Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

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.

Changes in Gut Microbiota Induced by Doxycycline Influence in Vascular Function and Development of Hypertension in DOCA-Salt Rats

“…We observed that in DOCA-salt animals, the gut microbiota was characterized by a reduced evenness, with no significant changes in F/B ratio and a higher proportion of lactate-producing bacteria, which was accompanied with high levels in plasma lactate. This signature of gut microbiota is consistent with the previous data shown in mice and rats with DOCA-salt hypertension [ 7 , 40 , 41 ]. The manipulation of the gut microbiota with oral antibiotic DOX reduced richness and number of species; however, it did not alter the bacterial load.…”

“…DOX treatment decreased lactate-producing bacteria, which also may be correlated with the reduction of plasma lactate levels that could contribute to the beneficial effect to reduce the BP; it has already been detailed that plasma lactate level is linked to increased blood pressure [ 42 , 43 ]. In fact, the decrease in gut lactate-producing bacterial populations by the immunosuppressive drug moletil mycophenolate and consumption of a high-fiber diet with Bifidobacterium breve reduces plasma lactate and hence prevents the rise of blood pressure, attenuation of both renal and cardiac fibrosis and the improvement of endothelial function in DOCA-salt rats [ 7 , 40 , 41 ].…”

“…In DOCA-salt rats, a leaky intestinal barrier has been previously described [ 40 , 41 ], characterized by increased permeability, combined with altered tight junction proteins including an increase in plasma LPS levels. DOX has been shown to produce beneficial effects on the intestinal epithelium, as well as the inhibition of inflammation and immunomodulatory effects, in addition to its essential antibiotic effect [ 44 , 45 , 46 ].…”

Antihypertensives and Antibiotics: Impact on Intestinal Dysfunction and Hypertension

“…Increased intestinal permeability associated with reduced tight junctional protein expression has been reported in several rodent models of hypertension, including Ang II (angiotensin II)–induced, deoxycorticosterone acetate (DOCA)-salt and spontaneously hypertensive rat (SHR) models. 3,24,25 For example, in SHR, a genetic model of progressive hypertension from 4 weeks of age, lower tight junction protein expression in the gut and increased intestinal permeability, along with enhanced gut sympathetic activity, was observed in adult rats but also young SHR before the onset of hypertension. 3 Similarly, findings of impaired intestinal integrity and increased sympathetic innervation density was demonstrated in the Ang II–induced model of hypertension in adult male Sprague-Dawley rats.…”

The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

“…Sodium retention in hypertension is associated with the failure of signals to decrease renal sodium transport when sodium intake is greater than what is needed to maintain a normal sodium balance [ 10 , 11 , 12 ]. Normal sodium balance is achieved by proper interactions among several organs, including the kidney, brain, heart, liver, intestines, muscle, skin, and immune system [ 13 , 14 , 15 , 16 , 17 , 18 ]. One of the main factors that maintains a normal sodium balance is the renal-selective action of dopamine produced by the kidney [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”