Intestinal lactate as a crucial molecular for intestinal epithelial cell renewal in sepsis

Critical Care You et al. Critical Care (2025) 29:451 https://doi.org/10.1186/s13054-025-05690-3 Open Access CO R R E S P O N D E N C E Intestinal lactate as a crucial molecular for intestinal epithelial cell renewal in sepsis Pan You1†, Xuepeng Zhang1*†, Maoxia Liu1, Qinyi Fu1 and Siyuan Chen1* Dear Editors, Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a major public health concern globally and is the leading cause of death among patients in ICU [1]. The gastrointestinal tract is particularly vulnerable to the effects of sepsis, with acute gastrointestinal injury (AGI) affecting more than 90% of septic patients [2]. Lactate is primarily produced through glycolysis, a key byproduct of glucose metabolism, and has often been misperceived as a metabolic waste product. However, emerging studies show that the proliferating intestinal stem cells rely heavily on lactate [3], and intragastric lactate supplementation can enhance intestinal epithelial cell renewal [4]. Recently, Liu et al. found that lactate accumulation regulates cell cycle and proliferation by remodeling protein functions [5]. Our previous study has revealed that sepsis induced by cecal ligation and puncture (CLP) suppress proliferation of intestinal stem cells (ISCs). But the underlying mechanism is still unknown. Whether lactate involves in the inhibition of ISCs proliferation is worth of study. In this study, the mid-jejunum of mice was isolated. After being washed three times with PBS, the isolated jejunum was homogenized for detecting L-lactate by using L-Lactate Assay Kit with WST-8 (S0208S, † Pan You and Xuepeng Zhang contributed equally to this work. *Correspondence: Xuepeng Zhang Siyuan Chen 1 Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu 610041, China Beyotimes, China). Consequently, we found that lactate levels in intestine were lower in CLP mice at 6 h, and 24 h after CLP procedure (Fig. 1a). On the contrary, lactate levels in serum were higher in CLP mice (Fig. 1b). Transcriptome analysis showed that the expression of pyruvate dehydrogenase in the intestine tissue of CLP mice increased, while the expression of lactate dehydrogenase decreased, suggesting that CLP may induce metabolic reprogramming in intestinal epithelial cells (Fig. 1c). There was no difference in the levels of 6-phosphogluconate and phosphoenolpyruvate in intestinal tissue between the two groups of mice (Fig. 1d). However, the lactate level in the intestinal tissue of CLP mice decreased while the citric acid level slightly increased, confirming that sepsis induced by CLP could lead to reprogramming of glucose metabolism in mice intestinal epithelial cells, leading to a decrease in lactate levels (Fig. 1e). We administered lactate to CLP mice by gavage for 7 days and found that CLP mice with lactate gavage show a slight increase in survival trend compared to the control group (Fig. 1f ). More importantly, the intestinal length of CLP mice in the lactate group was longer than that in the control group (Fig. 1g–h). Furthermore, jejunal histopathological analysis revealed that lactate gavage increased villus length in CLP mice (Fig. 1i). Our data indicate that lactate may play a crucial role in intestinal epithelial cell renewal in sepsis. However, there are some limitations in our study. Gavage of lactate is a non-cell-specific manner and it is hard to differentiate the actual mechanism by which the lactate is functioning. Second, the study did not administer lactate to sham mice, the effect of lactate on intestine of sham mice is still unknown. Future studies are needed to confirm the functional characteristics and underlying mechanisms. Ultimately, intestinal lactate may help protect intestinal cells © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. You et al. Critical Care (2025) 29:451 Page 2 of 3 Fig. 1 Lactate regulates intestinal epithelial cell renewal. (a–b) Lactate levels in intestinal tissue and serum in CLP (6 h, 24 h) and sham mice. (c) Transcriptomic differences in intestinal tissue between the two groups. (d–e) The levels of 6-phosphogluconate, phosphoenolpyruvate and lactate in CLP and sham groups. (f–h) Lactate treatment improves survival and intestinal length in CLP-induced septic mice. (i) Representative jejunal histopathology. Scale bars, 200 μm You et al. Critical Care (2025) 29:451 from sepsis-induced damage and potentially reverse disease progression. It holds promise as a therapeutic strategy for critically ill patients with sepsis. Abbreviations CLP Cecal ligation and puncture ISCs Intestinal stem cells Acknowledgements Not applicable. Author contributions PY, XPZ, and SYC conceived and designed the study. MXL and QYF curated the data and ensured quality control. PY acquired the data, conducted statistical analyses, and drafted the manuscript with input from XPZ. All authors contributed to data interpretation, critically reviewed the manuscript, and approved the final version. Funding This work was supported by the National Natural Science Foundation of China (82402537), the Natural Science Foundation of Sichuan Province (2025ZNSFSC1547and 2025ZNSFSC0666), the China Postdoctoral Science Foundation (2024M752263). Data availability The datasets used for the analysis in the current study are available from the corresponding author on reasonable request. Declarations Competing interests The authors declare no competing interests. Ethical approval and consent to participate The animal experiments were approved by the Animal Care and Use Committee of west China hospital of Sichuan University (20240315014), were performed in accordance with the National Institutes of Health Guide for Care Page 3 of 3 and Use of Laboratory Animals and the Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines 2.0. Consent for publication Not applicable. Received: 9 August 2025 / Accepted: 27 September 2025 References (...truncated)