Published online Jun 21, 2026. doi: 10.3748/wjg.v32.i23.117320
Revised: February 5, 2026
Accepted: March 12, 2026
Published online: June 21, 2026
Processing time: 185 Days and 16.9 Hours
Beta-1 receptor blockade is well characterized for its protective effects against septic symptoms, and esmolol (ES) is a selective β1-adrenoceptor antagonist.
To assess the effects of ES on lipopolysaccharide (LPS)-induced septic intestinal damage and explore the associated mechanism by focusing on the AMPK/m
Sepsis was induced via an intraperitoneal injection of LPS in male SD rats or LPS treatment in rat intestine epithelial cells. To assess their anti-sepsis effects, rats and cells were pretreated with ES, 3-methyladenine, rapamycin (RAPA), and/or compound C, 30 minutes before LPS exposure. Then, intestinal damage, intestinal fatty acid-binding protein (I-FABP) and diamine oxidase (DAO) levels in intes
LPS induced intestinal damage in a time-dependent manner and suppressed auto
The current findings demonstrate that ES ameliorates LPS-induced septic intestinal damage by activating auto
Core Tip: This study investigated the protective effects of esmolol (ES), a selective β1-blocker, against lipopolysaccharide-induced septic intestinal damage. Using both animal and cell models, researchers found that ES pretreatment reduced intestinal injury markers (intestinal fatty acid-binding protein and diamine oxidase), improved tissue damage scores, and suppressed inflammation by suppressing interleukin (IL)-1 tumor necrosis factor-α, IL-17, and IL-6 while enhancing IL-10. Mechanistically, ES enhanced autophagy through activation of the AMPK/mTOR/ULK1 signaling pathway, as shown by increasing the expression of Beclin-1, LC3-II, p-AMPK, p-ULK1 and numbers of autophagosomes, and decreasing the expression of p-mTOR. These effects were consistent in both in vivo and in vitro models. The findings suggest that ES alleviates septic intestinal injury by promoting autophagy via the AMPK/mTOR/ULK1 pathway.
- Citation: Zhang YB, Yu ZJ, Jin J, Liu MX, Ji FH, Yang XJ. Esmolol alleviates lipopolysaccharide-induced intestinal injuries by enhancing autophagy through the AMPK/mTOR/ULK1 pathway. World J Gastroenterol 2026; 32(23): 117320
- URL: https://www.wjgnet.com/1007-9327/full/v32/i23/117320.htm
- DOI: https://dx.doi.org/10.3748/wjg.v32.i23.117320
Sepsis, caused by the host’s imbalanced responses to infection, is a severe illness that results in organ malfunction and is conceived as a primary cause of high death rates in critical care units[1]. The disorder can cause many disturbances in the intestinal epithelium, including increased cytokine production, impaired barrier function, and increased epithelial apop
To maintain homeostasis and ensure life, cells degrade and recycle their own constituent parts through a process termed autophagy. Autophagy exhibits dual and time-dependent characteristics. Numerous investigations have demon
SD rats (male, 2 months old, weighing 250-300 g) were provided by Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (Zhejiang, China). Additionally, LPS (Sigma-Aldrich Co., Ltd., St. Louis, MO, United States), 3-MA (MedChem
A schematic of the experimental overview is presented in Figure 1. After treatment with sodium pentobarbital (10 mg/kg) for anesthesia, the rats underwent internal jugular vein catheterization, and the operative time was controlled within 15 minutes. Following surgery, rats were randomly divided into five groups: Sham, LPS, LPS + ES, LPS + 3-MA, and LPS + RAPA. The Sham and LPS groups were further divided into four subgroups, respectively, whereas the LPS + ES, LPS + 3-MA, and LPS + RAPA groups were each divided into two subgroups. Each subgroup included eight rats. Regarding the specifics of treatment, NS was continuously infused at a rate of 0.5 mL/h over varying spans of time depending on the group. Rats in the Sham group received NS over intervals of 3, 6, 12, and 24 hours (Figure 1A). Rats in the LPS group received a NS infusion at 0.5 mL/h for 3, 6, 12, and 24 hours (Figure 1B). Rats in the LPS + ES group received ES (15 mg/kg/h) continuously at a rate of 0.5 mL/h for 12 and 24 hours (Figure 1C). Rats in the LPS + 3-MA and LPS + RAPA groups received 3-MA (15 mg/kg) and RAPA (4 mg/kg), respectively, via intraperitoneal (ip) administration, along with NS at 0.5 mL/hour for 12 and 24 hours (Figure 1D). To establish the sepsis model, LPS (10 mg/kg)[19] was administered by ip injection for 30 minutes. The rats were treated for their specified times and then sacrificed. Serum samples and jejunum specimens were immediately collected for further analysis. In our methodology, we used 3-MA (an autophagy inhibitor) and RAPA (an autophagy promoter) to ascertain whether ES had any impact on autophagy modulation in LPS-induced intestinal injury.
