Causal relationship between gut microbiota and ageing: A multi-omics Mendelian randomization study.

Introduction: Observational studies and clinical trials have suggested a connection between gut microbiota and aging. However, the causal relationship between them remains undetermined.

Objectives: This study aimed to use bidirectional two-sample Mendelian randomization (TSMR) analysis to explore the causal relationship between gut microbiota and aging.

Methods: Summary statistics from genome-wide association studies (GWAS) on gut microbiota and seven aging-related phenotypes were employed for TSMR analysis. Reverse Mendelian randomization (MR) analysis was performed to assess the potential for reverse causality. Additionally, the relationship between Akkermansia muciniphila and inflammation-related proteins and metabolites was further investigated. The effects of Akkermansia muciniphila on aging were also examined in Caenorhabditis elegans by measuring both lifespan and healthspan.

Results: MR analysis of 207 microbial taxa and seven aging phenotypes revealed 44 causal relationships between the gut microbiota and aging. Akkermansia muciniphila was found to be causally linked to several aging-related traits, including mvAge, appendicular lean mass, and grip strength (P < 0.05). Reverse MR analysis identified 23 causal relationships, but no bidirectional causality was observed. Moreover, Akkermansia muciniphila is causally related to ST1A1, taurine bile acid, and mannose (P < 0.05). In Caenorhabditis elegans, treatment with Akkermansia muciniphila significantly extended lifespan (P < 0.05) and improved mobility in aging nematodes.

Conclusion: TSMR analysis uncovers multiple potential causal links between gut microbiota and aging, particularly Akkermansia muciniphila. Experimental results support its role in alleviating aging. This study provides a strong foundation for future research on gut microbiota's role in aging.