Background/Objectives: The solute carrier family 26, member 2 (SLC26A2) gene, which belongs to the family of SLC26 transporters, can be detected in multiple tissues. However, the studies of SLC26A2 in colon-related diseases are still limited and incompletely understood, especially in ulcerative colitis (UC). Methods: In this study, we attempted to search and identify putative UC candidate genes within a large number of known genes by multiple bioinformatics analyses. The potential cellular characteristics and biological functions of SLC26A2 in the pathogenesis of UC were also elucidated. Results: Notably, SLC26A2 was representative and down-regulated in the intestinal mucosa of patients with active UC, compared to healthy controls. Decreased levels of SLC26A2 were proved to have a more value in diagnosis of UC patients, and closely correlated with some UC characteristics, including the Mayo score and Paediatric Ulcerative Colitis Activity Index (PUCAI). Mechanistically, subsequent results from published datasets and our validated clinical data all strongly implied that SLC26A2 was negatively correlated with the IL-17 signaling pathway, and positively associated with the tight junction, which led to abnormal immune cell infiltration and inflammatory injuries. After establishing the UC mice models in vivo by orally administration of DSS in portable water, SLC26A2 was significantly down-regulated at the mRNA or protein level, when compared to that in the control groups. Furthermore, the correlation analyses confirmed that SLC26A2 was positively associated with CLDN3, and negatively correlated with IL-17A expression in colon tissues. In addition, according to the SLC26A2 expression, UC patients were divided into different subgroups. The potential target drugs for UC treatment, such as progesterone, tetradioxin, and dexamethasone, were initially predicted and exerted anti-inflammatory effects via the common molecule-SLC26A2. Conclusions: SLC26A2 might be served as a protective candidate in the UC pathogenesis as well as a potential drug target for UC treatment.

Ulcerative colitis (UC) is a chronic immune-mediated disease with a growing global burden. In this study, bioinformatics analysis and machine learning methods were employed to screen the potential immune microenvironment-related feature genes. We identified 4 immune-related genes that are consistently dysregulated in UC and correlate with immune infiltration, including APOBEC3B (Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3B), CXCL11, PLA2G2A, and TMEM173. Their diagnostic performance was verified in an external cohort and in our clinical samples. Then, the proportion of ambiguous clustering (PAC) successfully classified UC patients into 2 molecular subtypes, including subtype 1 (metabolism-related subtype) and subtype 2 (immune- related subtype). The single sample gene set enrichment analysis (ssGSEA) algorithm revealed that subtype 2, with a higher score, of the majority of immune cells presented a worse inflammatory response. In addition, we assessed scores of partial novel drugs querying the cMAP database and found that the efficacy of clinical small-molecule compounds presented different results across UC subtypes. These findings identify biomarkers, establish a concise immune-based classification of UC, and support subtype-guided therapy.