.,2014). Antioxidant supplementations (enzymatic and non-enzymatic) are available to reduce oxidative stress and improve sperm parameters (Dabaja and Schlegel 2014; Colagar and Marzony 2009; Jung and Ju 2014). But these chemicals also come with side effects and may contribute to other disease conditions. Probiotic organisms offer an alternative and ‘natural’ approach to overcome oxidative stress through possible mechanisms that include: (1) self-secretion of antioxidant metabolites; (2) inflection in the anti-oxidases activities; and (3) regulating the enzyme activities responsible for the synthesis of ROS production. In this way, probiotics may elevate oxidative stress and improve reproductive organ health (Chen et al.,2013).
Rationale for probiotics addressing obesity to restore male fertility:
Worldwide, thefrequency of the inactive lifestyle regime and the calorie-dense processed food in the current world population has contributed to a rise in cases of obesity (Nammi et al.,2004).Increasingobesity incidence leads to an increase in the numbers of infertile men (Martini et al., 2013).Obesity-related infertility is characterized by the impaired activity of hypothalamus-pituitary gonadal (HPG) axis (A.A. Dwyer and R.Quinton 2019). The decreased HPG activity in obese men appears to result in an increase in aromatase activity. Aromatase is the class of enzymes, synthesized in adipose tissue, responsible for the aromatization of the testosterone into the estradiol (Zhao et al.,2014). This may result in the reduction of testosterone, leading to several sexual health-related problems including reduced libido, spermatogenesis, reduced muscle and bone mass, low energy levels, fatigue, reduced physical performance, depressed mood, increased body fat, and impaired cognitive function (bassil et al.,2010). Aged obese mice that received a strain of Lactobacillus reuteri in their drinking water showed a significant reduction in body weight. The therapy also yielded an increase in the number of Leydig cells in testis, and in turn, showed an augmentation in testosterone levels and spermatogenesis, eventually allowing recovery of reproductive fitness (Poutahidiset al., 2014). Such approaches are highly desirable, as they would decrease the costs of obesity treatments and testosterone replacement therapy (TRT), and significantly diminish the risk of harm to the patient through invasive or noninvasive treatments.
Rationale for probiotics helping fight stress and improving male fertility:
Stress can be defined as a state of threatened homeostasis that produces different and pathophysiological changes depending on severity, type and duration (Tsigos et al.,2016). Chronic and acute stress is associated with dysbiosis in the gut; the altered gut microbiota has been linked with adverse health effects such as gastrointestinal permeability, inflammation, autoimmune disease, depression, anxiety, and metabolic diseases (Carabotti et al., 2015). Stressors seem to activate the hypothalamic pituitary adrenal (HPA) axis to released stress hormones (cortisol stimulating hormones (CRH), cortisol and epinephrine, norepinephrine), leading to the suppression of the hypothalamic-pituitary-gonadal (HPG) axis which reduces the concentration of luteinizing hormones (LH), reduces testosterone levels and increases cortisol, pro-inflammatory cytokines, and oxidative stress (M.G. Oyola, and R.J. Handa 2015). Chronic restraint stress in rat models results in an increased percentage of sperm head abnormalities and decreases the expression of testicular CYP11A1 protein, begetting a significant reduction of serum testosterone levels and sperm production (Arun et al., 2016).Therefore treatment with probiotics for chronic stress shows promise for having anti-anxiolytic and antidepressant effects, that might support cognition, cut off the plasma cortisol levels, and control the equilibrium of pro- and anti-inflammatory cytokines (Liang et al., 2015).Hence, based on this nascent evidence, we suggest that probiotic therapy can open new avenues for the treatment of male infertility problems and improved male sexual health. Further study in this area is warranted in order to identify potentially efficacious probiotic strains or multi-strain formulations.
- Agarwal, A., Mulgund, A., Hamada, A. and Chyatte, M.R., 2015. A unique view on male infertility around the globe. Reproductive biology and endocrinology, 13(1), p.37.
- Oliva, A., Spira, A. and Multigner, L., 2001. Contribution of environmental factors to the risk of male infertility. Human Reproduction, 16(8), pp.1768-1776.
- Hooper LV, Gordon JI: Commensal host-bacterial relationships in the gut. Science 2001, 292(5519):1115–1118.
- Tap, J., Mondot, S., Levenez, F., Pelletier, E., Caron, C., Furet, J. P., et al. (2009). Towards the human intestinal microbiota phylogenetic core. Microbiol.11, 2574–2584. doi: 10.1111/j.1462-2920.2009.01982.x
- Chouraqui, J.P., Grathwohl, D., Labaune, J.M., Hascoet, J.M., de Montgolfier, I., Leclaire, M., Giarre, M. and Steenhout, P., 2008. Assessment of the safety, tolerance, and protective effect against diarrhea of infant formulas containing mixtures of probiotics or probiotics and prebiotics in a randomized controlled trial. The American journal of clinical nutrition, 87(5), pp.1365-1373.
- Gaon, D., Garcia, H.U.G.O., Winter, L.U.I.S., Rodríguez, N.O.R.A., Quintas, R.I.C.A.R.D.O., Gonzalez, S.N. and Oliver, G.U.I.L.L.E.R.M.O., 2003. Effect of Lactobacillus strains and Saccharomyces boulardii on persistent diarrhea in children. Medicina (Buenos Aires), 63(4), pp.293-298.
