Altered Gut Microbiome Linked to Short Chain Fatty Acids Production in a Rat Model of Superimposed Preeclampsia

Abstract

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity. It affects 2–8% of all pregnancies, and its pathophysiology is not fully understood. Recent studies in preeclamptic patients have suggested a role for the gut microbiome (GM) in the disease. In addition, emerging evidence from both human and animal studies have reported that short‐chain fatty acids (SCFAs) and other gut‐derived metabolites such as lactate may modulate blood pressure (BP). We have characterized the Dahl salt‐sensitive (Dahl S) rat as a spontaneous rodent model of superimposed PE. The goal of our study was to determine if SCFAs production is impaired in PE. We hypothesized that preexisting chronic hypertension impairs maternal GM remodeling and maladaptation in SCFAs metabolism contributing to the development of superimposed PE. Female Sprague Dawley (SD) and Dahl S rats were maintained in conventional caging in the same room and on the same diet (Teklad 7034, 0.3% NaCl). Half of the rats of each strain were mated to have pregnant and virgin groups (n=7–9/group). Fecal samples were collected at baseline (BL), gestation day 20 (GD20) and one‐week postpartum (PP) to assess gut microbiome via 16S rRNA gene sequencing. Alpha diversity (Shannon index), beta diversity (Bray‐Curtis index), and linear discriminant analysis effect size (LEfSe) were determined from the sequenced data to assess microbial differences. PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states) was used to predict functional potential. At BL, Dahl S rats had higher alpha diversity (P<0.0001) and distinctly clustered beta diversity (p<0.001) compared to SD rats. Dahl S had higher Proteobacteria abundance (665,980 vs 51,240, p<0.05), a marker of dysbiosis. In response to pregnancy, we observed significant differences among groups in both alpha and beta diversity during late pregnancy. Also, Proteobacteria abundance in the SD rats rose from 0.56% (BL) to 13.46% (GD20) before subsiding to 7.36% (PP) suggesting that these changes may be a normal adaptation to pregnancy. The Dahl S, however, showed no change in proteobacteria: 5.29% (BL) to 6.35% (GD20) and 7.8% (PP). We found Dahl S groups to have significantly lower abundance of genera such as Odoribacter and Roseburia which are known to produce butyrate, a SCFA associated with lowering BP, compared to the SD rats. On the other hand, Dahl S rats were significantly enriched in lactate producing genera including Turibacter and Streptococcus. Increased lactate producers have been previously associated with increased BP. In addition, when comparing each pregnant group to its virgin counterpart of the same strain, we found that Dahl S rats had differentially regulated butanoate (33 hits, p=0.01 vs. 32 hits, p=0.43) and propanoate (31 hits, p=0.01 vs. 29 hits, p=0.57) metabolic pathways but not in SD groups. Altogether, these data suggest that superimposed PE may be associated with impaired pregnancy‐specific GM changes and dysregulation in SCFAs production. Future studies will assess the therapeutic potential of beneficial SCFAs supplementation for the treatment of PE in this model.Support or Funding InformationR01HL134711 ( J. M. Sasser) & funds to UMMC Molecular and Genomics Facility