Using PCA to compare IBS patients who had a clinical improvement in HADS‐D of ≥2 in response to the COMBO to those who did not, PCA showed that differences at Weeks 4 (PERMANOVA p = 0.14 and R2 = 0.038), 8 (PERMANOVA p = 0.073 and R2 = 0.047), 12 (PERMANOVA p = 0.053 and R2 = 0.048), and 16 (PERMANOVA p = 0.031 and R2 = 0.052) were driven by significant decreases in biomarkers TNF‐α, IL‐6, CRP, and subjective measures HADS Anxiety/Depression and PSQI global score (Figures 6A–D and S5; Table S3). This evidence concerns the gene IL6 and depressive disorder.