Multi-Omics Analyses Reveal Relationships Between Gut Microbiota and Frailty

Abstract

Introduction: Observational studies suggest a strong association between gut microbiota and frailty, but the underlying mechanisms remain unclear. This study aimed to investigate potential causal links and biological pathways linking gut microbiota and frailty.

Methods: We utilized summary-level data of gut microbiota and frailty data from MiBioGen and a genome-wide association meta-analysis. A bidirectional, two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between gut microbiota and frailty. Additional genetic and genomic analyses were conducted to identify common biological pathways.

Results: We identified eight causal relationships between the gut microbiota composition and frailty. Inverse-variance weighting suggested that genetic liability for the class Betaproteobacteria and genera Allisonella, Bifidobacterium, Clostridium innocuum, and Eubacterium coprostanoligenes was associated with increased frailty risk. In contrast, the class Bacteroidia, genus Eubacterium ruminantium, and the order Bacteroidales were associated with decreased risk. Reverse MR analysis provided no evidence for a causal effect of frailty on gut microbiota composition. In addition, TET2 was identified as a key hub gene associated with frailty, potentially linking gut microbiota to immune dysregulation and aging-related inflammatory pathways.

Conclusions: Our findings provide genetic evidence that gut microbiota composition influences frailty risk and highlight TET2 as a potential mechanistic link via immune dysregulation. These results suggest that microbiota-targeted interventions may offer novel strategies for the prevention and management of frailty in older adults.

Keywords: Mendelian randomization; TET2; frailty; gut microbiota.

FIGURE 1

Study overview.

FIGURE 2

Circos plot for gut microbiota and frailty. The outer layer of the Circos plot shows the exposure of all gut microbiota and the inner layer of the Circos plot shows five layers, each representing one MR method. The colors represent p values.

FIGURE 3

MR analysis. Causal effects were estimated using primary analysis IVW. The forest plot displays potential causal relationships between gut microbiota and frailty. Data are presented as odds ratios (OR), with corresponding 95% confidence intervals (CI).

FIGURE 4

(A) MR scatter plots. Scatterplot of the potential effects of single‐nucleotide polymorphisms (SNPs) on gut microbiota (class Betaproteobacteria, genus Allisonella, genus Bifidobacterium, genus Clostridium innocuum group, genus Eubacterium coprostanoligenes group, class Bacteroidia, genus Eubacterium ruminantium group, and order Bacteroidales) versus frailty. The slope of each line represents the causal effect estimate using the corresponding MR analysis model, and the intercept can be interpreted as an estimate of the average horizontal pleiotropic effect across the genetic variants. (B) Leave‐one‐out plots for MR results. Leave‐one‐out plots for the causal effects of gut microbiota on frailty.

FIGURE 5

Post‐correction boxplots and principal component analysis (PCA) plots showing consistent biology‐driven clustering. (A) Post‐correction boxplots. (B) PCA results. (C, D) Volcano plot and heatmap showing differentially expressed genes (DEGs) using limma analysis.

FIGURE 6

Functional analysis of DEGs. (A) Results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. (B) In the protein–protein interaction network, the darker the color, the greater the number of neighboring nodes. (C) PPI network with 97 nodes and 133 edges. Edge colors in the STRING database's predicted PPIs indicate multiple kinds of evidence supporting the prediction.

FIGURE 7

Development of gut flora‐related scores in frail older patients. (A) The difference in the antibacterial function between frailty and robust samples. (B) The relationships between gut microbe‐related function scores and hub genes in frail older patients.