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

Author

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, and Juan Duarte

Subjects
mycophenolate, gut dysbiosis, hypertension, oxidative stress, inflammation, (deoxycorticosterone acetate) DOCA-salt model, Therapeutics. Pharmacology, RM1-950
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.

Published
2020
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2. Changes in Gut Microbiota Induced by Doxycycline Influence in Vascular Function and Development of Hypertension in DOCA-Salt Rats

Author

Juan Duarte, Iñaki Robles-Vera, Manuel Gómez-Guzmán, Félix Vargas, Néstor de la Visitación, Rosario Jiménez, Miguel Romero, Marta Toral, and Manuel Sánchez

Subjects
Male, hypertension, Inflammation, (Deoxycorticosterone acetate) DOCA-salt model, Gut flora, Pharmacology, medicine.disease_cause, Article, Desoxycorticosterone Acetate, Gut dysbiosis, gut dysbiosis, medicine.artery, DOCA-salt model, medicine, polycyclic compounds, Animals, oxidative stress, TX341-641, Rats, Wistar, Endothelial dysfunction, Doxycycline, Aorta, Nutrition and Dietetics, biology, doxycycline, Nutrition. Foods and food supply, business.industry, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, Gastrointestinal Microbiome, Rats, Vasodilation, Disease Models, Animal, Blood pressure, Oxidative stress, inflammation, Hypertension, Endothelium, Vascular, medicine.symptom, business, Dysbiosis, Food Science, medicine.drug
Abstract

Previous experiments in animals and humans show that shifts in microbiota and its metabolites are linked to hypertension. The present study investigates whether doxycycline (DOX, a broad-spectrum tetracycline antibiotic) improves dysbiosis, prevent cardiovascular pathology and attenuate hypertension in deoxycorticosterone acetate (DOCA)-salt rats, a renin-independent model of hypertension. Male Wistar rats were randomly assigned to three groups: control, DOCA-salt hypertensive rats, DOCA-salt treated with DOX for 4 weeks. DOX decreased systolic blood pressure, improving endothelial dysfunction and reducing aortic oxidative stress and inflammation. DOX decreased lactate-producing bacterial population and plasma lactate levels, improved gut barrier integrity, normalized endotoxemia, plasma noradrenaline levels and restored the Treg content in aorta. These data demonstrate that DOX through direct effects on gut microbiota and its non-microbial effects (anti-inflammatory and immunomodulatory) reduces endothelial dysfunction and the increase in blood pressure in this low-renin form of hypertension., Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Ministerio de Ciencia e Innovación (PID2020-116347RB-I00), Junta de Andalucía (CTS-164, P20_00193), European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV; Ciberes), Instituto de Salud Carlos III (Sara Borrell Program), European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”)

Published
2021
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3. Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

Author

Mohan K. Raizada, Juan Duarte, Manuel Sánchez, Manuel Gómez-Guzmán, Marta Toral, Cristina González-Correa, Tao Yang, Javier Moleón, Iñaki Robles-Vera, Rosario Jiménez, Néstor de la Visitación, Miguel Romero, Ministerio de Economía y Competitividad (España), Junta de Andalucía, European Union, Instituto de Salud Carlos III - ISCIII, National Heart, Lung, and Blood Institute (United States), European Regional Development Fund (ERDF/FEDER), [Robles-Vera,I, de la Visitación,N, Sánchez,M, Gómez-Guzmán,M, Jiménez,R, Moleón,J, González-Correa,C, Romero,M, Duarte,J] Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain. [Sánchez,M, Gómez-Guzmán,M, Jiménez,R, Duarte,J] Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA,Granada, Spain. [Jiménez,R, Toral,M, Duarte,J] Ciber de Enfermedades Cardiovasculares (CIBERCV), Granada, Spain. [Yang,T] 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, USA. [Raizada,MK] Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA. [Toral,M] Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., This work was supported by Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164), with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain, and National Heart, Lung and Blood Institute (NHLBI) grant HL102033. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, 'FEDER una manera de hacer Europa')., Regional Government of Andalusia (España), Unión Europea, Instituto de Salud Carlos III, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)

Subjects
0301 basic medicine, Physiology, Clinical Biochemistry, mycophenolate, gut dysbiosis, hypertension, oxidative stress, inflammation, (deoxycorticosterone acetate) DOCA-salt model, (Deoxycorticosterone acetate) DOCA-salt model, 030204 cardiovascular system & hematology, Gut flora, medicine.disease_cause, Biochemistry, Anatomy::Cardiovascular System::Blood Vessels::Arteries::Aorta [Medical Subject Headings], Gut dysbiosis, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], oxidative stress, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Wistar [Medical Subject Headings], Endothelial dysfunction, mycophenolate, biology, Microbiota, Estrés oxidativo, Organisms::Bacteria::Bacteria, Anaerobic [Medical Subject Headings], Phenomena and Processes::Microbiological Phenomena::Microbiota [Medical Subject Headings], Hypertension, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Dysbiosis [Medical Subject Headings], Anaerobic bacteria, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, hypertension, Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Acetates [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Inflammation, Acetato de desoxicorticosterona, Article, Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Physiological Processes::Stress, Physiological::Oxidative Stress [Medical Subject Headings], 03 medical and health sciences, gut dysbiosis, Internal medicine, Hipertensión, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Hemodynamics::Blood Pressure [Medical Subject Headings], medicine, Mycophenolate, Molecular Biology, Neuroinflammation, Inflamación, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Mineralocorticoids [Medical Subject Headings], business.industry, lcsh:RM1-950, (deoxycorticosterone acetate) DOCA-salt model, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Hydroxy Acids::Lactates::Lactic Acid [Medical Subject Headings], Cell Biology, Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], medicine.disease, biology.organism_classification, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Endocrinology, Blood pressure, inflammation, Oxidative stress, business, Dysbiosis
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. MaleWistar 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 andDOCAgroups was found, whereas the cluster belonging toDOCA-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 e ect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation., Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad SAF2017-84894-R, Junta de Andalucía CTS-164, European Union (EU), Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) HL102033, European Union (Fondo Europeo de Desarrollo Regional, FEDER, "FEDER una manera de hacer Europa")

Published
2020
Full Text
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4. Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats.

Author

Robles-Vera, Iñaki, de la Visitación, Néstor, Sánchez, Manuel, Gómez-Guzmán, Manuel, Jiménez, Rosario, Moleón, Javier, González-Correa, Cristina, Romero, Miguel, Yang, Tao, Raizada, Mohan K., Toral, Marta, and Duarte, Juan

Subjects
GUT microbiome, MYCOPHENOLIC acid, ENDOTHELIUM diseases, HYPERTENSION, ANAEROBIC bacteria
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. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
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