Table 1.

Summary of controlled experiments on the role of SCFAs and GM in regulating PE progression.

Author	Year	Experimental Model	Outcome	Result	Ref.
Human cohort-controlled trial
Chang	2020	27 severe PE patients and 36 pregnant women with normal pregnancies	Comparison of GM abundance of intestinal flora and its relationship with SCFAs.	There was a consistent correlation between SCFAs and bacterial GM abundance in PE patients. The phylum Thick-walled and its subordinates were associated with increased SCFAs, whereas the phylum Aspergillus and its subordinate Escherichia_Shigella were associated with decreased SCFAs. All SCFAs were synchronously correlated with GM abundance differences, suggesting that GM abundance differences and the SCFAs they produce may play a synchronous role in the development of PE. Within the SCFAs, butyric and valeric acid were most strongly correlated with GM abundance differences.	(Chang et al., 2020)
Jin	2022	92 PE patients and 86 pregnant women with normal pregnancies	The variation of GM abundance in intestinal flora, its relationship with SCFAs, and its mechanism of action.	SCFAs can regulate the expression of a wide range of cytokines in macrophages via GPCRs, which have anti-inflammatory functions. For example, butyric acid promotes M2-type macrophage polarization and inhibits LPS-induced M1-type macrophage polarization, and also enhances autophagy, thereby inhibiting macrophage-induced inflammation and significantly improving PE symptoms in rats.	(Jin et al., 2022)
Hu	2019	Cohort 1: 50 patients with PE and 50 normal pregnant women. Cohort 2: 887 pregnancies in the second trimester, 24 of which developed PE in the late pregnancy.	Fetal thymus volume and diameter in cohort 1 of two groups. Relationship between serum SCFAs content and subsequent PE in Cohort 2 at 28 weeks of gestation.	In cohort 1, fetal thymus volume and fetal thymus diameter were reduced by 38% and 12.1% in patients with PE compared with normal pregnancy. Patients with PE in cohort 2 were found to have serum acetate levels at least ten times higher than those of butyrate and propionate, and the relative risk of PE was reduced for every 30% increase in serum acetate. In addition, maternal supplementation with acetate returned the overall amount of CD4+ T cells in PE-FMT mice pups to the normal control total, and acetate supplementation increased Foxp3+ expression in Treg cells.	(Hu et al., 2019)
Altemain	2021	11 PE patients and 22 pregnant women with normal pregnancies.	Composition of the GM in patients with DPE at 28 weeks of gestation. Assessment of the density of butyrate producing genes.	A trend towards significantly lower serum acetate, propionate and butyrate concentrations was found in patients with DPE, increased fecal SCFAs in normal controls and a significant decrease in butyrate in PE. And there was a negative association between acetate and Coprococcus abundance in women with DPE. A significant negative association was also found between fasting triglyceride levels and total butyrate levels in pregnant.	(Altemani et al., 2021)
Gomes	2016	205 pregnant women at 16 weeks’ gestation.	GM composition and levels of SCFAs in relationship to PAI-1 concentration and blood pressure in obese pregnancies.	In overweight and obese pregnancies at 16 weeks of gestation, GM abundance of butyrate production was negatively and significantly correlated with PAI-1 levels and blood pressure, whereas circulating PAI-1 was elevated in hypertensive patients. In addition, SCFAs were found to expand isolated human colonic arteries in vitro, and oral administration of butyrate reduced altered concentrations of IL-1β and TNF-α in mice induced by a high-fat diet.	(Gomez-Arango et al., 2016)
Tang	2022	6 patients with PE and 8 pregnant women with normal pregnancies.	Changes in the abundance of GM and the relationship between GM of PE and lncRNA.	The LPS levels in stool and placenta in PE group were significantly higher than those in control group, and the circulating lncRNABC030099 levels in plasma were also significantly higher than those in healthy subjects. The effect of GM on host lipid metabolism may be mediated by metabolites produced by GM, including SCFAs, secondary bile acids and trimethylamine, as well as LPS.	(Tang et al., 2022)
Huang	2021	Group NW: 21 normal women; Group NP: 28 normal pregnancies; Group APG: 25 pregnancies having decreased PIGF concentration; Group PE: 26 PE patients.	The correlation between GM and PE progression, and whether PIGF can predict placental abnormalities associated with PE.	Compared with healthy pregnant women, GM composition in group PE and group APG was significantly changed. At the genus level, a clear uneven distribution of GM abundance can be noticed, particularly in the genera with positive LDA score by linear discriminant analysis. The beneficial bacteria Lactobacillus was significantly reduced in the groups PE and APG, but it was only associated with blood pressure and albuminuria levels in the group PE.	(Huang et al., 2021)
Experiments on animals
