Effects of fenbendazole on fecal microbiome in BPH/5 mice, a model of hypertension and obesity, a brief report

Abstract

Fenbendazole (FBZ) is a common antiparasitic treatment used in research rodent colonies for biosecurity purposes. The effect of this compound has been studied in C57 mice, but never before in a strain of mice that has co-morbidities, such as the blood pressure high (BPH)/5. The BPH/5 mouse is an inbred genetic model of hypertension. While both male and female BPH/5 have high blood pressure, there is a metabolic sexual dimorphism with females displaying key features of obesity. The obese gut microbiome has been linked to hypertension. Therefore, we hypothesized that fenbendazole treatment will alter the gut microbiome in hypertensive mice in a sex dependent manner. To test the influence of FBZ on the BPH/5 gut microbiota, fecal samples were collected pre- and post-treatment from adult BPH/5 mice (males and non-pregnant females). The mice were treated with fenbendazole impregnated feed for five weeks. Post-treatment feces were collected at the end of the treatment period and DNA was extracted, and the V4 region of 16S rRNA was amplified and sequenced using the Illumina MiSeq system. The purpose was to analyze the fecal microbiome before and after FBZ treatment, the results demonstrate changes with treatment in a sex dependent manner. More specifically, differences in community composition were detected in BPH/5 non-pregnant female and males using Bray-Curtis dissimilarity as a measure of beta-diversity (treatment p = 0.002). The ratio of Firmicutes to Bacteroidetes, which has been identified in cases of obesity, was not altered. Yet, Verrucomicrobia was increased in BPH/5 males and females post-treatment and was significantly different by sex (treatment p = 5.85e-05, sex p = 0.0151, and interaction p = 0.045), while Actinobacteria was decreased in the post-treatment mice (treatment p = 0.00017, sex p = 0.5, interaction p = 0.2). These results are indicative of gut dysbiosis compared to pre-treatment controls. Lactobacillus was decreased with FBZ treatment in BPH/5 females only. In conclusion, fenbendazole does alter the gut microbial communities, most notable in the male rather than female BPH/5 mouse. This provides evidence that caution should be taken when providing any gut altering treatments before or during mouse experiments.

Reversal of maternal obesity attenuates hypoxia and improves placental development in the preeclamptic-like BPH/5 mouse model

“…Restricting the diet of the mice has the potential to place them in a negative energy balance which can allow for the development of adverse fetal outcomes including decreased nephron numbers, hypertension, proteinuria, or renal dysfunction after birth ( Luyckx, 2020 ). While excessive dietary restriction can be harmful, the method of food restriction utilized, pair feeding, which is matched to lean, gestation-matched control mice, acts to normalize obese BPH/5 mice weight and adiposity, and serum leptin by e7.5 ( Reijnders et al, 2019 ), and has demonstrated improvement in fetal and maternal outcomes ( Beckers et al, 2023 ). Pair-feeding BPH/5 showed a similar reduction in serum leptin by e7.5 (83%) as by e18.5 (95%).…”

“…Previous studies have shown inadequate spiral artery formation and smaller placental vessel area in BPH/5 placenta compared to C57 mice (Dokras et al, 2006). Furthermore, maternal weight loss and reduced leptin have been associated with prevention of FGR in this model (Beckers et al, 2023). To better understand the impact of hypoxia and pair-feeding on fetoplacental development, the placental vessel area in ad lib and pair-fed BPH/5 e18.5 placenta were assessed.…”

“…This was tested in vivo , which demonstrated that hyperleptinemic BPH/5 pregnant mice that are pair-fed have lower leptin along with reduced visceral adipose tissue ( Reijnders et al, 2019 ). Furthermore, maternal weight loss and lower circulating leptin has been shown to be associated with attenuation of late-gestational hypertension and FGR ( Beckers et al, 2023 ). However, the precise mechanism is under investigation.…”