Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection (1). As a vital immune organ, the gut plays a critical role in the pathophysiology of sepsis (2). Disruption of the intestinal mucosal barrier during sepsis represents an important contributor to systemic inflammation and organ dysfunction (Fig. 1) (3). Intestinal barrier damage not only facilitates the translocation of bacteria and toxins into the bloodstream (3) but also contributes to the development of multiple severe complications (Fig. S1). An imbalance in M1/M2 macrophage polarization has been identified as an important mechanism involved in intestinal injury during sepsis (Fig. 1) (4). Excessive activation of M1 macrophages promotes intestinal inflammation, whereas M2 macrophages are associated with inflammation resolution and tissue repair (5). Therefore, modulation of M1/M2 macrophage polarization has been proposed as a potential strategy for improving intestinal dysfunction associated with sepsis. Resveratrol, a natural polyphenolic compound found in grapes, red wine and other foods (6), has been recognized for its antioxidant, anti-inflammatory and immunomodulatory properties (6). Previous studies, summarized in Table SI, have demonstrated that resveratrol can attenuate excessive inflammatory responses and facilitate tissue repair by regulating M1/M2 macrophage polarization in experimental models. Therefore, investigating the potential role of resveratrol in ameliorating intestinal mucosal barrier dysfunction associated with sepsis is of considerable interest. The present review introduced and analyzed how resveratrol may exert protective effects against sepsis-induced intestinal mucosal barrier injury through the regulation of key signaling pathways involved in macrophage polarization, thereby influencing the balance between pro-inflammatory M1 and reparative M2 macrophage subsets. This regulatory activity may contribute to the suppression of excessive inflammatory responses, promotion of epithelial repair and alleviation of intestinal barrier dysfunction and bacterial translocation. The present review aimed to provide a theoretical framework for further understanding the potential application of resveratrol in sepsis management. The present review adhered to the TITAN 2025 Guidelines (7).

Literature searches were performed using Embase (https://www.embase.com/), PubMed (https://pubmed.ncbi.nlm.nih.gov/), Cochrane Library (https://www.cochranelibrary.com/) and Web of Science (https://www.webofscience.com/), with a focus on, but not limited to, publications between 2000 and 2026. The following keywords and various combinations were used to ensure broad coverage of the topic: 'Resveratrol' AND 'macrophage polarization' AND 'Sepsis' AND 'Intestinal Mucosa' AND 'Intestinal Barrier Function' ('resveratrol' OR 'RES' OR 'trans-resveratrol' OR 'macrophage' OR 'M1 macrophage' OR 'M2 macrophage' OR 'M1/M2' OR 'intestinal mucosa' OR 'tight junction' OR 'intestinal barrier' OR 'gut permeability' OR 'mucosal integrity' OR 'sepsis' OR 'cecal ligation and puncture' OR 'lipopolysaccharide' OR 'endotoxemia' OR 'septic shock'). Articles were included based on their relevance to the topic, with particular emphasis on studies investigating the potential effects of resveratrol on sepsis-induced intestinal mucosal injury. The inclusion and exclusion criteria are presented in Table SII. Additional screening of reference lists was conducted to identify further relevant studies.

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection typically caused by the invasion of pathogens, including bacteria, viruses and fungi, resulting in dysregulated immune responses and subsequent multiple organ dysfunction (Fig. S2) (8,9). Recent statistics from 44 intensive care units (ICUs) nationwide indicate that the incidence of sepsis is 20.6%, with a mortality rate of 35.5% (10). For severe sepsis, the mortality rate exceeds 50% (10). Up to 60% of critically ill patients develop gastrointestinal motility dysfunction, defined as acute gastrointestinal injury (AGI), which is associated with a 28-day mortality rate of 62.5% (11). Mortality rates vary according to the severity of sepsis-associated AGI. Furthermore, studies have indicated that dysfunction of the mechanical barrier is closely involved in the development and progression of sepsis-induced AGI and represents an important pathogenic mechanism underlying this condition (12).