This study adhered to ethical guidelines and received approval from the Experimental Animal Ethics Committee of Soochow University, No. SUDA20251118A01.
The IEC-6 rat intestinal crypt cell line was acquired from the American Type Culture Collection and cultured in an incubator with RPMI 1640 (HyClone, GE, United States) containing 10% fetal bovine serum, 10 U/mL penicillin-strep
Fresh jejunal tissues were cleaned three times with NS, preserved in 10% neutral formaldehyde buffer, dried, paraffin-embedded, and cut with a microtome. After dewaxing and staining with hematoxylin-eosin, the samples were examined under a digital light microscope (Olympus, Tokyo, Japan), and the length of the intestinal villi was measured using ImageJ (NIH).
To determine the viability of cells, 200 μL of a cell suspension was cultivated in 96-well flat-bottom culture plates at a density of 1 × 105 cells/well. Then, cells were treated with or without ES (1 × 10-4 g/mL)/CC (10 μmol/L) for 30 minutes, followed by incubation with or without LPS (100 μg/mL) for 6 hours. Afterward, 100 μL of MTT solution (1 mg/mL) was added to each well, followed by incubation at 37 °C in a 5% CO2 atmosphere for 4 hours. The supernatant was extracted, and 100 μL of dimethyl sulfoxide was added into each well, followed by incubation for 15 minutes. Cell viability was determined by the optical density measured at 490 nm using a microplate reader (Multiskan FC, Thermo Fisher Scientific, Waltham, MA, United States).
Intestinal tissues were homogenized and lysed for 30 minutes on ice in radioimmunoprecipitation assay buffer. Following pretreatment, the tissues were washed three times with cold phosphate-buffered saline (PBS) and RIPA buffer supplemented with phosphatase and protease inhibitors to obtain whole-cell lysates. The protein concentration was ascertained using BCA protein assay kits (Com Win Biotech), and protein samples of the same quantity were separated using 10% SDS-PAGE and then transferred to PVDF membranes (Amersham Pharmacia Biotech, United Kingdom). After blocking the membranes for 2 hours at room temperature using 5% skim milk in PBS and 0.1% Tween 20, the membranes were incubated with the following primary antibodies: Anti-β-actin, anti-Beclin-1, anti-p-AMPK (Thr172) (40H9), anti-p-ULK1 (Ser757) (D7O6U), anti-p-mTOR (Ser2448) (D9C2), and anti-LC3-II (abc62721). Protein bands were developed using enhanced chemiluminescence (Amersham Pharmacia Biotech) and quantified using ImageJ. The relative expression of proteins was presented as the fold change vs the control group using β-actin as the internal reference.
The levels of intestinal fatty acid-binding protein (I-FABP) and diamine oxidase (DAO) in rat serum; levels of IL-1, IL-6, and IL-10 in intestinal tissue; and levels of IL-1, IL-17, TNF-α, IL-6, and IL-10 in IEC-6 cell culture supernatant were detected using enzyme-linked immunosorbent assay (ELISA) kits (LIANKE Technology Co., Ltd.) following the manufacturer’s instructions. Briefly, 1 g of fresh tissue was ground into tissue homogenate and centrifuged at 3000 × g for 10 minutes. IEC-6 cells (1 × 106 cells) were collected via centrifugation at 2000 × g for 20 minutes. The supernatant of intestinal tissue and IEC-6 cells was then retained, and the levels of targets were measured by a microplate reader using corresponding kits (Thermo Fisher Scientific).
Fresh intestinal tissue samples (2 mm × 2 mm × 2 mm) were quickly and carefully obtained after the rats were sacrificed and incubated in tubes containing a fixation solution for 4 hours. Then, the intestinal tissues underwent penetration, dehydration, and embedding overnight, followed by detection using a transmission electron microscope (Dmetrix, China). The ultrastructural damage to the mitochondria was evaluated by determining the number of autophagosomes in different groups.
Total RNA was extracted using a TRIzol reagent kit (Thermo Fisher Scientific) according to the manufacturer’s protocol. RNA quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, United States) and confirmed using RNase-free agarose gel electrophoresis. After total RNA was extracted, eukaryotic mRNA was enriched using Oligo(dT) beads, and prokaryotic mRNA was enriched by removing rRNA using a Ribo-Zero™ Magnetic Kit (Epi
All data were presented as the mean ± SE. The overall effect of different treatments was determined using ANOVA followed by multiple comparisons using the Newman-Keuls test. All statistical analyses were performed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, United States) with a significant level of 0.05.
