Heart Failure Disturbs Gut-Blood Barrier and Increases Plasma Trimethylamine, a Toxic Bacterial Metabolite.

Adrian Drapala,Mateusz Szudzik,Emilia Samborowska,Dawid Chabowski,Marcin Ufnal,Katarzyna Kraszewska,Kinga Jaworska,Izabella Mogilnicka

doi:10.3390/ijms21176161

Abstract

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine-N-oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut–blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut–blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology.

Highlights

Despite significant progress in diagnostics and treatments, mortality rates due to cardiovascular disease, such as heart failure, continue to increase [1]
No significant differences in the average body weight and tibia length between Wistar Kyoto rats (WKY) and spontaneously hypertensive heart failure rats (SHHF) were observed
This study reports for the first time that heart failure disturbs the gut–blood barrier and increases gut-to-blood penetration of TMA, a toxic gut bacteria metabolite

Summary

Introduction

Despite significant progress in diagnostics and treatments, mortality rates due to cardiovascular disease, such as heart failure, continue to increase [1]. While the pathogenesis of cardiovascular disease and its associated risk factors continues to puzzle researchers, accumulating evidence suggests that the gut microbiota plays an important role in human health and disease, including cardiovascular disease, and may contribute significantly to the onset and/or progression of cardiovascular disease [2]. A growing body of evidence suggests that some bacteria-produced compounds may be considered mediators and/or markers of cardiovascular disease [3]. We have recently reported that trimethylamine (TMA), a product of the metabolism by gut bacteria of l-carnitine and choline, exerts toxic effects on the cardiovascular system. We have found that ageing compromises the gut–blood barrier, causing an increase in the penetration of TMA from the gut into the circulation [6]

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