A dormant microbial component in the development of pre-eclampsia

Abstract

Pre-eclampsia (PE) is a complex, multi-system disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE, and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused.\n\nWe here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is in fact microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of \"pre-eclampsia\" that we assessed has in fact also been shown to be raised in response to infection. An infectious component to PE fulfils the Bradford Hill criteria for ascribing a disease to an environmental cause, and suggests a number of treatments, some of which have in fact been shown to be successful.\n\nPE was classically referred to as endotoxaemia or toxaemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the aetiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.\n\nInsight, innovation, integrationMany descriptors of pre-eclampsia are widely accepted (e.g. abnormal trophoblast invasion, oxidative stress, inflammation and altered immune response, and anti-angiogenic responses). However, without knowing what causes them, they do not explain the syndrome. The Biological Insight of this manuscript is that there is considerable evidence to the effect that each of these phenomena (hence PE) are caused by the resuscitation of dormant bacteria that shed (known and potent) inflammagens such as LPS, often as a consequence of iron availability. PE is thus seen as a milder form of sepsis. The Technological Innovations come from the use of molecular markers (of microbes and omics more generally, as well as novel markers of coagulopathies) to measure this. The Benefit of Integration comes from bringing together a huge number of disparate observations into a unifying theme.