As presented in Figure 2, rats were pretreated with ES, 3-MA, or RAPA, followed by the induction of sepsis using LPS. Compared to rats in the Sham group (Figure 2A), intestinal tissue injury was more severe in rats in the LPS (Figure 2B) and LPS + 3MA groups (Figure 2D). However, in the LPS + ES (Figure 2C) and LPS + RAPA (Figure 2E) groups, edema, villus tipsloughing, and inflammatory cell infiltration into the mucosa were considerably attenuated at 12 hours and 24 hours compared to that in the LPS group.
The interstitial villus length was shortened in response to LPS stimulation at 12 and 24 hours compared to that in the Sham group (Figure 3, P < 0.05). However, ES and RAPA treatment significantly mitigated this shortening vs that in the LPS group at both 12 and 24 hours (Figure 3, P < 0.05). There was no difference between the LPS and LPS + 3MA groups at both 12 hours and 24 hours (P > 0.05, Figure 3). These data robustly suggest that ES can inhibit intestinal damage induced by LPS.
As markers of intestinal permeability, higher levels of I-FABP and DAO indicate more severe tissue damage. LPS and LPS + 3-MA considerably increased the production of I-FABP and DAO, in agreement with the observed pathologic changes in intestinal tissues in rats with sepsis, compared to the findings in the Sham group. Conversely, ES and RAPA sig
The initiation of autophagy in the LPS-induced sepsis model was detected at different timepoints, and the data revealed that the effects of LPS on autophagy changed overtime. An increase in LC3-II expression was observed in LPS-treated animals at 3 hours compared to that at baseline (P < 0.05). Notably, from 12 hours to 24 hours, there were significant decreases in the expression of LC3-II and Beclin-1 compared to the baseline levels (Figure 5, P < 0.05).
In the sepsis model induced by the ip injection of LPS (10 mg/kg), the AMPK/mTOR/ULK1 autophagy pathway was markedly suppressed. We observed decreased Beclin-1, LC3-II (Figure 6A-F), p-AMPK, p-ULK1 expression and increased p-mTOR expression (Figure 6G-N) following LPS treatment. Treatment with ES for 12 or 24 hours effectively suppressed the LPS-induced decreases in Beclin-1, LC3-II (Figure 6A-F), p-AMPK and p-ULK1 expression and increase in p-mTOR expression (Figure 6G-N). These results demonstrated that ES significantly reversed the LPS-induced inhibition of autophagy. Similar outcomes were obtained with RAPA treatment at 12 and 24 hours, as it increased the expression of Beclin-1, LC3-II (Figure 6A-F), p-AMPK, and p-ULK1 and decreased that of p-mTOR (Figure 6G-N).
The autophagy inhibitor 3-MA had no effect on LPS-induced autophagy. However, treatment with 3-MA for 12 hours slightly reversed the LPS-induced decrease in p-ULK1 expression (Figure 6G and H), and increase in p-mTOR expression (Figure 6B and I). Additionally, treatment with 3-MA for 24 hours reversed the LPS-induced decrease in p-AMPK ex
The number of autophagosomes was clearly lower in the LPS group than in the Sham group (Figure 7). Meanwhile, the number of autophagosomes was restored by ES and RAPA treatment, but it was not influenced by 3-MA.
To assess the impact of LPS on cell autophagy, IEC-6 cells were exposed to LPS at various concentrations (0, 1, 5, 10, 50, and 100 μg/mL) for 6 hours. The results demonstrated that LPS restrained cell autophagy in a concentration-dependent manner (Figure 8A-C). Furthermore, IEC-6 cells were treated with or without 100 μg/mL LPS for various intervals (0, 0.5, 1, 2, 6, 12, and 24 hours). As depicted in Figure 8D-F, LPS suppressed cell autophagy in a time-dependent manner.
To evaluate the protective effect of ES on IEC-6 cells, cells were pretreated with ES (1 × 10-5, 1 × 10-4, and 1 × 10-3 g/mL) for 30 minutes and then incubated with LPS (100 μg/mL) for 6 hours. ES treatment increased the expression of Beclin-1 and LC3-II in LPS-treated cells (Figure 8G-I). Meanwhile, ES (1 × 10-4 g/mL) increased the viability of LPS-treated IEC-6 cells; thus, the optimal ES concentration was 1 × 10-4 g/mL (Figure 8J).
