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. 2024 Nov;240(11):e14226.
doi: 10.1111/apha.14226. Epub 2024 Sep 10.

Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension

Moritz I Wimmer  1   2   3   4 , Hendrik Bartolomaeus  1   2   3   4 , Harithaa Anandakumar  1   2   3   4 , Chia-Yu Chen  2   3   4   5 , Valentin Vecera  1   2   3   4 , Sarah Kedziora  2   3   4   5 , Sakshi Kamboj  6 , Fabian Schumacher  7 , Sidney Pals  2 , Ariana Rauch  1   2   3   4 , Jutta Meisel  2   3   5 , Olena Potapenko  1   2   3 , Alex Yarritu  1   2   3   4 , Theda U P Bartolomaeus  2   3   4   5 , Mariam Samaan  2   3   5 , Arne Thiele  1   2   3   4 , Lucas Stürzbecher  2   8   9 , Sabrina Y Geisberger  3   4 , Burkhard Kleuser  7 , Peter J Oefner  6 , Nadine Haase  2   3   4   5 , Ulrike Löber  2   3   4   5 , Wolfram Gronwald  6 , Sofia K Forslund-Startceva  2   3   4   5   10 , Dominik N Müller  2   3   4   5 , Nicola Wilck  1   2   3   4
Affiliations

Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension

Moritz I Wimmer et al. Acta Physiol (Oxf). 2024 Nov.

Abstract

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.

Keywords: cardiac remodeling; hypertension; inflammation; metformin; microbiome; short‐chain fatty acids.

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References

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