Uterine Microbiota: Residents, Tourists, or Invaders?

Abstract

Uterine microbiota have been reported under various conditions and populations; however, it is uncertain the level to which these bacteria are residents that maintain homeostasis, tourists that are readily eliminated or invaders that contribute to human disease. This review provides a historical timeline and summarizes the current status of this topic with the aim of promoting research priorities and discussion on this controversial topic. Discrepancies exist in current reports of uterine microbiota and are critically reviewed and examined. Established and putative routes of bacterial seeding of the human uterus and interactions with distal mucosal sites are discussed. Based upon the current literature, we highlight the need for additional robust clinical and translational studies in this area. In addition, we discuss the necessity for investigating host-microbiota interactions and the physiologic and functional impact of these microbiota on the local endometrial microenvironment as these mechanisms may influence poor reproductive, obstetric, and gynecologic health outcomes and sequelae.

Keywords: endometrial cancer; endometrium; gynecologic and reproductive health; host–microbe interactions; infertility; inflammation; microbiome; pathophysiology.

Figure 1

Timeline of uterine microbiota reports in the literature. Color legend: black denotes time periods in which the uterus was considered sterile, green indicates the time period during which culture-based techniques were used, and red indicates the uses of high-throughput sequencing techniques. (A) From 1958 to 2006: literature detailing culture-based methods of quantification of the uterine microbiome (shown in green). (B) The decline in the perceived sterility of the endometrial microbiome according to literature reported over time. (C) Overall timeline from 1900 to 2017 [from assumption of sterility of uterine microbiome to detailed quantification of bacterial species through next-generation sequencing (NGS)]. (D) NGS: 2007–2017 (shown in red) uterine microbiome literature that has been published to date utilizing this technology.

Figure 2

Established and putative bacterial transmission routes between uterine microbiome and distal sites. (A) Putative hematogenous spread of bacteria emanating from the gut and oral microbiome or other means of circulation of bacteria through the blood. Viability has been demonstrated to be conserved during translocation through blood with intracellular dormancy being an example of how bacteria remain viable in blood. (B) Ascension of bacteria through the cervix has been well established and is a likely source of bacterial transmission. (C) Transmission of bacteria through routes, other than those illustrated, include assisted reproductive technology-related gynecologic procedures whereby bacteria from the vaginal microbiome are introduced to the uterus, such as oocyte retrieval. Other routes of colonization may exist beyond hematogenous spread. The insertion or removal of intrauterine devices may introduce bacteria into the uterus as well as potentially aid in ascension through the “tails” that extend from the uterus through the endocervical canal.

Figure 3

Putative pathophysiological impact of uterine microbiome on the endometrial epithelium. (A) Presence of uterine microbiota may impact the genomic stability of uterine epithelia through modulation of transcription factors and other genomic and epigenetic alterations. This may subsequently lead to the prevention of autophagy. (B) Downregulation of cell–cell junction expression is a key method of epithelial barrier breach and allows for the movement of bacteria in between epithelial cells. Similarly, the degradation of the extracellular matrix by matrix metalloproteinases also disrupts epithelial barrier integrity. (C) Microbial-secreted metabolites such as short-chain fatty acids (SCFAs) can encourage the growth of specific species and suppress growth of other bacteria. Reactive oxygen species (ROS) and changes in the pH of the uterine microenvironment may also drive disease. (D) Inflammation triggered by TLR activation and subsequent pro-inflammatory pathways can recruit immune cells and lead to the secretion of antimicrobial peptides (AMPs), which leads to the depletion of bacterial abundance. TLR-mediated signaling can also regulate mucin synthesis of both membrane-associated and secreted mucins that may impact colonization.