In IEC-6 cell cells treated with LPS (100 μg/mL), the AMPK/mTOR/ULK1 autophagy pathway was significantly suppressed. We observed decreased Beclin-1 and LC3-II expression and increased p-mTOR expression (Figure 9A-D). Treatment with ES for 6 hours completely suppressed the LPS-induced decreases in Beclin-1, LC3-II and increase in p-mTOR expression (Figure 9A-D). ES also completely suppressed the LPS-induced decreases p-AMPK and p-ULK1 (Figure 9E-G). These results revealed that ES markedly reversed the LPS-induced inhibition of autophagy. Similarly, RAPA increased the expression of Beclin-1, LC3-II, p-AMPK and p-ULK1 expression and decreased p-mTOR expression. The autophagy inhibitor 3-MA had no effect on LPS-induced autophagy. However, the LPS-induced increases in p-AMPK and p-ULK1 expression were slightly reversed by treatment with 3-MA (Figure 9E-G).
To further characterize the molecular targets of ES, transcriptome sequencing was performed using IEC-6cells from the Sham, LPS, and LPS + ES groups. Figure 10A displays a heatmap of the clustering analysis of differentially expressed mRNAs between the Sham, LPS, and LPS + ES groups. Figure 10B illustrates the identification of 495 DEG sin the LPS group relative to the Sham group. Among these, 304 genes were upregulated, and 191 were downregulated. By contrast, the LPS + ES group featured 36 DEGs vs the LPS group, including 19 upregulated and 17downregulated genes (Figure 10C). KEEG functional enrichment analysis (Figure 10D) revealed that, relative to the LPS group, the DEGs in the LPS + ES group were primarily associated with the TNF, IL-17, and NF-κB signaling pathways. GO functional enrichment analysis between the LPS and LPS + ES groups identified that ES primarily affected cytokine activity, response to chemical, positive regulation of inflammatory response, signaling receptor binding, and autophagy (Figure 10E).
ELISA was employed to assess alterations in inflammatory factors within IEC-6 cells 6 hours after drug administration in each group. The findings revealed that, in comparison to the Sham group, the LPS and LPS + CC groups exhibited marked elevation of IL-1, IL-6, TNF-α, IL-17, and IL-10 expression. Following ES treatment, the pro-inflammatory cytokines IL-1, IL-6, TNF-α, and IL-17 were suppressed, whereas the anti-inflammatory cytokineIL-10 was upregulated. When comparing the LPS + ES + CC and LPS + ES groups, the former exhibited upregulation of the pro-inflammatory cytokines IL-1, IL-6, TNF-α, and IL-17 alongside downregulation of the anti-inflammatory cytokine IL-10 (Figure 11).
To investigate the role of the AMPK/mTOR/ULK1 autophagy pathway in the protective effects of ES on LPS-induced intestinal injury, IEC-6 cells were challenged with LPS to mimic the in vitro environment. The protective effect of ES was neutralized by the AMPK inhibitor CC (Figure 12A; P < 0.05). Compared with the findings in the Sham group, cell viability was decreased in the LPS and LPS + CC groups after 6h of stimulation. After 6 hours of ES treatment, cell viability was increased significantly. However, the combination of LPS + ES + CC reversed this trend.
Western blotting revealed that the expression of Beclin-1 and activated LC3-II was reduced in the LPS group (Figure 12B-D), suggesting impaired autophagy during LPS-induced intestinal injury. Additionally, downregulation in p-AMPK and p-ULK1, along with upregulation in p-mTOR, was observed (Figure 12E-H), indicating inactivation of the AMPK/mTOR/ULK1 signaling pathway. ES pretreatment significantly restored the impairment of autophagy and the AMPK/mTOR/ULK1 pathway after stimulation at 6 hours with LPS. However, the ameliorating effect of ES was counteracted by CC (Figure 12).
The findings of this study demonstrated that ES administration reduced intestinal damage in rats and cells with LPS-induced sepsis, and the effects of ES were associated with the regulation of inflammatory factors and activation of autophagy via modulation of the AMPK/mTOR/ULK1 signaling pathway. The potential molecular mechanism of these effects is presented in Figure 13. Based on the current data, ES could be used as a therapeutic drug to improve intestinal function in patients with sepsis. High morbidity and mortality rates are common in sepsis[20], and the gastrointestinal tract is one of the organs most severely affected by sepsis[21]. The disorder can induce a chain of events that lead to intestinal mucosa degradation, which makes it easier for pathogens and poisons to enter the bloodstream[22,23]. Thus, protecting the mucosal lining of the gastrointestinal tract is a critical goal in both the prevention and management of sepsis[24,25].
