Introduction and Objective: Type 1 diabetes (T1D) is an autoimmune disease in which Treg dysfunction contributes to immune imbalance. While lactate-driven lactylation shows context-dependent immunomodulatory effects, its role in Treg regulation in T1D remains unclear. Here, we attempt to investigate the role of lactate in T1D and explore therapeutic strategies targeting gut microbiota-derived lactate.Methods: Effects of lactate were assessed in human cohorts and mouse models. Single-cell and bulk transcriptomics, lactylation proteomics, ChIP-seq, and lactylation-deficient Creb1 K136R knock-in mice were used for mechanistic studies. Gut microbiota-derived lactate intervention was evaluated in a clinical trial.Results: Circulating L-lactate levels were reduced in patients with T1D and positively associated with C-peptide while inversely correlated with glycemia. In NOD mice, lactate exerted dose-dependent effects, with low-dose lactate reducing diabetes incidence and autoimmune pathology, whereas excessive lactate accelerated disease progression. Single-cell sequencing identified a lactate-induced effector Treg subset (Lac-Treg). Mechanistically, CREB1 lactylation at Lys136 restrained canonical CREB1 activity and reprogrammed a Bcl6-centered transcriptional program to sustain Treg function, whereas its loss promoted pro-inflammatory CD4+ T cell skewing and accelerated T1D. Finally, Lacticaseibacillus paracasei was reduced in the gut microbiota of T1D patients, and clinical trial data showed that its oral supplementation was associated with increased lactate levels, improved C-peptide secretion, and better glycemic control.Conclusion: To summarize, lactate exerts dose-dependent immunoregulatory effects in T1D via a lactate-CREB1 lactylation-BCL6 axis that controls Treg function and immune tolerance, shaping disease progression. Restoring systemic lactate levels via modulation of gut microbiota reshapes immunometabolic balance and represents a promising therapeutic strategy for T1D.
Y. Liu: None. F. Sun: None. C. Wang: None.
Noncommunicable Chronic Diseases?National Science and Technology Major Project (2024ZD0531400, 2023ZD0507302), the National Key R&D Program of China (2022YFA0806101), the National Natural Science Foundation of China (81920108009, 82130023, 82570968, 82200923), the Research and Innovative Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital (2024AOXIANG03), the Continuous Funding Program for High?Level Research Achievements at Shanxi Bethune Hospital (2024GSPYJ10 and 2024GSPYJ13) and the IGP Funding from QBRI, Hamad Bin Khalifa University
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