Robles	2020	10 five-week-old Wistar Kyoto rats (WKY) and fifty SHR rats	SHR rats were orally treated with butyrate or acetate to observe its cardiovascular effects.	Treatment with acetate and butyrate inhibited the development of hypertension and normalized Firmicutes and Bacteroides (F/B) ratios. In addition, Th17 cell/Treg cell balance in mesenteric lymph nodes was restored, endotoxemia was normalized, and mRNA expression levels of tight junction protein occlusive protein and ZO-1 in colon were increased.	(Robles-Vera et al., 2020)
Yong	2022	15 normal pregnant rats, 15 PE model group, 15 PE model sodium butyrate treated group.	The influence of administering sodium butyrate on the progression of PE.	Sodium butyrate significantly reduced host blood pressure, inflammatory factor expression and urinary protein levels, and increased placental weight as well as expression levels of placental growth factor and gut barrier markers. Also, sodium butyrate treatment decreased the Treg/Th17 cell ratio of spleen and small intestine immune cells in pregnant rats, and also improved the abundance of Bacteroides and Firmicutes.	(Yong et al., 2022)
Onyszkiewicz	2019	4-16 weeks male Wistar rats.	Butyric acid may exert hemodynamic effects via intestinal signaling to lower blood pressure.	A 2-3-fold increase in butyric acid concentration in the colon produces a significant hypotensive effect, which appears to be mediated by colonic afferent nerve signaling and GPR41/43 receptors. It may also involve vasodilation induced by hematogenous butyric acid.	(Onyszkiewicz et al., 2019)
Smith	2013	SPF mice, GF mice	SCFAs regulates the size and function of colonic Treg cell pools and how to prevent colitis in mice.	It was found that the concentration of SCFAs in the colonic cavity of GF mice was decreased, and the expression of Foxp3 and IL-10 was increased after treatment with propionate. When treated with a combination of vancomycin and SCFAs, the reduction of Treg cells was completely restored. By constructing a model of T cell transfer in colitis, it was found that the frequency and number of Foxp3+Treg cells increased in mice receiving the propionic acid and SCFAs mixture.	(Smith et al., 2013)
Sun	2018	C57BL/6 and Rag-/- mice, construction of colitis model mice	How SCFAs regulates Th1 cell function.	SCFAs promotes the production of IL-10 by GM-specific Th1 cells, which is mediated by GPCR43, as a way to reduce Th1 cell-induced gut inflammation. The mechanism is dependent on the mTOR and STAT3 activation, thus promoting the expression of the transcription factor Blimp-1 in Th1 cells.	(Sun et al., 2018)
Hsu	2018	Pregnant SD rats	To investigate whether early GM-targeted therapy with probiotic Lactobacillus casei and prebiotic inulin can prevent high-fructose (HF) diet-induced programmed hypertension.	Prebiotic treatment to prevent HF-induced hypertension was found to be associated with reduced plasma acetate levels and reduced renal mRNA expression, whereas probiotic treatment increased plasma propionate levels and restored the HF-induced reduction in FAR2 (Fatty Acyl-CoA Reductase 2) expression. Maternal HF diet has long-term programming effects on GM in adult offspring. Maternal GM-targeted therapies may be influencing the progression of hypertension by reprogramming and, in turn, influencing the progression of hypertension.	(Hsu et al., 2018)
Marques	2017	Male C57BL/6 mice.	Whether a high-fiber diet and acetate supplementation may play a protective role in cardiovascular disease.	Studies have shown that high fiber intake alters GM and increases the abundance of acetate producing bacteria, and that acetate improves intestinal ecological dysregulation by altering the ratio of Firmicutes to Bacteroides. Acetate supplementation significantly reduced systolic and diastolic blood pressure, cardiac fibrosis and left ventricular hypertrophy in hypertensive mice.	(Marques et al., 2017)
Kim	2018	Adult C57BL6 mice and Sprague–Dawley (SD) rats	Validating whether hypertensive patients have different GM and whether GM markers can predict hypertension	Plasma concentrations of intestinal fatty acid binding protein (I-FABP), LPS, and intestinal-targeted pro-inflammatory Th17 cells were found to be significantly increased in hypertensive patients, indicating increased intestinal inflammation and permeability, suggesting that intestinal barrier dysfunction and microbiome function are associated with human hypertension.	(Kim et al., 2018)
Bartolomaeus	2019	Wild-type NMRI or apolipoprotein E knockout-deficient mice.	To study the effects of SCFAs on cardiac injury and atherosclerosis in hypertensive mice.	In both models, propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction and hypertension and significantly reduced susceptibility to ventricular arrhythmias, as well as reduced the area of aortic atherosclerosis. Propionate treatment reduced systemic inflammation as evidenced by a reduction in splenic effector memory T cell frequency and splenic Th17 cells in both models.	(Bartolomaeus et al., 2019)