Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites

Abstract

Introduction: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension. Methods: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry. Results: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline. Conclusion: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality

“…The large variability in clinical expression and outcomes of COVID-19 was associated with host factors such as old age, gender, comorbidities, ethnicity, and lower economic status [ 2 , 4 , 6 ]. Emerging studies suggest that host-genetic factors may also contribute to the difference in COVID-19 phenotypes [ [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] ].…”

“…Studies investigating the role of host genetic factors in COVID-19 pathogenesis are rapidly growing, revealing several gene susceptibility variants, although with different levels of evidence [ 7 , 8 , [10] , [11] , [12] , [13] , [14] , [15] ]. Two approaches have been used, including candidate gene [ 7 , 8 , 10 , 11 ] or genome-wide association [ 13 , 15 ].…”

“…Studies investigating the role of host genetic factors in COVID-19 pathogenesis are rapidly growing, revealing several gene susceptibility variants, although with different levels of evidence [ 7 , 8 , [10] , [11] , [12] , [13] , [14] , [15] ]. Two approaches have been used, including candidate gene [ 7 , 8 , 10 , 11 ] or genome-wide association [ 13 , 15 ]. Selected gene candidates included ACE-2 , TMPRSS2 , IFITM3, Toll-like receptor 3 ( TLR3 ), and interferon regulatory factor 7 ( IRF7 ) based on their role in SARS-CoV-2 tropism to the human cells, including binding, entry, and replication as well as host-immune response to the virus [ [7] , [8] , [9] , [10] , [11] , [12] ].…”

“…Two approaches have been used, including candidate gene [ 7 , 8 , 10 , 11 ] or genome-wide association [ 13 , 15 ]. Selected gene candidates included ACE-2 , TMPRSS2 , IFITM3, Toll-like receptor 3 ( TLR3 ), and interferon regulatory factor 7 ( IRF7 ) based on their role in SARS-CoV-2 tropism to the human cells, including binding, entry, and replication as well as host-immune response to the virus [ [7] , [8] , [9] , [10] , [11] , [12] ]. Several variants of ACE2 and TMPRSS2 genes were identified, but none was associated with COVID-19 severity [ 7 , 8 , 10 ].…”

“…Selected gene candidates included ACE-2 , TMPRSS2 , IFITM3, Toll-like receptor 3 ( TLR3 ), and interferon regulatory factor 7 ( IRF7 ) based on their role in SARS-CoV-2 tropism to the human cells, including binding, entry, and replication as well as host-immune response to the virus [ [7] , [8] , [9] , [10] , [11] , [12] ]. Several variants of ACE2 and TMPRSS2 genes were identified, but none was associated with COVID-19 severity [ 7 , 8 , 10 ]. In contrast, the variant G allele rs12252 of IFITM3 gene was recognized as a risk factor for COVID-19 hospital (but not ICU) admission in the Caucasian population, and for severity in Chinese patients [ 11 , 12 ].…”