Influences of environmental factors during preeclampsia

Abstract

Preeclampsia is a pregnancy-specific disorder that impacts 5–8% of pregnancies and has long-term cardiovascular and metabolic implications for both mother and fetus. The mechanisms are unclear; however, it is believed that preeclampsia is characterized by abnormal vascularization during placentation resulting in the manifestation of clinical signs such as hypertension, proteinuria, and endothelial dysfunction. Although there is no current cure to alleviate the clinical signs, an emerging area of interest in the field is the influence of environmental factors including diet on the risk of preeclampsia. Because preeclampsia has serious cardiovascular implications to both the mother and fetus and most antihypertensive medications are contraindicated in pregnancy, it is important to investigate other potential therapeutic options such as dietary manipulation. The emerging field of nutrigenomics links diet with the gene expression of known pathways such as oxidative stress and inflammation via microbiome-mediated metabolites and could serve as one potential avenue of therapeutic targets for preeclampsia. Although the exact role of nutrition in the pathogenesis of preeclampsia is unknown, this review will focus on known pathways involved in the development of preeclampsia and how dietary intake modulates the microbiome, oxidative stress, and inflammation with an emphasis on nutrigenomics as a potential avenue of further investigation to better understand this pathology.

NUTRITION IN PREECLAMPSIA

Dietary behavior is a modifiable factor that has been shown to be impactful in cardiovascular disease. Plant-based diets have been associated with a lower risk for cardiovascular disease, cardiometabolic disease, and chronic kidney disease (30, 40, 42). These beneficial effects of consuming a plant-based diet are also observed in preeclampsia. It has been reported that women in The Norwegian Mother and Child Cohort Study (MoBa) who consumed an elevated dietary intake of vegetables and plant foods had a lower risk of developing preeclampsia compared with women who ate more processed meat (9). Additionally, the source and quantity of the dietary fiber impacts the risk for developing preeclampsia. Qiu et al. (44) demonstrated that women consuming the highest quartile for dietary total fiber intake during the preconception and early pregnancy period had a 67% lower risk of developing preeclampsia compared with women in the lowest quartile of dietary fiber consumption. This inverse relationship between fiber intake and risk of preeclampsia was observed for both water-soluble and insoluble fiber sources. The exact mechanisms responsible for the protective role of plant-based diets are unknown, but a possible explanation for the inverse relationship between risk of preeclampsia and dietary composition intake is from alterations in the gut microbiota and the metabolites produced from the microbiota. Though an increasing amount of evidence supports the role of the microbiome in chronic health, it is unclear how the composition of microbiota or production in metabolites will impact downstream processes such as oxidative stress and immunity, both known contributors to preeclampsia. One area of recent interest is the developing field of nutrigenomics that focuses on the interaction between dietary intake and microbiota-derived metabolites to influence gene expression of these pathways. Our understanding of nutrigenomics is currently limited, but it has the potential to identify the relationship between genetic predispositions to disease and dietary intake. This review focuses on the known involvements of such pathways as oxidative stress and the immune system and the role of dietary intake to influence these pathways to alter/improve maternal outcomes in preeclampsia. These potential interactions have been summarized in Fig. 1 based on studies investigating the link among diet, microbiome, and pathological pathways.

Fig. 1.

Proposed pathway linking diet with the development of preeclampsia based on studies cited within this review. Specific dietary intake alters the risk of preeclampsia through interrelated mechanisms beginning with adaptations in microbiota composition and metabolites. These alterations can have implications on gene expression of known pathways such as oxidative stress and inflammation that could modify function of these pathways, which ultimately can influence the risk of developing preeclampsia.

