New insights on the association between genes, gut microbiota, and mental health

Study links gut microbiome diversity and genetic variants in inflammatory bowel disease patients to increased risk of mental health disorders, revealing potential biomarkers and therapeutic targets.

In a cohort study published in npj Genomic Medicine, researchers investigated the potential relationship between inflammatory bowel disease (IBD) and comorbid mental disorders (CMDs).

They found that patients with IBD and CMDs showed lower microbiome diversity and specific microbial patterns linked to IBD. They suggested that genetic variants may influence gut bacteria associated with both IBD and CMD.

Background

IBD, including ulcerative colitis (UC) and Crohn’s disease (CD), involves chronic inflammation of the gut, significantly impacting quality of life. Risk factors for IBD include genetic variants, immune cytokines, gut dysbiosis, and environmental triggers.

Patients with IBD have notably higher rates of CMDs, such as anxiety and depression, compared to the general population, with disease activity worsening these conditions.

Research shows CMDs and IBD may share molecular pathways, suggesting a gut-brain axis link. Microbiome studies reveal unique bacterial profiles in IBD patients with CMDs, and recent findings suggest gut dysbiosis might drive this relationship.

Moreover, genetic studies show a weak but significant correlation between IBD and CMDs, with some shared genetic variants in stress-regulating genes influencing both gut and brain function.

In the present study, researchers quantified gut microbial diversity, abundance, microbial quantitative trait loci (mbQTL), and polygenic risk scores (PRS) to examine how genetic variants and gut microbiota interact to increase the risk of CMD in inflammatory bowel disease IBD patients.

About the study

The present study enrolled 507 patients with IBD (UC = 290; CD = 217) and 75 healthy controls above 17 years of age between 2018 and 2022 from a hospital in Korea. Genetic and fecal microbiome data were obtained, and psychometric scores, namely Hospital Anxiety and Depression Scale (HADS), were used to explore connections between IBD, CMDs, and gut dysbiosis.

Stool samples were analyzed with 16S ribosomal ribonucleic acid (rRNA) sequencing to assess microbial diversity and abundance, adjusting for demographic and lifestyle factors. MRS was calculated for each participant to estimate IBD-related microbial burden associated with CMD.

Genetic data, processed via genotyping and whole-genome imputation, was used to estimate PRS for IBD, depression, and anxiety, along with mbQTL analysis to identify genetic influences on microbiota associated with both IBD and CMD.

Results and discussion

Among IBD patients, 12.9% had significant anxiety or depression. Differences in non-psychological characteristics were minimal between CMD-affected and CMD-free patients with IBD.

Significantly lower microbial diversity (Shannon index) was observed in IBD patients, especially in those with CMD. CMD-affected IBD patients showed reduced alpha diversity and significant dissimilarities in beta diversity compared to controls and CMD-free IBD patients.

Researchers also identified 21 taxa differing between CMD-affected and CMD-free IBD patients. Higher MRS correlated with an increased CMD risk (P = 7.33 ×10−3) and an odds ratio of 5.0 in high-MRS patients.

Additionally, significant gut microbiome dissimilarity was observed between IBD patients and healthy controls, with trends suggesting CMD risk in a subset of the IBD-associated microbiota. Overall, 106 taxa were identified with significant differential abundance in IBD, offering potential biomarkers and therapeutic targets for IBD and CMD management.

IBD-risk variants did not appear to influence CMD susceptibility in this cohort significantly. Furthermore, patients with CMD did not exhibit higher PRSs for anxiety or depression compared to those without CMD, suggesting a weak genetic effect of mental disorder-risk variants on CMD development in IBD patients.

A significant association was found between the T allele of rs35866622 in the FUT2-FUT1 (short for fucosyltransferase) locus and the reduced abundance of the genus Ruminococcus. The identified variant is linked to the IBD risk, particularly affecting the FUT2 gene, which plays a role in the secretion of H antigens in the gut mucosa.

The presence of nonfunctional FUT2 alleles significantly impacts the abundance of several taxa associated with IBD dysbiosis. Thus, the findings suggest that the IBD-risk allele at the FUT2-FUT1 locus may lower Ruminococcus abundance, potentially increasing susceptibility to both IBD and CMD while highlighting the distinct etiology of CMD in IBD patients compared to the general population.

The study is strengthened by its simultaneous analysis of gut microbiome and genome-wide SNP data within a single cohort. It enables robust, case-control and case-only comparisons that reduce confounding factors like genetic background, diet, and disease activity.

However, the study is limited by a small CMD sample, reliance on stool samples alone, relative abundance analysis, and missing HADS data for controls.

Conclusion

In conclusion, the study showed that gut microbiota and genetic variants linked to IBD are associated with CMDs in IBD patients.

The findings highlight gut bacteria and genetic markers as potential biomarkers and therapeutic targets for mental disorders, offering insights into CMD mechanisms in IBD.

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