# Causal Relationships Between the Gut Microbiota, Inflammatory Cytokines, and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Analysis

## TL;DR

This study uses genetic data to explore whether gut bacteria and inflammation are causally linked to ALS and finds that inflammation does not mediate the relationship.

## Contribution

The study provides novel causal insights into the relationship between gut microbiota, inflammatory cytokines, and ALS using Mendelian randomization.

## Key findings

- There is one positive and three negative causal relationships between gut microbiota and ALS.
- Inflammatory cytokines show one positive and one negative association with ALS.
- Inflammatory cytokines do not mediate the causal pathway from gut microbiota to ALS.

## Abstract

The relationship between gut microbiota (GM) and amyotrophic lateral sclerosis (ALS) is well‐documented. However, the causal nature of this association and the potential mediating role of inflammatory cytokines (ICs) have yet to be elucidated.

We performed Mendelian randomization (MR) analyses utilizing data derived from genome‐wide association studies (GWAS) of GM, ICs, and ALS. Initially, we conducted bidirectional two‐sample MR analysis to determine the causal relationships between GM, ICs, and ALS. Subsequently, a two‐step MR mediation analysis was performed to investigate the role of ICs as mediators. The primary statistical approach was the inverse variance weighted (IVW) method.

Through MR analysis, we identified one positive causal relationship and three negative causal relationships between GM and ALS. There was one positive association and one negative association between ICs and ALS. In addition, ICs do not appear to mediate the pathway from GM to ALS.

This study established a causal relationship between GM, ICs, and ALS, suggesting that ICs do not function as mediators in the pathway from GM to ALS. These findings provide new perspectives on potential ALS prevention and treatment strategies.

Schematic representation of the study design and the two‐step Mendelian randomization analysis.