Unraveling microbial signatures in the comorbidity of autoimmune diseases and depression

Depression is a common comorbidity in autoimmune diseases (ADs), including inflammatory bowel disease (IBD), a well-characterized AD with prominent gut involvement and strong host-microbiome interactions. Yet, its underlying microbial associations remain insufficiently understood. This study aimed to explore the gut microbial composition and function in patients with ADs comorbid depression, including a subgroup with IBD comorbid depression, and to identify potential microbial and metabolic signatures associated with this comorbidity. We analyzed two curated cohorts from the American Gut Project: an AD cohort ( n = 344; AD with depression: n = 115, AD without depression: n = 120, healthy controls: n = 109), and an IBD subgroup ( n = 75; IBD with depression: n = 25, IBD without depression: n = 30, healthy controls: n = 20). Gut microbial profiles were evaluated using 16S rRNA gene sequencing (V4 region). Microbial diversity was assessed via α- and β-diversity indices. Differential abundance analysis was conducted using Linear Discriminative Analysis Effect Size (LEfSe) and Linear Discriminant Analysis (LDA) methods. Functional predictions were performed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology inference. Microbial co-occurrence networks were also constructed to explore taxonomic interaction patterns. In the AD cohort, β-diversity was significantly reduced in patients with comorbid depression compared to those without, whereas α-diversity did not show statistically significant differences. A total of 40 microbial taxa were significantly different between patients with AD comorbid depression and AD without depression. In the IBD subgroup, 12 taxa were differentially abundant between patients with and without depression. Functional pathway predictions suggested disruptions in carbohydrate metabolism, energy metabolism, and glycan biosynthesis in patients with AD and comorbid depression compared to those without depression. Microbial network analysis revealed distinct co-occurrence structures in patients with comorbid depression. This exploratory study suggests that individuals with ADs or IBD and comorbid depression exhibit distinct gut microbiome compositions and functional potentials compared to non-depressed counterparts. These associations may offer insights into gut-brain interactions in autoimmunity and mental health. However, due to the cross-sectional design, mechanistic and clinical inferences remain speculative and require validation in future studies.