- Pohjavuori, E., Viljanen, M., Korpela, R., Kuitunen, M., Tiittanen, M., Vaarala, O. and Savilahti, E., 2004. Lactobacillus GG effect in increasing IFN-γ production in infants with cow’s milk allergy. Journal of Allergy and Clinical Immunology, 114(1), pp.131-136.
- Azcárate-Peril, M.A., Sikes, M. and Bruno-Bárcena, J.M., 2011. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer?. American Journal of Physiology-Gastrointestinal and Liver Physiology, 301(3), pp.G401-G424.
- Lenoir, M., Del Carmen, S., Cortes-Perez, N.G., Lozano-Ojalvo, D., Muñoz-Provencio, D., Chain, F., Langella, P., de LeBlanc, A.D.M., LeBlanc, J.G. and Bermúdez-Humarán, L.G., 2016. Lactobacillus casei BL23 regulates T reg and Th17 T-cell populations and reduces DMH-associated colorectal cancer. Journal of gastroenterology, 51(9), pp.862-873.
- Poutahidis, T., Springer, A., Levkovich, T., Qi, P., Varian, B.J., Lakritz, J.R., Ibrahim, Y.M., Chatzigiagkos, A., Alm, E.J. and Erdman, S.E., 2014. Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice. PLoS One, 9(1), p.e84877.
- Pickard, J.M., Zeng, M.Y., Caruso, R. and Núñez, G., 2017. Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. Immunological reviews, 279(1), pp.70-89.
- Gérard, P., 2009. 57 Gastrointestinal Tract: Microbial Metabolism of Steroids.
- Plaza-Diaz, J., Ruiz-Ojeda, F.J., Gil-Campos, M. and Gil, A., 2019. Mechanisms of action of probiotics. Advances in Nutrition, 10(suppl_1), pp.S49-S66.
- Al-Asmakh, M., Stukenborg, J.B., Reda, A., Anuar, F., Strand, M.L., Hedin, L., Pettersson, S. and Söder, O., 2014. The gut microbiota and developmental programming of the testis in mice. PloS one, 9(8).
- Agarwal, A., Sharma, R., Gupta, S., Harlev, A., Ahmad, G., Du Plessis, S.S., Esteves, S.C., Wang, S.M. and Durairajanayagam, D. eds., 2017. Oxidative stress in human reproduction: shedding light on a complicated phenomenon. Springer.
- Saalu, L.C., 2010. The incriminating role of reactive oxygen species in idiopathic male infertility: an evidence based evaluation. Pakistan journal of biological sciences, 13(9), p.413.
- Agarwal, A., Virk, G., Ong, C. and Du Plessis, S.S., 2014. Effect of oxidative stress on male reproduction. The world journal of men’s health, 32(1), pp.1-17.
- Dabaja, A.A. and Schlegel, P.N., 2014. Medical treatment of male infertility. Translational andrology and urology, 3(1), p.9.
- Colagar, A.H. and Marzony, E.T., 2009. Ascorbic Acid in human seminal plasma: determination and its relationship to sperm quality. Journal of clinical biochemistry and nutrition, 45(2), pp.144-149.
- Jung, J.H. and Seo, J.T., 2014. Empirical medical therapy in idiopathic male infertility: Promise or panacea?. Clinical and experimental reproductive medicine, 41(3), pp.108-114.
- Chen, X.L., Gong, L.Z. and Xu, J.X., 2013. Antioxidative activity and protective effect of probiotics against high-fat diet-induced sperm damage in rats. Animal, 7(2), pp.287-292.
- Nammi, S., Koka, S., Chinnala, K.M. and Boini, K.M., 2004. Obesity: an overview on its current perspectives and treatment options. Nutrition journal, 3(1), p.3.
- Martini, A.C., Molina, R.I., Tissera, A., Ruiz, R.D. and Cuneo, M.F.D., 2013. The impact of obesity on male reproduction: its biological significance. Expert review of endocrinology & metabolism, 8(2), pp.139-148.
- Dwyer, A.A. and Quinton, R., 2019. Classification of Hypothalamic-Pituitary-Gonadal (HPG) Axis Endocrine Disorders. In Advanced Practice in Endocrinology Nursing(pp. 853-870). Springer, Cham.
- Zhao, J., Zhai, L., Liu, Z., Wu, S. and Xu, L., 2014. Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue. Oxidative medicine and cellular longevity, 2014.
- Bassil, N. and Morley, J.E., 2010. Late-life onset hypogonadism: a review. Clinics in geriatric medicine, 26(2), pp.197-222.
- Tsigos, C., Kyrou, I., Kassi, E. and Chrousos, G.P., 2016. Stress, endocrine physiology and pathophysiology. In Endotext [Internet]. MDText. com, Inc..
- Carabotti, M., Scirocco, A., Maselli, M.A. and Severi, C., 2015. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology: quarterly publication of the Hellenic Society of Gastroenterology, 28(2), p.203.
- Oyola, M.G. and Handa, R.J., 2017. Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity. Stress, 20(5), pp.476-494.
- Arun, S., Burawat, J., Sukhorum, W., Sampannang, A., Maneenin, C. and Iamsaard, S., 2016. Chronic restraint stress induces sperm acrosome reaction and changes in testicular tyrosine phosphorylated proteins in rats. International Journal of Reproductive BioMedicine, 14(7), p.443.
- Liang, S., Wang, T., Hu, X., Luo, J., Li, W., Wu, X., Duan, Y. and Jin, F., 2015. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience, 310, pp.561-577.