Ursodeoxycholic acid alleviates α-Casein-induced cow’s milk protein allergy via the TGR5/NF-κB signaling pathway

Cow’s milk protein allergy (CMPA), one of the most common food allergies in infant, is primarily manifesting gastrointestinal symptoms and closely associated to the disorders of gut microbiota. Ursodeoxycholic acid (UDCA), a gut microbiota derived secondary bile acid, is significantly decreased in infant with CMPA. However, the effect and mechanism of UDCA in colitis of CMPA is unknown. Our analysis demonstrated that UDCA administration alleviated the systemic allergic symptoms, improved body weight gain, and mitigated histopathological damage in both liver and colon tissues in a mouse model of α-Casein-induced CMPA. UDCA restored intestinal barrier integrity by increasing goblet cell numbers and enhancing the expression of the tight junction gene in colonic tissue. In α-Casein-sensitized RAW264.7 cells, UDCA promoted the healing and migration. Additionally, UDCA significantly down-regulated the secretion and mRNA levels of key pro-inflammatory factors (IL-1β, TNF-α, IL-6) and the production of inflammatory mediators (NO, ROS). Mechanistically, UDCA increased the cAMP level and up-regulated G-protein coupled receptors (TGR5) expression and inhibited the NF-κB signaling pathway, as evidenced by reduced phosphorylation and nuclear translocation of p65 in vivo and in vitro. Pharmacological antagonism with SBI-115 confirmed that UDCA suppressed α-Casein-induced NF-κB p65 activation primarily by targeting TGR5. This study suggested that UDCA may alleviate CMPA by targeting TGR5 to enhance intestinal barrier function and modulate immune response via NF-κB signaling, highlighting its potential as a therapeutic strategy for allergic diseases.