P0090The role and mechanisms of SLC6A19 in the pathogenesis of Ulcerative Colitis through regulation of intestinal epithelial barrier homeostasis

Background Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the colon characterized by impaired intestinal epithelial barrier function, a key feature of its complex pathogenesis. SLC6A19 is an important intestinal amino acid transporter that contributes to amino acid homeostasis and barrier integrity. This study investigates the role and mechanisms of SLC6A19 in regulating the intestinal epithelial barrier in UC, with potential implications for novel therapies. Methods This study integrates clinical samples, SLC6A19 knockout mice, in vitro cell models, and transcriptomics to elucidate the role and underlying mechanisms of SLC6A19 in the amino acid metabolic axis that maintains the homeostasis of the intestinal epithelial barrier in inflammatory bowel disease (IBD). First, we will characterize SLC6A19 expression in the intestinal mucosa of IBD patients and examine its association with barrier injury severity and clinical phenotype. In SLC6A19 knockout mouse models, we will assess how SLC6A19 influences the progression of intestinal inflammation and the integrity of the epithelial barrier. Finally, at the cellular level, we will examine how SLC6A19 maintains epithelial barrier integrity and regulates tight junction proteins. Results Compared with healthy controls, SLC6A19 expression in intestinal tissues from patients with IBD is significantly reduced; furthermore, SLC6A19 mRNA levels are significantly negatively correlated with Mayo scores in UC patients. SLC6A19-/- mice show increased susceptibility to DSS-induced colitis than WT mice. Amino acid-targeted metabolomics revealed significant reductions in valine, ornithine, and other amino acids in SLC6A19-/- mice. Transcriptomic sequencing of gut tissue indicated upregulation of genes such as KDM5D, and enrichment of signaling pathways including branched-chain amino acid degradation, the urea cycle, and the TCA cycle. In vitro lipopolysaccharide(LPS) exposure reduces SLC6A19 expression in a dose-dependent manner. Moreover, SLC6A19 knockdown increased barrier permeability in vitro, reduceed ZO-1 and E-cadherin expression, increased α-KG/succinate ratio, phosphorylation of eIF2α, increased expression of the amino acid starvation response effector ATF4, and increased transcription of the downstream target gene KDM5D. Conclusion SLC6A19 plays a crucial role in maintaining the homeostasis of the intestinal epithelial barrier in IBD. This finding provides a new potential therapeutic target for IBD, namely improving the intestinal epithelial barrier function by modulating the expression or function of SLC6A19, and may represent a promising new strategy for future IBD therapy. References: 1.Bretto E, Ribaldone D G, Caviglia G P, et al. Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies [J]. Biomedicines, 2023, 11(8). 2.Neurath M F, Artis D, Becker C. The intestinal barrier: a pivotal role in health, inflammation, and cancer [J]. Lancet Gastroenterol Hepatol, 2025, 10(6): 573-592. 3.Broer S, Gauthier-Coles G. Amino Acid Homeostasis in Mammalian Cells with a Focus on Amino Acid Transport [J]. J Nutr, 2022, 152(1): 16-28. 4.Broer A, Juelich T, Vanslambrouck J M, et al. Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse [J]. J Biol Chem, 2011, 286(30): 26638-51. Conflict of interest: Dr. Song, Xiaomei: No conflict of interest. Hu, Chaoqun: No conflict of interest. Zhang, Yingzhi: No conflict of interest. Yang, Wang: No conflict of interest. Yang, Jian: No conflict of interest. Min, Zou: No conflict of interest. Guo, Hong: No conflict of interest.