TY - JOUR
T1 - An Analysis of the Gut Microbiota and Related Metabolites following PCSK9 Inhibition in Statin-Treated Patients with Elevated Levels of Lipoprotein(a)
AU - Caparrós-Martín, Jose A.
AU - Maher, Patrice
AU - Ward, Natalie C.
AU - Saladié, Montserrat
AU - Agudelo-Romero, Patricia
AU - Stick, Stephen M.
AU - Chan, Dick C.
AU - Watts, Gerald F.
AU - O’Gara, Fergal
N1 - Funding Information:
This work was supported by resources from the Human Microbiome Programme at Curtin University. P.M. was supported by a Summer Scholarship from the Faculty of Health Sciences (Curtin University). The human cohort study was funded by Regeneron Pharmaceuticals Inc.
Funding Information:
G.F.W. has received honoraria for lectures, advisory boards or research grants from Amgen Inc., Arrowhead, AstraZeneca, Esperion, Kowa, Novartis, Regeneron, and Sanofi. The other authors declare no specific conflict of interest, financial or otherwise. The research funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2024 by the authors.
PY - 2024/1/15
Y1 - 2024/1/15
N2 - Background. Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development. We showed that statins modulate the gut microbiota including the production of microbial metabolites involved in the regulation of cholesterol metabolism such as short chain fatty acids (SCFAs) and bile acids (BAs). Whether this pleiotropic effect of statins is associated with their antimicrobial properties or it is secondary to the modulation of cholesterol metabolism in the host is unknown. In this observational study, we evaluated whether alirocumab, a PCSK9 inhibitor administered subcutaneously, alters the stool-associated microbiota and the profiles of SCFAs and BAs. Methods. We used stool and plasma collected from patients enrolled in a single-sequence study using alirocumab. Microbial DNA was extracted from stool, and the bacterial component of the gut microbiota profiled following an amplicon sequencing strategy targeting the V3-V4 region of the 16S rRNA gene. Bile acids and SCFAs were profiled and quantified in stool and plasma using mass spectrometry. Results. Treatment with alirocumab did not alter bacterial alpha (Shannon index, p = 0.74) or beta diversity (PERMANOVA, p = 0.89) in feces. Similarly, circulating levels of SCFAs (mean difference (95% confidence interval (CI)), 8.12 [−7.15–23.36] µM, p = 0.25) and BAs (mean difference (95% CI), 0.04 [−0.11–0.19] log10(nmol mg−1 feces), p = 0.56) were equivalent regardless of PCSK9 inhibition. Alirocumab therapy was associated with increased concentration of BAs in feces (mean difference (95% CI), 0.20 [0.05–0.34] log10(nmol mg−1 feces), p = 0.01). Conclusion. In statin-treated patients, the use of alirocumab to inhibit PCSK9 leads to elevated levels of fecal BAs without altering the bacterial population of the gut microbiota. The association of alirocumab with increased fecal BA concentration suggests an additional mechanism for the cholesterol-lowering effect of PCSK9 inhibition.
AB - Background. Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development. We showed that statins modulate the gut microbiota including the production of microbial metabolites involved in the regulation of cholesterol metabolism such as short chain fatty acids (SCFAs) and bile acids (BAs). Whether this pleiotropic effect of statins is associated with their antimicrobial properties or it is secondary to the modulation of cholesterol metabolism in the host is unknown. In this observational study, we evaluated whether alirocumab, a PCSK9 inhibitor administered subcutaneously, alters the stool-associated microbiota and the profiles of SCFAs and BAs. Methods. We used stool and plasma collected from patients enrolled in a single-sequence study using alirocumab. Microbial DNA was extracted from stool, and the bacterial component of the gut microbiota profiled following an amplicon sequencing strategy targeting the V3-V4 region of the 16S rRNA gene. Bile acids and SCFAs were profiled and quantified in stool and plasma using mass spectrometry. Results. Treatment with alirocumab did not alter bacterial alpha (Shannon index, p = 0.74) or beta diversity (PERMANOVA, p = 0.89) in feces. Similarly, circulating levels of SCFAs (mean difference (95% confidence interval (CI)), 8.12 [−7.15–23.36] µM, p = 0.25) and BAs (mean difference (95% CI), 0.04 [−0.11–0.19] log10(nmol mg−1 feces), p = 0.56) were equivalent regardless of PCSK9 inhibition. Alirocumab therapy was associated with increased concentration of BAs in feces (mean difference (95% CI), 0.20 [0.05–0.34] log10(nmol mg−1 feces), p = 0.01). Conclusion. In statin-treated patients, the use of alirocumab to inhibit PCSK9 leads to elevated levels of fecal BAs without altering the bacterial population of the gut microbiota. The association of alirocumab with increased fecal BA concentration suggests an additional mechanism for the cholesterol-lowering effect of PCSK9 inhibition.
KW - alirocumab
KW - atherosclerotic cardiovascular disease
KW - bile acids
KW - cholesterol
KW - gut microbiota
KW - LDL
KW - PCSK9
KW - short chain fatty acids
KW - statins
UR - http://www.scopus.com/inward/record.url?scp=85183418256&partnerID=8YFLogxK
U2 - 10.3390/microorganisms12010170
DO - 10.3390/microorganisms12010170
M3 - Article
C2 - 38257996
AN - SCOPUS:85183418256
SN - 2076-2607
VL - 12
JO - Microorganisms
JF - Microorganisms
IS - 1
M1 - 170
ER -
