# The Association Between Irritable Bowel Syndrome and Generalized Anxiety Disorder and Influencing Factors: A Mediation Mendelian Randomization Study

## TL;DR

This study finds that irritable bowel syndrome (IBS) increases the risk of generalized anxiety disorder (GAD) and identifies gut microbes, metabolites, and immune factors that may play a role in this connection.

## Contribution

The study reveals IBS as a causal risk factor for GAD and identifies specific gut microbiota and metabolites that mediate this relationship.

## Key findings

- IBS increases the risk of GAD with an odds ratio of 1.328.
- IBS mediates the effects of immune cells, gut microbiota, and plasma metabolites on GAD.
- The protective effect of 'Bilophila' against GAD is reduced by 13.30% through IBS mediation.

## Abstract

Previous studies showed that irritable bowel syndrome (IBS) and generalized anxiety disorder (GAD) share a common pathogenic mechanism. However, research on links between immune cells, plasma metabolites, inflammatory factors, and gut microbiota and these diseases remains limited. This study aimed to probe causal relationships between these factors and IBS/GAD using Mendelian randomization (MR) analysis. Among factors associated with IBS, 25 gut microbial taxa, 103 plasma metabolites, 7 inflammatory factors, and 42 immune cell characteristics had causal relationships with IBS. Among factors associated with GAD, 35 gut microbial taxa, 72 plasma metabolites, 6 inflammatory factors, and 43 immune cell characteristics had causal links to GAD. IBS was appointed as a risk factor for GAD [odds ratio (OR) = 1.328; p < 0.001]. Mediation analysis showed that IBS acted as a mediator, modulating the effects of 1 immune cell, 1 gut microbiota, and 2 plasma metabolites on GAD. IBS attenuated the protective effects of “Bilophila” on GAD onset (13.30%). This study respectively revealed the potential causal roles of multiple factors in IBS and GAD, as well as the causal relationship between IBS and GAD. Additionally, the mediating role of IBS was unveiled, delivering fresh perspectives on the pathogenesis of IBS and GAD.

Based on Mendelian randomization analysis, this study established a significant causal effect of irritable bowel syndrome (IBS) on increasing generalized anxiety disorder (GAD) risk (odds ratio = 1.328; p < 0.001) and identified dozens of gut microbial taxa, plasma metabolites, inflammatory factors, and immune cell characteristics with potential causal relationships to either IBS or GAD. Critically, mediation analysis revealed IBS acts as an intermediary, attenuating protective effects—such as a 13.30% reduction for the gut genus ‘Bilophila’ against GAD—while also mediating effects of specific immune cells and metabolites, providing novel mechanistic insights into both conditions.