Alterations of sphingosine-1-phosphate and its receptors in type 1 diabetes mellitus: an integrated clinical and single-cell transcriptomic study

<h4>Background</h4>Type 1 diabetes (T1DM) is a T cell-mediated autoimmune disease. The sphingosine-1-phosphate (S1P) signaling pathway regulates lymphocyte trafficking, but its status in T1DM remains poorly characterized. This study investigated S1P and sphingosine-1-phosphate receptor 1(S1PR1) alterations in T1DM through integrated single-cell transcriptomic and clinical analysis.<h4>Main methods</h4>We performed single-cell RNA sequencing (scRNA-seq)on colonic tissues from T1DM patients and healthy controls, complemented by analysis in non-obese diabetic (NOD) mice at pre-diabetic (4 weeks) and disease stages (12 weeks).Serum total S1P, HDL-bound S1P, and apolipoprotein M (ApoM) were quantified, and transcriptomic functional enrichment of intestinal T cell subsets was further performed.<h4>Results</h4>scRNA-seq showed differences in S1P receptor expression in intestinal immune cells between T1DM patients and healthy controls. S1PR1 expression was lower in T cell subsets, particularly CD8+ effector T cells, in T1DM patients. In NOD mice, S1PR1 expression showed a clustered pattern at 4 weeks and was more diffuse with lower levels in lymphocytes at 12 weeks. Clinically, serum total S1P was significantly elevated in T1DM and independently increased T1DM risk, while high-density lipoprotein-bound (HDL-bound) sphingosine-1-phosphate (HDL-S1P) was decreased with unchanged apolipoprotein M (ApoM) levels. Serum S1P positively correlated with glycated hemoglobin (HbA1c) and interleukin-6 (IL-6), and was inversely associated with hypoglycemic episodes. Transcriptomic enrichment indicated functional reprogramming of intestinal CD8⁺ effector T and regulatory T cells.<h4>Conclusion</h4>T1DM is associated with alterations in the S1P-S1PR1 pathway, characterized by reduced intestinal S1PR1 expression, elevated circulating total S1P, and decreased functional HDL-bound S1P despite stable ApoM.S1P is independently associated with T1DM status and correlates with glycemic control and inflammation, suggesting its potential as a disease-related biomarker.