MICROBIOME AND PREECLAMPSIA

In recent years, the microbiome has been an area of interest not only in the role of host metabolism and nutrition absorption but also in many chronic diseases such as hypertension and kidney disease (29, 33). Dietary components and habits play an important role in influencing the microbiota composition of the gut. David et al. (19) demonstrated that the gut microbiome communities respond differently to a plant-based diet versus an animal-based diet. This study determined there was a significant increase in β-diversity of the microbiome population when the subjects were fed an animal-based diet. Interestingly, when these same subjects were fed a plant-based diet, there was no change in β-diversity of the microbiome from baseline measurements. Although β-diversity is a metric utilized to identify the differences of microbiota composition between samples, further investigation into bacteria phyla composition has demonstrated gut dysbiosis in chronic diseases such as diabetes, obesity, and cardiovascular disease (25). In particular, the firmicutes-to-bacteroidetes ratio (F/B ratio) is a metric utilized as a hallmark of gut dysbiosis with an expansion of the firmicutes population and a reduction in the bacteroidetes population occurring in these pathologies. There are reports in both hypertensive humans and experimental models of hypertension that the F/B ratio is increased relative to the normotensive control groups (58). Yang et al. (58) further demonstrated that administration of minocycline, a broad-spectrum antibiotic, attenuated the angiotensin II (ANG II)-induced hypertension and reduced the F/B ratio to control levels [mean value (%) − control: 6.60, ANG II: 37.22, ANG II + minocycline: 2.57] demonstrating that the composition of the gut microbiota is important in the context of hypertension. In addition to the gut microbiota composition, concentrations of gut-derived metabolic end products, such as short-chain fatty acids (SCFA), have been implicated in both physiological and pathophysiological pathways.

Short-chain fatty acids are the end products of fermentation by the microbiota, which are absorbed from the gut into the circulation that impact multiple processes such as energy metabolism and immune system regulation (34), but reduced levels of SCFAs have also been implicated in the development of hypertension (13). More specifically in experimental models of hypertension, levels of acetate and butyrate are decreased in spontaneously hypertensive rats as well as ANG II-induced hypertension (58). Interestingly, treatment with minocycline resulted in a normalization of both the levels of acetate and butyrate to control levels. Additionally, there is evidence that SCFAs exhibit an inverse relationship with levels of oxidative stress and inflammation in chronic diseases such as hypertension and kidney disease (4, 13, 27, 34). These studies would suggest that increasing bacterial populations that are responsible for producing SCFAs such as acetate and butyrate could be beneficial in treating hypertensive patients.

Concentrations of SCFAs have also been shown to be influenced by dietary intake. In the study by David et al. (19), the animal-based diet resulted in a ~40% reduction in acetate and butyrate while causing a ~50% increase in amino acid fermentation, suggesting that dietary intake may shift the composition of the microbiome and subsequent production of microbiome-derived metabolites. The investigators also performed RNA sequencing (RNA-Seq) on stool samples from both plant- and animal-based diets to identify differentially expressed genes of the gut microbiome involved with metabolic pathways. The results indicated opposing effects in amino acid catabolism and biosynthesis whether subjects were consuming a plant-based diet or animal-based diet (19). Specifically in the glucose metabolism pathway, these diets demonstrated opposing directionality of enzyme expression in the phosphoenolpyrutvate-pyruvate-oxaloacetate node of the tricarboxylic acid cycle. For example, consumption of a plant-based diet resulted in an upregulation in oxaloacetate decarboxylase and orthophosphate dikinase, whereas animal-based diets caused an upregulation in pyruvate kinase and pyruvate carboxylase. This importantly provided evidence of how dietary modulations could eventually cause systemic effects through the gut microbiota.

The gut microbiome has also been implicated as a contributing factor in preeclampsia. Chen et al. (15) demonstrated a drastic shift in the gut microbiome of women with preeclamsia compared with women who had a healthy pregnancy. Moreover, the relative abundance of genera of bacteria such as Bacteroidetes, Proteobacteria, and Enterobacteriacceae has been shown to be higher in preeclamptic women versus healthy pregnant women (55). This recent publication by Chen et al. concludes that the development of preeclampsia in this cohort may be due to bacterial translocation from the gut to the placenta (15). Further investigations are necessary to explore the possibility of a gut-placental axis and to demonstrate a causal relationship between the microbiome and preeclampsia. While these associations between the microbiome composition and blood pressure have been made (23), it is not well understood how the gut bacteria result in elevations in blood pressure for the host. It is thought that gut-derived metabolites produced by the microbiome could play a key role in this process since the bacteria found in the gut are responsible for aiding in the breakdown of indigestible particles into nutrients and fecal waste (39). The gut-derived byproducts can vary depending on the dietary intake of the host, and one category of byproducts that has been investigated thus far is SCFAs, the byproducts of fiber fermentation. It is not clear how these metabolites are released systemically to elicit their effects on the host; however, there have been multiple reports about the contributions of SCFAs during pregnancy.