Nevertheless, there is little clinical evidence to support the use of ES to treat intestinal damage caused by sepsis, and it is not considered a frontline treatment[5]. The effects of ES on sepsis have long been debated. For instance, some studies indicated that heart rate could be safely controlled by selective β1-blockers during septic shock[26]. However, the mechanism by which ES promotes intestinal epithelial cell survival in sepsis is unknown.
Under physiological conditions, only trace levels of I-FABP are present in the bloodstream[27]. Thus, circulating I-FABP has been suggested as a biomarker of intestinal permeability[28], and it may represent translocation from the gut into the circulation. Another intracellular enzyme found in the intestinal epithelium is DAO. These two enzymes can readily cross the intestinal mucosa and enter the peripheral circulation when intestinal permeability becomes abnormally high because of mucosal disruption[28]. In the current study, we found higher serum levels of DAO and I-FABP in the LPS group than in the Sham group, suggesting increased permeability in LPS-treated rats. However, ES significantly lowered the serum concentrations of DAO and I-FABP, implying that ES attenuated the intestinal damage induced by LPS. Meanwhile, ES suppressed the levels of IL-1 and IL-6 and increased those of IL-10 in rats with LPS-induced sepsis. The complex relationship between intestinal function and autophagy is highlighted by a substantial body of evidence. Autophagy plays a significant role in several aspects of intestinal physiology, including metabolic regulation, preservation of the intestinal epithelial structure, functioning of specialized intestinal epithelial groups, control of inflammatory pathways, and prevention of infection[29]. Reduced resistance to enteric infections might arise from intestinal epithelial cells lacking autophagy genes[30-32]. Previous research demonstrated an increase in autophagic activity during the hyperdynamic phase of sepsis, which is subsequently followed by a decrease in autophagy[33]. The expression of marker proteins associated with autophagy, including LC3 and Beclin-1, increased for up to 8 hours after CLP cecal ligation puncture and then returned to baseline by 12 hours[34], and ghrelin activated autophagy in intestinal epithelial cells, protecting the small intestinal epithelium against sepsis-related damage[34]. In another study of the mechanism underlying the effects of sodium tanshinone IIA sulfonate against LPS-induced small intestinal injuries, the recovery of the intestine was associated with the suppression of inflammatory factors and amplification of autophagy[35]. An improved survival rate was also observed in septic animals administered an autophagy inhibitor following endotoxemia[36]. However, the effects of autophagy modulation can yield different outcomes at different intervals. In the current study, we recorded a surge in LC3-II expression 3 hours post-LPS exposure, whereas Beclin-1 and LC3-II expressions were suppressed at 12 and 24 hours, which indicates a time-dependent control of LPS-induced autophagy.
Transcriptomics is the scientific study of transcripts and their expression levels in cells or tissues. Using RNA se
To further explain the pathways involved in the anti-sepsis function of ES, the current study explored the AMPK/mTOR/ULK1 pathway. Recent research revealed that puerarin protects against cerebral ischemia/reperfusion injury by modifying the AMPK/mTOR/ULK1 signaling pathway in rats[43]. In this pathway, the mTOR complex can be controlled by AMPK[44], and it contributes to the activation of ULK1[15]. However, whether this signaling transduction is involved in the effects of ES on LPS-induced intestinal injuries has not been documented. Our data illustrated that both ES and RAPA (an autophagy activator) entirely reversed LPS-induced changes in the expression of LC3-II, Beclin-1, p-AMPK, p-ULK1, and p-mTOR, along with an increased number of autophagosomes in the intestinal tissues of the sepsis model, ascertaining the involvement of AMPK/mTOR/ULK1-mediated autophagy in the effects of ES. In contrast, 3-MA (an autophagy inhibitor)[29] showed no impact on LPS-induced autophagy. The protective effect of ES was neutralized by the AMPK inhibitor. CC was found to reverse the induction of autophagy and AMPK/ULK1/mTOR pathway activity by ES.
Collectively, the findings outlined in the current study highlight that ES can alleviate intestinal injury in rats and cells with sepsis by augmenting autophagy, regulating inflammatory factors, and the effects were associated with the AMPK/mTOR/ULK1 signaling pathway. However, the data in the current study only revealed a relationship between the function of ES and changes in this pathway. Whether the activation of AMPK/mTOR/ULK1 signaling is indispensable for the anti-sepsis effects of ES requires more comprehensive validation, which will provide valuable information for the future treatment of septic intestinal damage.
We are highly appreciative of Professor Guo-Xing Zhang for sponsoring reagents and equipment.
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