Investigating the Role of Gut Microbiota in Generalized Anxiety Disorder

Abstract

Anxiety disorders, including generalized anxiety disorder (GAD), are prevalent mental health conditions with a complex etiology. The gut microbiota and diet have emerged as important factors in modulating anxiety symptoms. This thesis aimed to investigate the relationship between gut microbiota composition and anxiety symptoms in the context of GAD. This involved an in silico analysis of a cohort of GAD patients and healthy controls, coupled with experiments using a microbiota-humanized mouse model. A comprehensive in silico analysis was conducted using basic statistics and machine learning techniques on the human cohort. The analysis explored the associations between anxiety symptoms and various factors, including demographics, dietary intake, gastrointestinal symptoms, inflammatory markers, stool metabolites, microbiota composition, and PICRUSt2 microbiota predicted function. GAD patients exhibited higher gut microbiota abundance of Bacteroides, which was positively associated to carbohydrate degradation pathways. Machine learning analysis identified abdominal pain as a key indicator for distinguishing GAD donors. Moreover, anxiety symptoms were negatively correlated with inulin intake in GAD patients, altogether suggesting an association between a carbohydrate degradation imbalance in the GAD microbiota, abdominal pain, and anxiety symptoms. To investigate further, germ-free mice were colonized with stool samples from healthy controls and GAD patients, and they were fed either a low or high-fiber (inulin) diet. Assessments included behavioral tests, microbiota analysis, colonic gene expression, and mucus degradation. Bacteroides abundance positively correlated with anxiety-like behavior, mucus degradation, and expression of colonic genes related to immune activation, pain, and intestinal permeability, further supporting the results observed in the donor cohort. Improvements in metabolic parameters were also observed in mice fed high-fiber diet. Furthermore, we found that inulin dosage played a crucial role in mediating the observed immune activation and anxiety-like behavior, with excessive inulin supplementation showing a detrimental effect. This study provides insights into the complex relationship between dietary fiber, gut microbiota composition, and anxiety symptoms in mice and humans. Further studies are needed to determine optimal dosages of inulin supplementation as a potential therapeutic approach for managing anxiety symptoms.