1. Gut Microbiota-Generated Phenylacetylglutamine and Heart Failure
Beth Lovano, Marco Witkowski, Ulf Landmesser, Stanley L Hazen, Joseph A DiDonato, Ilja Demuth, Maradumane L Mohan, Xinmin S Li, Kymberleigh A Romano, Laurie Castel, W H Wilson Tang, Arash Haghikia, Sathyamangla Venkata Naga Prasad, Christopher M Menge, Jennifer A Buffa, Elisabeth Steinhagen-Thiessen, Arjun Deb, Maximilian König, Fredrik Bäckhed, Lin Li, Ina Nemet, Yu Sun, David R Van Wagoner, Prasenjit Prasad Saha Circ Heart Fail . 2022 Dec 16;e009972. doi: 10.1161/CIRCHEARTFAILURE.122.009972.
Background:The gut microbiota-dependent metabolite phenylacetylgutamine (PAGln) is both associated with atherothrombotic heart disease in humans, and mechanistically linked to cardiovascular disease pathogenesis in animal models via modulation of adrenergic receptor signaling.Methods:Here we examined both clinical and mechanistic relationships between PAGln and heart failure (HF). First, we examined associations among plasma levels of PAGln and HF, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide in 2 independent clinical cohorts of subjects undergoing coronary angiography in tertiary referral centers (an initial discovery US Cohort, n=3256; and a validation European Cohort, n=829). Then, the impact of PAGln on cardiovascular phenotypes relevant to HF in cultured cardiomyoblasts, and in vivo were also examined.Results:Circulating PAGln levels were dose-dependently associated with HF presence and indices of severity (reduced ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide) independent of traditional risk factors and renal function in both cohorts. Beyond these clinical associations, mechanistic studies showed both PAGln and its murine counterpart, phenylacetylglycine, directly fostered HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction, and B-type natriuretic peptide gene expression in both cultured cardiomyoblasts and murine atrial tissue.Conclusions:The present study reveals the gut microbial metabolite PAGln is clinically and mechanistically linked to HF presence and severity. Modulating the gut microbiome, in general, and PAGln production, in particular, may represent a potential therapeutic target for modulating HF.Registration:URL: https://clinicaltrials.gov/; Unique identifier:NCT00590200and URL: https://drks.de/drks_web/; Unique identifier: DRKS00020915.
2. Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia
Nuria López-Oslé, Arantza Arza, Domingo González-Lamuño, Ana Vinuesa, Elena Aznal, Raquel López-Oceja, Ainara Cano, Leticia Ceberio, Fernando Andrade, Javier de Las Heras, Gorka de Frutos, María Unceta Suarez J Clin Med . 2021 Aug 19;10(16):3674. doi: 10.3390/jcm10163674.
Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for urinary PAG quantification in 35 participants with hyperphenylalaninemia (HPA) and 33 age- and sex-matched healthy controls. We have found that (a) PKU patients present higher urine PAG levels than healthy control subjects, and that (b) there is a significant correlation between urine PAG and circulating Phe levels in patients with HPA. In addition, we show a significant strong correlation between Phe levels from venous blood samples and from capillary finger-prick dried blood spot (DBS) samples collected at the same time in patients with HPA. Further research in order to assess the potential role of urine PAG as a non-invasive biomarker in PKU is warranted.
3. A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
Nilaksh Gupta, Masanori Funabashi, Tomas Cajka, Stanley L Hazen, Joseph A DiDonato, Maradumane L Mohan, Kymberleigh A Romano, W H Wilson Tang, Federico E Rey, Amanda E Ramer-Tait, Sathyamangla Venkata Naga Prasad, Weifei Zhu, Sarah M Skye, Lin Li, Oliver Fiehn, Ina Nemet, Michael A Fischbach, Yuping Wu, Prasenjit Prasad Saha Cell . 2020 Mar 5;180(5):862-877.e22. doi: 10.1016/j.cell.2020.02.016.
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
