The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth

Abstract

Preterm Birth (PTB, < 37 completed weeks' gestation) is one of the leading obstetrical problems in the United States affecting approximately 1 of every 9 births. Even more concerning are the persistent racial disparities in PTB with particularly high rates in African Americans. There are several recognized pathophysiologic pathways to PTB, including infection and/or exaggerated systemic or local inflammation. Intrauterine infection is a causal factor linked to PTB, thought to result most commonly from inflammatory processes triggered by microbial invasion of bacteria ascending from the vaginal microbiome. Trials to treat various infections have shown limited efficacy in reducing PTB risk, suggesting that other complex mechanisms, including those associated with inflammation, may be involved in the relationship between microbes, infection, and PTB. A key mediator of the inflammatory response, and recently shown to be associated with PTB, is the complement system, an innate defense mechanism involved in both normal physiologic processes that occur during pregnancy implantation, as well as processes that promote the elimination of pathogenic microbes. The purpose of this paper is to present a mechanistic model of inflammation-associated PTB, which hypothesizes a relationship between the microbiome and dysregulation of the complement system. Exploring the relationships between the microbial environment and complement biomarkers may elucidate a potentially modifiable biological pathway to preterm birth.

The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction

“…The complement system was proposed as a key player in adverse pregnancy outcome, as female microbiota composition regulates complement function in the maternal vasculature (99). Complement dysregulation in the intrauterine space, promotes inflammation and triggers a cascade of physiological changes (cervical changes, degradation of collagen, uterine decidua activation and uterine contractility), which in turn increases risk for preterm delivery (97).…”

Cervical alterations in pregnancy

“…[52, 73–78] Emerging fields that study the microbiome of the vagina also may begin to elucidate the microbial causes of premature cervical remodeling. [79–82] However in many cases, no clear infectious or microbial etiologies are found. [83] Thus, the third hypothesis being explored is one where the normal sterile inflammatory process, which remodels the cervix at term, is triggered prematurely.…”

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth

“…Recent evidence suggest that the overall shift in the inflammatory environment, rather than the presence of individual microbial communities during microbiome disruption, contributes to spontaneous PTB [3]. In line with this notion, anti-microbial treatments have shown limited efficacy in reducing PTB risk [4]. Interestingly, an inflammatory insult contributes not only to the PTB risk but also to the risk of fetal mortality and morbidities.…”