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Review
. 2016 Nov 29;3:60.
doi: 10.3389/fmed.2016.00060. eCollection 2016.

A Dormant Microbial Component in the Development of Preeclampsia

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Free PMC article
Review

A Dormant Microbial Component in the Development of Preeclampsia

Douglas B Kell et al. Front Med (Lausanne). .
Free PMC article

Abstract

Preeclampsia (PE) is a complex, multisystem 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. We 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, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of "preeclampsia" that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills 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. PE was classically referred to as endotoxemia or toxemia 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 etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

Keywords: amyloidoses; biomarkers; coagulopathies; dormancy; infection; preeclampsia; sepsis.

Figures

Figure 1
Figure 1
Two main sources (fetal and maternal) can drive a pregnancy toward preeclampsia.
Figure 2
Figure 2
There are four main “causes” of preeclampsia, represented by the colored outer circles, and these can also interact with each other. That part of the figure is redrawn from Pennington et al. (113). In addition, we note here, as the theme of this review, that microbes can themselves cause each of the features in the outer colored circles to manifest.
Figure 3
Figure 3
Another detailed representation of factors known to cause or accompany PE, redrawn from Magee et al. (114).
Figure 4
Figure 4
A mind map of the overall structure of the review.
Figure 5
Figure 5
The chief physiological macrostates exhibited by microorganisms.
Figure 6
Figure 6
An 11-stage systems biology model of the factors that we consider cause initially formant microbes to manifest the symptoms (and disease) of preeclampsia.
Figure 7
Figure 7
Preeclampsia bears some similarities to and may be considered as a milder form of, the changes that occur during genuine sepsis leading to a systematic inflammatory response syndrome, septic shock, and multiple organ dysfunction.
Figure 8
Figure 8
Some structures of various statins.

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