Despite the establishment of the links between ulcerative colitis (UC) and depression, between UC and gut microbiota, few correlations between depression and gut microbiota have yet been demonstrated especially in ulcerative colitis patients. The objective of our study was therefore to determine whether the comorbidity of depressive disorder in ulcerative colitis patients correlate with alterations in the gut microbiota and to identify the specific microbiota signatures associated with depression.Between March 2017 and February 2018, 31 healthy volunteers, 31 UC patients without depression, and 31 UC patients with depression from Longhua Hospital were enrolled. Clinical data and fecal samples were collected for each patient. Fecal bacteria were identified using 16 s rRNA sequencing. We compared microbial composition among the 3 groups using bioinformatic analysis.Patients with UC with depression had higher disease severity (P < .05). The UC without depression group had moderate reduction of microbial abundance and uniformity compared to the control group. The UC with depression group had the lowest microbial abundance. With regard to the vital bacteria in the microbiota-gut-brain axis, patients with UC and depression had the lowest abundance of Firmicutes, Clostridia, and Clostridiales but the highest abundance of Proteobacteria, Gammaproteobacteria, and Bacilli.The presence of depression in UC patients presented significant differences in the composition of gut microbiota compared with UC patients without depression, with increased abundance of Firmicutes and reduced abundance of Proteobacteria. Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.