Indole-3-propionic Acid, a Gut Microbiota-Derived Tryptophan Metabolite, Promotes Endothelial Dysfunction …, 2024, Geddo et al.

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SNT Gatchaman

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Indole-3-propionic Acid, a Gut Microbiota-Derived Tryptophan Metabolite, Promotes Endothelial Dysfunction Impairing Purinergic-Induced Nitric Oxide Release in Endothelial Cells
Geddo, Federica; Antoniotti, Susanna; Gallo, Maria Pia; Querio, Giulia

Different gut microbiota-derived metabolites influence cardiovascular function, and, among all, the role of indole-3-propionic acid (IPA), from tryptophan metabolism, shows controversial effects. The aim of this study was to evaluate its role in endothelial dysfunction.

IPA effects were studied on bovine aortic endothelial cells (BAE-1). First, IPA cytotoxicity was evaluated by an MTS assay. Then, the levels of intracellular reactive oxygen species (ROS) were evaluated by a microplate reader or fluorescence microscopy with the CellROX® Green probe, and nitric oxide (NO) production was studied by fluorescence microscopy with the DAR4M-AM probe after acute or chronic treatment.

Finally, immunoblotting analysis for endothelial nitric oxide synthase (eNOS) phosphorylation (p-eNOS) was performed. In BAE-1, IPA was not cytotoxic, except for the highest concentration (5 mM) after 48 h of treatment, and it showed neither oxidant nor antioxidant activity. However, the physiological concentration of IPA (1 μM) significantly reduced NO released by adenosine triphosphate (ATP)-stimulated BAE-1. These last data were confirmed by Western blot analysis, where IPA induced a significant reduction in p-eNOS in purinergic-stimulated BAE-1.

Given these data, we can speculate that IPA negatively affects the physiological control of vascular tone by impairing the endothelial NO release induced by purinergic stimulation. These results represent a starting point for understanding the mechanisms underlying the relationship between gut microbiota metabolites and cardiometabolic health.

Link | PDF (International Journal of Molecular Sciences) [Open Access]
 
Trp is an essential amino acid for animal cells, so, to supply cellular needs, it has to be introduced through exogenous sources, such as diet. Part of the introduced Trp can be metabolized by entering one of the major pathways, namely serotonin, kynurenine, and indole pathways. IPA is synthesized from the indoles pathway, primarily by gut bacteria from Clostridiaceae and Peptostreptococcaceae families, and it has been highlighted as a ligand for the nuclear receptors aryl hydrocarbon receptor (AhR) and pregnane-X receptor (PXR), thus affecting protein expression. Like other secondary metabolites from the gut microbiota, IPA figures as a possible candidate able to influence CVD development. The lack of consistent works pointing out its role in vascular health moved our interest to clarify if IPA could be considered a marker of endothelial dysfunction.
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One of the main physiological triggers of endothelial nitric oxide release is the purinergic pathway, with ATP among the most relevant modulators. After ATP binds the P2Y2 receptor on endothelial cells, a subsequent intracellular Ca 2+ increase mediates the activation of eNOS through its phosphorylation at Ser1179 and the release of NO, directly involved in vascular smooth muscle cell relaxation.
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the present paper shows for the first time the possible role of acute IPA exposure in the inhibition of ATP-stimulated eNOS phosphorylation at Ser1179, highlighting a potential negative impact of the molecule on the physiological control of vascular tone.
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