Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic gastrointestinal inflammation significantly impacting quality of life. While its etiology remains unclear, risk factors include genetic variants, immunological cytokines, gut dysbiosis, and environmental factors. Epidemiological studies consistently demonstrate a higher prevalence of comorbid mental disorders (CMDs), such as anxiety and depression, in IBD patients compared to the general population. This elevated prevalence is observed even in patients with inactive IBD, suggesting a complex interplay beyond simple disease-related distress. Previous research has linked high disease activity in IBD to increased anxiety and depression prevalence, and CMDs have been associated with worse IBD prognosis and increased surgical risk. Intriguingly, studies have indicated that depression preceding IBD diagnosis increases the likelihood of developing IBD, and antidepressant treatment might reduce IBD risk. These observations suggest a bidirectional relationship between mental health and IBD, moving beyond simple correlation to potentially shared underlying pathophysiological mechanisms. The convergence of molecular signatures in both IBD and mental disorders suggests the existence of shared biomarkers and common pathological pathways potentially linked through the gut-brain axis. Studies have highlighted alterations in gut microbiome composition in IBD patients with CMD compared to those without. Furthermore, fecal microbiota transplantation from IBD patients with depression induced IBD-like colitis and depression-like behaviors in mice, providing further evidence of a gut-microbiome-brain axis. This study aimed to comprehensively investigate the contribution of both human genetic factors and gut microbial dysbiosis to the high prevalence of CMDs in IBD patients within a homogenous genetic background.

Existing literature strongly supports an association between IBD and CMDs. Multiple studies have reported a significantly higher prevalence of anxiety and depression in IBD patients compared to the general population. This association persists even when considering disease activity, suggesting that the link between IBD and mental health is not merely a consequence of the disease's physical symptoms but rather a more complex interplay. The evidence suggests that the relationship may be bidirectional, with pre-existing mental health conditions potentially influencing the risk of developing IBD and vice-versa. Furthermore, the discovery of shared molecular signatures and the established gut-brain axis has prompted research into the role of the gut microbiome in mediating this relationship, specifically investigating the differences in microbial composition between IBD patients with and without CMD. Animal studies using fecal microbiota transplantation have shown promise in understanding the role of gut microbiota in both IBD and related mental health conditions.

This study employed a single-center cohort design, recruiting 507 IBD patients (290 UC, 217 CD) and 75 healthy controls from the Kyung Hee University Hospital in Korea. Genome-wide variant data were obtained from peripheral blood samples, while 16S rRNA amplicon sequencing data were generated from fecal samples. The Hospital Anxiety and Depression Scale (HADS) assessed anxiety and depression in a subset of 225 IBD patients. The study carefully controlled for potential confounders such as age, BMI, smoking, and alcohol consumption. Statistical analysis included comparing microbial diversity (alpha and beta diversity) between groups, identifying differentially abundant taxa (DATs) using DESeq2, and developing a microbial risk score (MRS) reflecting individual microbial burden for IBD. Polygenic risk scores (PRSs) for IBD and mental disorders were calculated based on existing GWAS data. Finally, microbiome quantitative trait loci (mbQTL) analysis was performed to identify genetic variants associated with the abundance of CMD-risk taxa. The study employed rigorous statistical methods to adjust for potential confounding factors and ensure the reliability of the findings. Case-control and case-only analyses were used to identify shared risk factors and elucidate potential causal relationships between IBD risk factors and mental disorders. A novel microbial risk score (MRS) was developed to quantify individual microbial burden for IBD, and mbQTL analysis examined the interplay between human genetic variants and the abundance of specific microbiota.

The study revealed significantly lower gut microbial diversity (Shannon, Simpson, richness, Faith's PD indices) in IBD patients compared to controls, with even lower diversity observed in CMD-affected IBD patients. A total of 106 DATs were identified in IBD patients versus controls, and 21 DATs distinguished CMD-affected from CMD-free IBD patients. Notably, 13 of the CMD-associated taxa were also IBD-associated, showing consistent abundance changes in both conditions, suggesting shared microbial signatures. A newly developed microbial risk score (MRS) demonstrated a significant association between higher IBD-specific MRS and increased CMD risk (P = 7.33 × 10⁻³; OR = 5.0 for the high-MRS group). Genome-wide association study (GWAS) data showed no significant association between the genetic burden of IBD-risk variants and CMD susceptibility in IBD patients. However, mbQTL analysis identified rs35866622 in the FUT2-FUT1 locus as associated with lower abundance of Ruminococcus, a genus linked to both IBD and CMD. This variant is also a known IBD risk variant, suggesting a possible mechanism linking genetic predisposition to both IBD and CMD through modulation of gut microbiota composition. The study emphasizes the importance of gut dysbiosis in CMD development among IBD patients and suggests a potential mediating role of the gut microbiome in the genetic predisposition to both diseases.

The findings of this study strongly support the hypothesis that IBD-associated gut dysbiosis plays a significant role in the increased risk of CMDs in IBD patients. The lower microbial diversity and the enrichment of IBD-associated microbial risk factors in CMD-affected patients highlight the importance of the gut microbiome's contribution. The lack of significant association between PRS for IBD and CMD suggests that gut dysbiosis may be a more prominent factor in CMD development within the context of IBD than the shared genetic component between the two conditions. The identification of an IBD-risk variant (rs35866622) as an mbQTL for Ruminococcus offers a potential mechanistic link between genetics and microbiome composition, contributing to the susceptibility to both IBD and CMD. The consistent changes in abundance of several microbial taxa in both IBD and CMD suggest shared pathophysiological pathways. Future research should focus on understanding the mechanisms by which these microbial alterations contribute to the development of mental health issues in IBD patients. The FUT2-FUT1 locus and its association with Ruminococcus abundance represents a potential therapeutic target.

This study provides comprehensive evidence for the significant role of gut dysbiosis in the high prevalence of CMDs among IBD patients. The findings highlight the importance of the gut microbiome in the complex interplay between IBD and mental health, and suggest a potential mediating effect through genetic mechanisms. The identification of specific microbial taxa and a genetic variant associated with both IBD and CMD risk offers valuable insights for future research and potential therapeutic targets. Further studies are warranted to elucidate the specific mechanisms involved and to investigate the potential of targeted interventions to improve both physical and mental health outcomes in IBD patients.

The relatively small number of CMD-affected patients in the study might limit the power to detect smaller effects. The reliance on public GWAS data from European populations for PRS and mbQTL analysis introduces uncertainty regarding cross-ancestry transferability. The use of stool samples might not fully capture the entire gut microbiome composition. The analysis focused on relative abundances rather than absolute abundances of taxa, and HADS data were not available for the control group. These limitations should be considered when interpreting the results.