A Dormant Microbial Component in the Development of Preeclampsia

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.

Immunological tolerance, pregnancy and pre-eclampsia: the roles of semen microbes and the father1

“…Interestingly, recent analyses [19; 45] of placental gene expression in PE implicate changes in the expression of TREM1 (triggering receptor on myeloid cells-1) and the metalloprotease INHA, and in one case [19] also LTF (lactotransferrin), that also occur during infection [46][47][48][49]. Although we highlighted the role of antibiotics as potentially preventative of PE [32], and summarised the significant evidence for that, we had relatively little to say about immunology, and ignored another well-known antidote to infectious organisms in the form of vaccines. There is certainly also an immune component to preeclampsia (e.g.…”

“…The 'two-stage' theory is well established, and nothing we have to say changes it. However, none of this serves to explain what 'initiating' or 'external' factors are typically responsible for the poor placentation, inflammation, and other observable features of PE [32].…”

“…Microbes are ubiquitous in the environment, and one potential external or initiating factor is lowlevel microbial infection. In a recent review [32], we developed the idea (and summarised extensive evidence for it) that a significant contributor to pre-eclampsia might be a (largely dormant [33][34][35][36] and non-replicating) microbiome within the placenta and related tissues, also detectable in blood and urine. Others (e.g.…”

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

“…These results are of particular importance when it is noted that bacterial involvement might play a role in both the development and progression of PD, and specifically, circulating bacterial inflammagens such as LPS have been implicated (Tufekci et al, 2011;De Chiara et al, 2012;Potgieter et al, 2015;Friedland and Chapman, 2017). We have also suggested that LPS may both maintain systemic inflammation, as well as the disease aetiology itself in PD (but also in other inflammatory diseases like type 2 diabetes, pre-eclampsia, sepsis, rheumatoid arthritis and Alzheimer's disease, where LPS presence has been implicated in the aetiology of the condition) (Kell and Kenny, 2016;Pretorius et al, 2016a;Pretorius et al, 2016b;Pretorius et al, 2017a;Pretorius et al, 2017b;Pretorius et al, 2017c;Kell and Pretorius, 2018b). Indeed in 2018, we showed that LPS from E. coli could be identified with fluorescent LPS E. coli antibodies in clots of PD, type 2 diabetes and AD (de Waal et al, 2018).…”

“…What is not immediately clear is the actual origin of the inflammation and how and why it is chronic. For this and other diseases (Potgieter et al, 2015;Kell and Kenny, 2016;Pretorius et al, 2016a;Pretorius et al, 2017a;de Waal et al, 2018;Kell and Pretorius, 2018a;Kell and Pretorius, 2018b) we have brought together evidence that a chief cause may be (dormant) microbes that upon stimulation, especially with unliganded iron (Kell, 2009), can briefly replicate and shed potent (and well known) inflammagens such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA) Kell and Pretorius, 2018a). These are well-known ligands for receptors such as Toll-like receptor 4 (TLR4) and can thus stimulate inflammation, as observed through a variety of inflammatory cytokines (Olumuyiwa-Akeredolu et al, 2019).…”