In a study investigating obesity in early pregnancy, Gomez-Arango et al. (23) demonstrated a negative correlation with abundance of butyrate-producing bacteria in the gut and blood pressure. This group also demonstrated that the reduction in levels of butyrate were associated with elevated levels of the inflammatory marker, plasminogen activator inhibitor-1. Additionally, Chang et al. (14) demonstrated that fecal levels of butyric and valeric acid were reduced in preeclamptic patients, suggesting that these metabolites influence the disease process; however, it is not fully understood how these gut-derived metabolites contribute to preeclampsia. An additional known gut microbiota-derived metabolite that may play a role in preeclampsia is lipopolysaccharide (LPS) also known as endotoxin. An elevation in microbiota-derived LPS could be responsible for the improper immune response associated with preeclampsia. It has been documented that both plasma and fecal levels of LPS are elevated slightly in preeclamptic women compared with control (55). Interestingly, in an animal model of LPS-induced preeclampsia, treatment with butyrate improved the preeclamptic-like phenotype relative to controls. These results, which link the metabolites from the microbiota, suggest that butyrate and LPS could be mechanistic targets to understand the pathogenesis of preeclampsia. However, the direct mechanism whereby gut-derived metabolites interact with known pathways remains unclear, two avenues that may help explain how dietary habits contribute to the development of preeclampsia are oxidative stress and the immune system.

OXIDATIVE STRESS AND PREECLAMPSIA

The exact mechanisms for the development of preeclampsia are unknown, but the disease process is thought to occur in two phases: reduced remodeling of the maternal spiral arteries resulting in a hypoxic placenta followed by development of hypertension and proteinuria, which could be a compensatory mechanism (37). In a healthy pregnancy, remodeling of the maternal spiral arteries by the extravillous trophoblast creates a continuous low flow perfusion that results in a low oxygen tension in the intervillous space, which turns to a high oxygen tension area as embryogenesis is completed (10). If this transition from low to high oxygen tension occurs too quickly, it leads to a formation of reactive oxygen species that begins a cascade of events that reduce remodeling of the spiral arteries, including increased inflammation and release of antiangiogenic factors into the maternal circulation like soluble fms-like tyrosine kinase-1 and endoglin (61). These factors work in concert to cause hypertension, endothelial dysfunction, and end-organ damage in the mother (45, 49). Oxidative stress involves the production of reactive oxygen species, which include superoxide, hydrogen peroxide, and hydroxyl radicals. Since these are highly reactive molecules, they can elicit both structural and physiological damage to DNA, RNA, and proteins that could contribute to the pathogenesis of preeclampsia.

The source of oxidative stress, in terms of preeclampsia, can originate in multiple cells types within the placenta such as trophoblasts, endothelial cells, stromal cells of the villi, and specialized immune cells called Hofbauer cells (5). When improper placentation occurs, it is proposed that excess levels of oxidative stress from within the placenta are released into the maternal circulation via extracellular vesicles that subsequently lead to upregulation of gene expression in immune cells as well as endothelial cells throughout the maternal circulation. Additionally, it is also thought that a reduced antioxidant defense could contribute to this pro-oxidant environment. Kirbas et al. (31) reported that total antioxidant status was reduced in maternal serum samples of women with early-onset severe preeclampsia. In a meta-analysis of over 25 years of research, it was demonstrated that preeclamptic women exhibit an imbalance between pro-oxidant and antioxidant capacity (54). This imbalance potentially leads to an accumulation of free radicals that can have deleterious effects to endothelial function in the mother as well as influence the function of trophoblasts that are responsible for remodeling of the maternal spiral arteries during the placentation phase (56). Yet, the impact of dietary habits on the oxidative status in preeclampsia is less understood.

There are some studies investigating the role of fiber intake on oxidative stress, which demonstrated that higher fiber levels reduced oxidized low-density lipoprotein and increased total antioxidant capacity in nonpregnant subjects (20, 24). In a smaller cohort, Scholl et al. (50) reported a fivefold increase in urinary isoprostane excretion and a threefold decrease in antioxidant capacity in a preeclamptic population that was associated with an increase in dietary fat intake. A case-control study in Jordan demonstrated that reduction in beneficial dietary factors such as fiber, beta-carotene, and vitamin C were associated with preeclampsia due to a reduction in antioxidant capacity (60). Yet, supplementation of diets with antioxidant nutrients, such as vitamin C and E, has not been beneficially therapeutic as initially hypothesized (47). This might perhaps be due to a larger producer of oxidative stress masking the therapeutic effects of antioxidant supplementation. Further investigations into the link between placental-derived oxidative stress and manifestation of preeclampsia as well as whether nutritional approaches could be a therapeutic option to treat oxidative stress in pregnancy by targeting gut-derived oxidative stress.