The mechanical barrier, located at the apical region of the extracellular space, is primarily composed of intestinal mucosal epithelial cells and tight junctions (TJs) (13) (Fig. S3). These epithelial cells form a complex network through TJ proteins, adhesion junctions and desmosomes, establishing an essential physical barrier that limits the entry of potential pathogens into the intestinal tissue (13). Upon infection or injury, signals are rapidly transmitted to resident immune cells within the mucosa, allowing recognition of microbial 'nonself' components (13). TJs regulate the paracellular transport of solutes and macromolecules and restrict the penetration of antigens, bacterial toxins and pathogens across the intestinal barrier, thereby serving as critical structural components of intestinal defense (14). As a key component of the host defense system, the intestinal mucosal barrier prevents external pathogens and toxins from entering the bloodstream while playing an essential role in maintaining intestinal microecological homeostasis (Fig. S4) (15). During sepsis and septic shock, antibiotic administration and parenteral nutrition may disturb the intestinal microbiota, whereas intestinal microcirculatory dysfunction contributes to ischemia and hypoxia of intestinal epithelial cells (16). These pathological changes impair epithelial cell function, disrupt TJ protein activity and compromise intestinal barrier integrity (Fig. S4). Consequently, increased intestinal permeability facilitates the translocation of endotoxins and inflammatory mediators into the circulation, which may contribute to the development of multiple organ dysfunction (16) (Fig. S4). Sepsis-associated systemic inflammation affects intestinal microvascular perfusion, resulting in ischemic injury, mucosal damage and epithelial dysfunction (16) (Fig. S5). In addition, inflammatory responses may directly affect intestinal epithelial cells, promoting apoptosis and increasing intestinal permeability (Fig. S6) (17). The maintenance of intestinal barrier integrity depends on the normal expression and function of TJ proteins, which can be altered by inflammatory factor activation during sepsis (Fig. S7). During sepsis, excessive immune activation and enhanced systemic inflammatory responses can disrupt TJ protein structures (Fig. S7). thereby contributing to impaired cellular integrity (18,19).

Macrophages are versatile immune cells involved in a wide range of biological functions, making them a critical focus in studies of phagocytosis, cellular immunity and molecular immunology (20). These cells originate from circulating monocytes, which are derived from hematopoietic stem cell precursors in the bone marrow (Fig. S8). After maturation and differentiation in the bone marrow, monocytes enter the bloodstream. Under specific stimuli, such as infection or inflammation, monocytes migrate across blood vessels into tissues, where they differentiate into macrophages (21). In response to disturbances in homeostasis, such as bacterial LPS exposure, macrophages contribute to restoring tissue balance by clearing pathogens and harmful microorganisms through phagocytosis, endocytosis and the release of inflammatory mediators (Fig. S8). This process is referred to as macrophage polarization (22). During polarization, cytokines and chemokines alter macrophage phenotypes and enhance their responsiveness to changes in the tissue microenvironment (Fig. S9) (22). Macrophage polarization is dynamic and plastic and occurs in specific spatial and temporal contexts, allowing transitions between M1 (proinflammatory) and M2 (anti-inflammatory) states (Fig. S9) (23). The balance between these polarized states is important in determining the body's response to inflammation and injury.

