Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats
Iñaki Robles-Vera,
Néstor de la Visitación,
Manuel Sánchez,
Manuel Gómez-Guzmán,
Rosario Jiménez,
Javier Moleón,
Cristina González-Correa,
Miguel Romero,
Tao Yang,
Mohan K. Raizada,
Marta Toral,
Juan Duarte
Affiliations
Iñaki Robles-Vera
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Néstor de la Visitación
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Manuel Sánchez
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Manuel Gómez-Guzmán
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Rosario Jiménez
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Javier Moleón
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Cristina González-Correa
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Miguel Romero
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
Tao Yang
Microbiome Consortium and Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43537, USA
Mohan K. Raizada
Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32611, USA
Marta Toral
Ciber de Enfermedades Cardiovasculares (CIBERCV), 18011 Granada, Spain
Juan Duarte
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain
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.
