Abstract
Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.
Highlights
Systemic arterial hypertension is a complex, multifactorial and multisystem disorder influenced by genetic and environmental factors, and the most important modifiable risk factor that contributes signifi cantly to worldwide cardiovascular morbidity and mortality
The percentage of bacteria from the phylum Fir micutes was significantly higher in spontaneously hypertensive rats (SHR) than in Wistar Kyoto rats (WKY), while the proportions of Actinobacteria and Bacteroidetes were decreased in SHR when comparing to other groups
We found an increase in the expression of tyrosine hydroxylase (TH), a crucial enzyme for the generation of noradrenaline, in the gut from SHR compared to WKY group, which was abolished by chronic Mycophenolate mofetil (MMF) treatment (Fig. 6D)
Summary
Systemic arterial hypertension is a complex, multifactorial and multisystem disorder influenced by genetic and environmental factors, and the most important modifiable risk factor that contributes signifi cantly to worldwide cardiovascular morbidity and mortality. An imbalance in the gut microbiota composition relative to Abbreviations: BP, blood pressure; CM-H2DCFDA, 5-(and-6-)chloromethyl-2′-7′-dichlorodihydrofluorescein diacetate; DAPI, 4,6-diamidino-2-phenylindole dichlorohydrate; DHE, dihydroethidium; DNA, deoxyribonucleic acid; DOCA-salt, deoxycorticosterone acetate; F/B, Firmicutes/Bacteroidetes; FoxP3, forkhead box P3; GOLD, Genomes OnLine Database; IL, interleukin; KEGG, Kyoto Encyclopedia of Genes and Genomes pathways; L-NAME, NG-nitro-L-arginine methyl ester; LEfSe, Linear discriminant analysis effect size; LDA, Linear discriminant analysis; LPS, lipopolysaccharide; MLN, mesenteric lymph nodes; MMF, mofetil mycophenolate; MPA, mycophenolic acid; MUC, mucin; NO, nitric oxide; OTU, operational taxonomic unit; PCA, principal component analysis; PICRUSt, phylogenetic investigation of communities by reconstruction of unobserved states; PVN, paraventricular nucleus; RDP, Ribosome Database Project; RORγ, retinoid-related orphan receptor-γ; ROS, reactive oxygen species; SBP, systolic blood pressure; SCFAs, short chain fatty acids; SHR, spontaneously hypertensive rats; Th, T helper; TH, tyrosine hy droxylase; TNF-α, tumor necrosis factor-alpha; Tregs, regulatory T cells; WKY, Wistar Kyoto rats; ZO-1, zonula occludens-1
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