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 investigation of 4,033 potential causal relationships between 37 traits representing gut microbiome composition and function and 109 age-related phenotypes, using two-samples Mendelian randomization. Five causal relationships remained significant after multiple testing correction and sensitivity analyses, specifically between two taxa of Coriobacteriales and the risk of developing age-related macular degeneration, species Bifidobacterium adolescentis and levels of TNFSF12 protein in plasma, and the lactose-galactose degradation microbial I pathway and levels of IL-15Rα and TRAIL proteins in plasma. The causal relationship between the lactose-galactose degradation I pathway and TRAIL protein levels was further confirmed using independent data. These results support the role of gut microbiome in regulating the inflammatory circuit, albeit future studies are needed to investigate the underlying biological mechanisms.

The authors have declared no competing interest.

This study was supported by project DSB AD006.371 "InvAt" FOE 2022 and project DBA.AD005.225 "NutrAGE" FOE 2021. In addition, we acknowledge Marie-Curie Fellowship to D.Z., acronym "Sex Dimorphism" (GA n. 101066678) that indirectly made this study possible.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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No data was generated for this study. We used public data, download links are available in Supplementary Table 1. The scripts used for all the analyses are publicly available in the GitHub repository: https://github.com/Sanna-s-LAB/Mendelian-randomization-Project.git

https://github.com/Sanna-s-LAB/Mendelian-randomization-Project.git