An Analysis of the Gut Microbiota and Related Metabolites following PCSK9 Inhibition in Statin-Treated Patients with Elevated Levels of Lipoprotein(a)

Jose A Caparrós-Martín; Patrice Maher; Natalie C Ward; Montserrat Saladié; Patricia Agudelo-Romero; Stephen M Stick; Dick C Chan; Gerald F Watts; Fergal O'Gara

doi:10.3390/microorganisms12010170

An Analysis of the Gut Microbiota and Related Metabolites following PCSK9 Inhibition in Statin-Treated Patients with Elevated Levels of Lipoprotein(a)

Microorganisms. 2024 Jan 15;12(1):170. doi: 10.3390/microorganisms12010170.

Authors

Jose A Caparrós-Martín^{1

2}, Patrice Maher², Natalie C Ward³, Montserrat Saladié², Patricia Agudelo-Romero^{1

4}, Stephen M Stick^{1

4

5}, Dick C Chan⁶, Gerald F Watts^{6

7}, Fergal O'Gara^{1

2

8}

Affiliations

¹ Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia.
² Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia.
³ Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, WA 6009, Australia.
⁴ The University of Western Australia, Perth, WA 6009, Australia.
⁵ Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA 6008, Australia.
⁶ Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia.
⁷ Cardiometabolic Service, Departments of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA 6000, Australia.
⁸ BIOMERIT Research Centre, School of Microbiology, University College Cork, T12 XF62 Cork, Ireland.

Abstract

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.

Keywords: LDL; PCSK9; alirocumab; atherosclerotic cardiovascular disease; bile acids; cholesterol; gut microbiota; short chain fatty acids; statins.

Grants and funding

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.