Abstract
Microbiota is involved in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzed whether MMF improves dysbiosis in mineralocorticoid-induced hypertension. Male Wistar rats were assigned to three groups: untreated (CTR), deoxycorticosterone acetate (DOCA)-salt, and DOCA treated with MMF for 4 weeks. MMF treatment reduced systolic BP, improved endothelial dysfunction, and reduced oxidative stress and inflammation in aorta. A clear separation in the gut bacterial community between CTR and DOCA groups was found, whereas the cluster belonging to DOCA-MMF group was found to be intermixed. No changes were found at the phylum level among all experimental groups. MMF restored the elevation in lactate-producing bacteria found in DOCA-salt joined to an increase in the acetate-producing bacteria. MMF restored the percentage of anaerobic bacteria in the DOCA-salt group to values similar to control rats. 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. This study demonstrates for the first time that MMF reduces gut dysbiosis in DOCA-salt hypertension models. This effect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation.
Highlights
Systemic arterial hypertension is a complex, multifactorial, and multisystem disorder influenced by genetic and environmental factors, and is the most important modifiable risk factor that contributes significantly to worldwide cardiovascular morbidity and mortality
The characteristics of dysbiosis are different between systemic renin–angiotensin system (RAS)-dependent hypertension, such as in spontaneous hypertensive rats (SHR) [1,3,5,6,7], and systemic RAS-independent forms, such as hypertension induced by mineralocorticoid receptor activation [8,9]
We found that mRNA levels of C-C chemokine ligand 2 (CCL2) and macrophage marker CD11b were increased in brain paraventricular nucleus (PVN) from hypertensive rats, which were normalized by Mycophenolate mofetil (MMF) (Figure 7A)
Summary
Systemic arterial hypertension is a complex, multifactorial, and multisystem disorder influenced by genetic and environmental factors, and is the most important modifiable risk factor that contributes significantly to worldwide cardiovascular morbidity and mortality. The improvement of gut dysbiosis induced by probiotic bacteria [7,9,14], dietary fiber [8], or by drug treatment [6,15], in several experimental models of hypertension, was involved in their antihypertensive effects. Raizada’s group has linked hypothalamic neuroinflammation and increased sympathetic drive with changes in gut physiology and microbiota associated with angiotensin II-induced hypertension [16]. This suggests a role for a dysfunctional autonomic nervous system in gut dysbiosis
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