Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine

Abstract

Reproduction is a complex process, which is based on the cooperation between the endocrine-immune system and the microbiota. Testicular immunity is characterized by the so-called immune privilege, a mechanism that avoids autoimmune attacks against proteins expressed by spermatozoa. Testicular microbiota is connected with the gut microbiota, the most prevalent site of commensals inthe body. Both microbiotas take part inthe development of the immune system and protection againstpathogen invasion. Dysbiosis is caused by concurrent pathologies, such as obesity, diabetes, infections and trauma. The substitution of beneficial bacteria with pathogens may lead to destruction of spermatozoa directly or indirectly and, ultimately, to male infertility. Novel therapeutic interventions, i.e., nutritional interventions and supplementation of natural products, such as, probiotics, prebiotics, antioxidants and polyphenols, may lead to the restoration of the otherwise-impaired male reproductive potential, even if experimental and clinical results are not always concordant. In this review, the structure and immune function of the testis will be described with special reference to the blood-testisbarrier. The regulatory role of both the gut and testicular microbiota will be illustrated in health and disease, also emphasizing therapeutic attempts with natural products for the correction of male infertility, in the era of personalized medicine.

Keywords: immune privilege; male infertility; microbiota; personalized medicine; polyphenols; probiotics; spermatogenesis; testis.

Figure 1

Structure of the testis. The structure of the testis consists of the epithelium of the seminiferous tubules and the intestitium. In turn, the interstium harbors Leydig cells, immune cells and lymphatic vessels.

Figure 2

Blood–testis barrier composition. The blood–testis barrier, besides in gap junctions, desmosome-like junctions and tight junctions, has Sertoli cells (SCs). SCs participate in the nutrition and growth of germ cells, maintenance of the immune privilege and clearance of autoantigens and apoptotic cells via phagocytosis.

Figure 3

Macrophages, Dendritic cells and T cells sustain the testicular immune response. ED-2 macrophages, DCs and Treg cells keep immune privilege. Conversely, ED-1 macrophages and Th17 cells take part inchronic orchitis progression. Leydig cells attenuate autoimmune orchitis via release oftestosterone. SCs maintain the immune privilege via activation of tolerogenic DCs and Treg cells.

Figure 4

The gut–testis axis. The existence of the gut–testis axis is supported by different evidence. Fecal transplantation from high-fat diet mice to normal mice accounts for endotoxemia occurrence and altered spermatogenesis. In turn, endotoxemia abrogates synthesis of testosterone from Leydig cells, thus reducing the number of spermatozoa with increased release of pro-inflammatory cytokines. Insulin resistance as a result of an altered intestinal permeability leads to a reduced spermatogenesis.

Figure 5

Microbial invasion of the testis. UPEC and C. trachomatis damage the male genital tract via production of pro-inflammatory cytokines and nitric oxide, with tissue scarring. COVID-19 infection is characterized by a reduction of Leydig cells, infiltration of T and B cells and elevated expression of ACE-2.