INFLAMMATION AND PREECLAMPSIA

In addition to the proposed role of oxidative stress in preeclampsia, there is also supportive evidence for the influence of oxidative stress on activation of the immune system. Upon release of reactive oxygen species from the hypoxic placenta, a systemic inflammatory response is produced, which leads to endothelial dysfunction and hypertension (8). Both innate and adaptive immune mechanisms have been implicated in preeclampsia (57), but an in-depth discussion on this vast topic is beyond the scope of this brief review. Instead, the specific contribution of T cells to the pathogenesis of preeclampsia will be highlighted.

In a healthy pregnancy, there is a balance between the immunostimulatory T-helper type 1 (Th1) and immunoinhibitory T-helper type 2 (Th2) cells. There has been a reported shift in the Th1/Th2 imbalance in preeclamptic women favoring the pro-inflammatory Th1, and accompanied with this Th1/Th2 imbalance is the production of pro-inflammatory cytokines (6). Additionally, T regulatory cells (Tregs) play an important role in proper implantation and placentation during normal pregnancy. However, a decreased number of Tregs has been observed in preeclamptic women relative to a healthy pregnancy (7), and this reduction in anti-inflammatory Tregs may trigger pathways involved in the heightened immune response observed in preeclampsia.

Interestingly, these T cell populations are differentiated in response to dietary intake. Clinical data has shown a link between dietary intake and modulation of the immune system in pregnancy, as well as in several inflammatory diseases such as inflammatory bowel disease (28), obesity (41), and chronic kidney disease (11). Dietary Inflammatory Index (DII) is a literature-derived dietary index developed by Shivappa et al. (51) to determine the inflammatory potential of an individual’s diet. Pregnant women participating in the Project Viva cohort were given self-administered food frequency questionnaires during the first and second trimesters to calculate the DII score for each subject. A high DII score indicates consumption of a more proinflammatory diet. It was reported that dietary intake of fiber had a strong negative association with DII score and intake of SCFAs had a strong positive association with DII score. There were only modest correlations with systemic inflammation and dietary fiber in this study.

Furthermore, preeclampsia not only activates immune function in the mother but also has implications on the development of the fetal immune system. Maternal malnutrition causes immunosuppression in the mother, which reduces the availability of maternal immunoglobulins for the fetus (36). In a recent study from Hu et al. (26), it was determined in an animal model of preeclampsia that both maternal and fetal Treg development and function were improved when the dams were treated with the SCFA, microbial metabolite acetate. The authors also demonstrated in their human cohort that acetate levels were reduced in the preeclamptic population suggesting a protective effect in pregnancy. These types of SCFAs are observed in diets that are high in fiber as well as in Mediterranean diets (16), but how can these nutrients elicit their protective effects on the immune system?

NUTRIGENOMICS: POTENTIAL LINK BETWEEN THE GUT AND PREECLAMPSIA?

Preeclampsia is a complicated disease with multiple pathways contributing to the phenotype, but it is possible that these systems are working in concert to elicit their detrimental effects. The microbiome is a conceivable connection between dietary nutrients and the known pathological pathways that contribute to preeclampsia. It is unclear how these gut-derived metabolites play a functional role in contributing to a disease state; however, there is evidence suggesting that these metabolites could be eliciting their effects through regulating gene expression via epigenetic modifications (48). Epigenetic modifications are heritable changes in gene function without alterations in the genome that occur in three different categories: DNA methylation, histone modifications, and noncoding RNAs (43). These epigenetic modifications impact both gene expression and function in health and disease, and the potential influence of dietary byproducts on these epigenetic modifications is termed nutrigenomics. This is a budding area of interest in the field of pregnancy and developmental programming since there are implications for both the mother and fetus (53).

