Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension
Creators: name: Wimmer, Moritz I.
name: Bartolomaeus, Hendrik
name: Anandakumar, Harithaa
name: Chen, Chia-Yu
name: Vecera, Valentin
name: Kedziora, Sarah
name: Kamboj, Sakshi
name: Schumacher, Fabian
name: Pals, Sidney
name: Rauch, Ariana
name: Meisel, Jutta
name: Potapenko, Olena
name: Yarritu, Alex
name: Bartolomaeus, Theda U. P.
name: Samaan, Mariam
name: Thiele, Arne
name: Stürzbecher, Lucas
name: Geisberger, Sabrina Y.
name: Kleuser, Burkhard
name: Oefner, Peter J.
name: Haase, Nadine
name: Löber, Ulrike
name: Gronwald, Wolfram
name: Forslund-Startceva, Sofia K.
name: Müller, Dominik N.
name: Wilck, Nicola
Publisher: name: Universität Regensburg
Year: 2024
Subjects: subject: cardiac remodeling; hypertension; inflammation; metformin; microbiome; short‐chain fatty acids
subject: 610 Medizin
subject: Animals
subject: Metformin/pharmacology
subject: Hypertension/drug therapy
subject: Male
subject: Gastrointestinal Microbiome/drug effects
subject: Blood Pressure/drug effects
subject: Ventricular Remodeling/drug effects
subject: Rats
subject: Rats, Transgenic
subject: Disease Models, Animal
subject: Hypoglycemic Agents/pharmacology
subject: Fatty Acids, Volatile/metabolism

description: Aims:
Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats.

Methods:
Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry.

Results:
Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure.

Conclusion:
Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators.