Exploring Causal Links Between Gut Microbiota and Geriatric Syndromes: A Two-Sample Mendelian Randomization Analysis

Abstract

Background: Both observational studies and clinical trials have demonstrated a link between the gut microbiota and the geriatric syndrome. Nevertheless, the exact nature of this relationship, particularly concerning causality, remains elusive. Mendelian randomization (MR) is a method of inference based on genetic variation to assess the causal relationship between an exposure and an outcome. In this study, we conducted a two-sample Mendelian randomization (TSMR) study to fully reveal the potential genetic causal effects of gut microbiota on geriatric syndromes. Methods: This study used data from genome wide association studies (GWAS) to investigate causal relationships between the gut microbiota and geriatric syndromes, including frailty, Parkinson's disease (PD), delirium, insomnia, and depression. The primary causal relationships were evaluated using the inverse-variance weighted method, MR Egger, simple mode, weighted mode and weighted median. To assess the robustness of the results, horizontal pleiotropy was examined through MR-Egger intercept and MR-presso methods. Heterogeneity was assessed using Cochran's Q test, and sensitivity was evaluated via the leave-one-out method. Results: We identified 41 probable causal relationships between gut microbiota and five geriatric syndrome-associated illnesses using the inverse-variance weighted method. Frailty showed five positive and two negative causal relationships, while PD revealed three positive and four negative causal connections. Delirium showed three positive and two negative causal relationships. Similarly, insomnia demonstrated nine positive and two negative causal connections, while depression presented nine positive and two negative causal relationships. Conclusions: Using the TSMR method and data from the public GWAS database and, we observed associations between specific microbiota groups and geriatric syndromes. These findings suggest a potential role of gut microbiota in the development of geriatric syndromes, providing valuable insights for further research into the causal relationship between gut microbiota and these syndromes.

Keywords: Geriatric syndrome; Gut microbiota; Mendelian randomization; SNPs.

Figure 1

Flowchart describing the Mendelian randomization investigation in this study. MR, Mendelian randomization; PD, Parkinson's Disease (A) and three assumptions of Mendelian randomization (B).

Figure 2

(A)Causal effects of the gut microbiome on frailty based on MR analyses. From inside to outside, the P values of IVW, MR Egger, SM, Wmode and WM represented, respectively. IVW, inverse variance weighted; SM, simple mode; Wmode weighted mode; WM, weighted median. (B)Forest plot showing Mendelian randomization results for causal effects of gut microbiota on frailty risk. CI: confidence interval; OR: odds ratio.

Figure 3

(A)Causal effects of the gut microbiome on Parkinson's disease (PD) based on MR analyses. From inside to outside, the P values of IVW, MR Egger, SM, Wmode and WM represented, respectively. IVW, inverse variance weighted; SM, simple mode; Wmode weighted mode; WM, weighted median. (B)Forest plot of Mendelian randomization results for causal effects of gut microbiota on PD risk.

Figure 4

(A) Causal effects of the gut microbiome on delirium based on MR analyses. From inside to outside, the P values of IVW, MR Egger, SM, Wmode and WM represented, respectively. IVW, inverse variance weighted; SM, simple mode; Wmode weighted mode; WM, weighted median. (B) Forest plot of Mendelian randomization results for causal effects of gut microbiota on delirium risk.

Figure 5

(A) Causal effects of the gut microbiome on insomnia based on MR analyses. From inside to outside, the P values of IVW, MR Egger, SM , Wmode and WM represented, respectively. IVW, inverse variance weighted; SM, simple mode; Wmode weighted mode; WM, weighted median. (B) Forest plot of Mendelian randomization results for causal effects of gut microbiota on insomnia risk.

Figure 6

(A) Causal effects of the gut microbiome on depression based on MR analyses. From inside to outside, the P values of IVW, MR Egger, SM, Wmode and WM represented, respectively. IVW, inverse variance weighted; SM, simple mode; Wmode weighted mode; WM, weighted median. (B) Forest plot of Mendelian randomization results for causal effects of gut microbiota on depression risk.