Marilen Benner

MICROBIOTA AND ENDOMETRIAL HEALTH 141 6 THE NON-STERILE UTERUS? Microbiota and mammals depend on their symbiotic relationship. While microbes receive a steady nutrient supply through the host, the host benefits from vital contributions of the microbe to physiological processes such as epithelial homeostasis, and is supplied with a natural barrier against colonization by pathogenic species (11, 12). Bacterial colonization also plays a crucial role in modulation of host immunity. Metagenomic analysis has propelled research on natural colonization of the human body forward, revealing microbiota at body sites that were previously considered to be sterile. This includes the upper reproductive tract and placenta, challenging the classic dogma of a ‘sterile womb’ as coined by Henry Tissier more than a century ago (13). Due to the earlier limitations in microbial characterization and challenges in sample acquisition, the significance of endometrial bacteria may have been missed or overlooked (14). Now, increasing evidence in favour of an endometrial microbiome (15-23) and a placental commensal colonization (24, 25) indicates the need for a paradigm shift. The endometrium: An immunologically suited niche for microbiota In the gut, the intestinal immune system needs to be highly adapted to withstand the continuous threat posed by colonization of the large mucosal surface, separated from host tissue by only a single layer of epithelial cells (26). In a symbiotic colonization, bacterial growth is safe for the host as long as it is contained within an assigned compartment. Therefore, tissue invasion must be limited, thus preventingpotentially harmful inflammation or disruption of the niche for the necessary symbiotic relationship. Hooper and Macpherson (26) described three types of immunological barriers needed for intestinal microbial homeostasis: anatomically limiting exposure of resident bacteria to the systemic immune system; immune mediators restricting direct contact between epithelia and microbes; and rapid detection and killing of bacteria upon barrier breach. All three pre-requisites are met by the endometrial mucosa. In the uterus, the single layer of columnar epithelial cells that proliferate to form glandular cells in the secretory phase of the menstrual cycle forms a strong barrier through tight junctions (27). The uterine mucosal surface and the endometrial fluid (EF) contain infection-controlling molecules, known as antimicrobial peptides (AMPs), with fluctuating levels during the menstrual cycle (28). AMPs are known to contribute to the health of the female reproductive tract with implications for fertility and pregnancy (29). An example of an AMP found in the uterus is the secretory leukocyte protease inhibitor, which has antiviral and antifungal properties, and also acts as a bactericidal against gram-negative as well as gram-positive bacteria such as Escherichia coli and Staphylococcus aureus (30). Furthermore, the endometrial lymphocytes in the mucosal layer are present throughout all stages of the menstrual cycle, ready to act upon pathogen invasion (31). Therefore, according to the required properties, the uterus could offer a safe niche for symbiotic colonization.