Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.

Despite recent evidence supporting the metabolic plasticity of CD4⁺ T cells, it is uncertain whether the metabolic checkpoint pyruvate dehydrogenase kinase (PDK) in T cells plays a role in the pathogenesis of colitis. To investigate the role of PDK4 in colitis, we used dextran sulfate sodium (DSS)-induced colitis and T-cell transfer colitis models based on mice with constitutive knockout (KO) or CD4⁺ T-cell–specific KO of PDK4 (Pdk4^fl/flCD4^Cre). The effect of PDK4 deletion on T-cell activation was also studied in vitro. Furthermore, we examined the effects of a pharmacologic inhibitor of PDK4 on colitis. Expression of PDK4 increased during colitis development in a DSS-induced colitis model. Phosphorylated PDHE1α, a substrate of PDK4, accumulated in CD4⁺ T cells in the lamina propria of patients with inflammatory bowel disease. Both constitutive KO and CD4⁺ T-cell–specific deletion of PDK4 delayed DSS-induced colitis. Adoptive transfer of PDK4-deficient CD4⁺ T cells attenuated murine colitis, and PDK4 deficiency resulted in decreased activation of CD4⁺ T cells and attenuated aerobic glycolysis. Mechanistically, there were fewer endoplasmic reticulum–mitochondria contact sites, which are responsible for interorganelle calcium transfer, in PDK4-deficient CD4⁺ T cells. Consistent with this, GM-10395, a novel inhibitor of PDK4, suppressed T-cell activation by reducing endoplasmic reticulum–mitochondria calcium transfer, thereby ameliorating murine colitis. PDK4 deletion from CD4⁺ T cells mitigates colitis by metabolic and calcium signaling modulation, suggesting PDK4 as a potential therapeutic target for IBD.