The crossroads between nutrients and epigenetic modifications is the microbiota. Both the composition of the gut bacteria as well as the production of gut-derived metabolites, such as SCFAs, can fluctuate based on the host diet. In fact, data support the concept that SCFAs released by commensal bacteria modulate cellular processes through histone modifications in an experimental model of colitis (35). Additional work has demonstrated that epigenetic modifications are affected by variations in metabolites, which ultimately, modify the proliferation and function of T cells (4, 52) and generation of oxidative stress in chronic disease states (59); however, further investigations are necessary to fully understand if these systems are integrated to contribute to disease. There are reports of epigenetic regulation of placental genes in preeclamptic women, but dietary intake was not reported in the study (32). Further investigations into how maternal nutrigenomics contribute to the development of preeclampsia are necessary to better understand the interplay among the microbiome, oxidative stress, and the immune system.

One potential experimental model that could be utilized to investigate how these pathways converge is the Dahl Salt-Sensitive (SS) rat. In response to a high-salt challenge, the Dahl SS rat exhibits hypertension and renal damage through activation of pathways related to oxidative stress (2) and the immune system (21, 46). In addition to the sodium-dependent effects of the diet, sodium-independent components of the diet, more specifically the dietary protein source, can impact the severity of salt-sensitive hypertension in this model (3, 38). A simple substitution of the dietary protein source from a casein-based protein to a grain-based protein resulted in the attenuation of salt-sensitive hypertension and renal damage, accompanied with a reduction in infiltrating renal immune cells (3). Recent publications have demonstrated that these different diets also impact the function of infiltrating renal T cells, which may involve differential DNA methylation of the T cell genome in response to a high-salt challenge (1, 18). These effects of the dietary protein source have been specifically linked to the diet consumed by the parents during gestation and lactation (3, 22). An embryo transfer study was performed between two different colonies of the Dahl SS rat: one maintained on the casein-based diet and on maintained on the grain-based diet. Ultimately, it was the diet of the surrogate mother that predicted the offspring’s severity of salt-induced hypertension and renal disease in later life, where offspring born of grain-fed dams exhibited a blunted response relative to those born to casein-fed dams (22). Finally, preliminary data suggest that some Dahl SS rats maintained on the casein-based diet develop maternal syndrome, which is a pregnancy-specific increase in blood pressure and proteinuria. Yet, Dahl SS rats fed a grain chow are protected from this phenotype suggesting that this model would be vital in understanding dietary intake and its effects in pregnancy (17). These studies taken together can highlight the potential knowledge that could be gained from investigating the interactions between dietary habits, gut-derived metabolites, and epigenetic modifications to health and disease in the Dahl SS rat.

Perspectives and Significance

Understanding the pathogenesis of preeclampsia is vital to improve immediate outcomes for both mother and fetus as well as the long-term health. Since most antihypertensive medications are contraindicated during pregnancy, the notion of reducing the risk of preeclampsia with a dietary therapeutic is an attractive opportunity for the field. As information about the microbiota continues to develop, this is an opportunity to further investigate how both microbiota composition and metabolite production could influence gene expression that occurs during a healthy pregnancy as well as during preeclampsia. Investigations into dietary therapeutics have been beneficial for other cardiovascular diseases, and it seems plausible that a dietary intervention could be beneficial in the state of preeclampsia for both mother and fetus.

In conclusion, preeclampsia is a multifaceted disease that has implications for both mother and fetus. While there is sufficient data indicating the involvement of many different molecular pathways in the pathogenesis of preeclampsia, to date, the only way to alleviate the clinical signs of preeclampsia is delivery of the fetus and placenta. Pharmacological therapies to treat preeclampsia in a clinical setting are limited due to the contraindications for the placental and fetal development that are associated with most pharmacological agents. This makes the possibility of dietary interventions and manipulations appealing as a therapeutic target for preeclampsia. More investigations are necessary to understand how epigenetic modifications impact placental formation and function through molecular pathways like oxidative stress and the immune system. Investigations into the modulation of these pathways through metabolites released by the microbiome in response to dietary changes could be beneficial to fully elucidate the link between preeclampsia and nutrition.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

J.H.D. and J.M.A.-B. prepared figures; J.H.D. drafted manuscript; J.H.D., J.M.A.-B., and D.L.M. edited and revised manuscript; J.H.D., J.M.A.-B., and D.L.M. approved final version of manuscript.