Research Paper Advance Articles
Causal relationships between gut microbiome and hundreds of age-related traits: evidence of a replicable effect on ApoM protein levels
- 1 Institute for Genetic and Biomedical Research (IRGB) of the National Research Council (CNR), Monserrato (CA), Italy
Received: February 24, 2025 Accepted: July 22, 2025 Published: August 1, 2025
https://doi.org/10.18632/aging.206293How to Cite
Copyright: © 2025 Grosso et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive two-sample Mendelian Randomization investigation, testing 55130 potential causal relationships between 37 traits representing gut microbiome composition and function and age-related phenotypes, including 1472 inflammatory and cardiometabolic circulating plasma proteins from UK Biobank Pharma Proteomic Project and 18 complex traits. A total of 91 causal relationships remained significant after multiple testing correction (false discovery rate p-value <0.05) and sensitivity analyses, notably two with the risk of developing age-related macular degeneration and 89 with plasma proteins. The link between purine nucleotides degradation II aerobic pathway and apolipoprotein M was further replicated using independent genome-wide association study data. Finally, by taking advantage of previously reported biological function of Faecalibacterium prausnitzii we found evidence of regulation of six proteins by its function as mucosal-A antigen utilization. These results support the role of gut microbiome as modulator of the inflammatory and cardiometabolic circuits, that may contribute to the onset of age-related diseases, albeit future studies are needed to investigate the underlying biological mechanisms.
Abbreviations
AMD: Age-related macular degeneration; BH: Benjamini-Hochberg; C7: Complement component C7; CD3G: T-cell surface glycoprotein CD3 gamma chain; SV: Structural Variant; FDR: False Discovery Rate; GalNAc: N-acetylgalactosamine; GV: Genetic variant; GWAS: Genome-wide association study; HDL: high-density lipoproteins; IV: Instrumental variable; IVW: Inverse Variance Weighted; LD: Linkage disequilibrium; MAF: Minor allele frequency; MR: Mendelian Randomization; MR-PRESSO: MR-Pleiotropy Residual Sum and Outlier; QC: Quality control; SERPINA3: Alpha-1-antichymotrypsin; SFTPD: Pulmonary surfactant-associated protein D; SIGLEC8: Sialic acid-binding Ig-like lectin 8; SNP: Single-nucleotide polymorphism; STROBE: Strengthening the reporting of observational studies in epidemiology; TREM2: Triggering receptor expressed on myeloid cells 2; UKB-PPP: UK Biobank Pharma Proteomic Project; WM: Weighted Median.