As research on resveratrol has progressed, increasing attention has been directed toward its safety profile, particularly regarding toxicological evaluation, contraindications, special populations, precautions and potential drug interactions. The incidence and severity of resveratrol-related adverse effects appear to be largely dose-dependent. Hebbar et al (115) administered different doses of resveratrol (0.3, 1.0 and 3.0 g/kg) to rats for 28 days. The results showed that rats treated with 0.3 g/kg herbal water extract (HWE) exhibited no significant adverse effects, whereas rats receiving 1.0 and 3.0 g/kg HWE developed dehydration, respiratory distress, nephrotoxicity (indicated by elevated serum blood urea nitrogen and creatinine levels), kidney injury and anemia potentially associated with suppressed erythropoietin synthesis. Another study reported that oral administration of resveratrol at doses ≤0.1 g/day did not result in observable adverse effects during either short-term or long-term administration (up to 1 year). However, occasional adverse effects, including gastrointestinal discomfort, diarrhea and heat rash, were observed at oral doses of 1.0 and 1.5 g/day. At doses exceeding 2.5 g/day, more severe reactions, including nausea, vomiting and abdominal pain, were reported (116), suggesting potential toxicity associated with high-dose resveratrol administration. Clinical studies have further indicated that oral administration of 0.15 g/kg resveratrol to healthy obese men for 30 days markedly reduced aspartate aminotransferase (AST) levels and liver fat accumulation (117). In patients with nonalcoholic fatty liver disease, administration of 0.05 g/kg resveratrol reduced total cholesterol and triglyceride levels and improved lipid metabolism, whereas higher doses (3.0 g/day for 8 weeks) increased AST and alanine aminotransferase levels (118). Overall, low-dose resveratrol appears to have a favorable safety profile with limited hepatic or renal toxicity. However, high-dose resveratrol administration, particularly in patients with nonalcoholic fatty liver disease, requires further evaluation and should be approached cautiously.

Low-dose resveratrol can reduce ROS levels in oocytes, increase glutathione levels, promote oocyte maturation and improve blastocyst formation rates in vitro (119-121). In addition, resveratrol supplementation may enhance antioxidant capacity in pregnant and lactating mice, increase uterine artery blood flow and reduce placental inflammation and hepatic triglyceride accumulation. However, some studies have suggested that resveratrol may induce fetal pancreatic enlargement or abnormalities (122), raising concerns regarding its safety during pregnancy. Furthermore, resveratrol, which exhibits phytoestrogen-like activity, may exert estrogenic effects. Long-term exposure may potentially influence the growth of hormone-sensitive cancer cells in breast, ovarian and uterine tissues (123,124). Therefore, caution is warranted when considering resveratrol use in individuals with cancer-related risks and during pregnancy. Although the pleiotropic effects of resveratrol, including anti-inflammatory, antioxidant, immunomodulatory and mitochondrial protective activities, may provide potential benefits, this complexity also makes it challenging to determine the primary mechanisms underlying clinical effects and to design targeted clinical trials.

Additionally, resveratrol may alter the pharmacokinetics of coadministered drugs, including absorption and metabolism, through inhibition of cytochrome P450 (CYP450) isoenzymes, potentially resulting in safety concerns. Resveratrol markedly inhibits CYP1A2 and CYP2C9 activity, affecting drug metabolism, potentially reducing therapeutic efficacy and increasing the risk of adverse effects (125). Therefore, when resveratrol is administered together with drugs metabolized by CYP1A2 and CYP2C9 in clinical settings, monitoring of blood drug concentrations may be necessary to optimize dosing strategies or consider alternative therapies.

Resveratrol has been extensively investigated as a multi-target candidate due to its anti-inflammatory, antioxidant, autophagy-modulating and microbiota-regulating properties (126). However, the transition from preclinical findings to clinical application remains challenging due to unresolved methodological, pharmacological and pathophysiological limitations (126). Most current formulation strategies primarily focus on improving bioavailability, while insufficient attention has been paid to the stage-specific pathophysiology of sepsis (127). Therefore, future delivery strategies may need to be phase-adapted, targeting early hyperinflammation, mid-phase intestinal barrier dysfunction, or late-stage immunoparalysis with distinct pharmacokinetic characteristics. The current delivery field also faces methodological limitations, as most efficacy data are generated from relatively healthy animal models (128). The pharmacokinetic characteristics of resveratrol under septic conditions remain insufficiently investigated, representing an important knowledge gap (126). Furthermore, safety assessments based on non-critical illness conditions may not fully reflect the complex physiological changes associated with sepsis. A sepsis-specific toxicological evaluation framework incorporating drug-drug interactions (DDIs), reversibility of immunomodulatory effects and metabolite profiling under organ dysfunction conditions is therefore needed. Current studies have generated substantial evidence regarding the preventive effects of resveratrol; however, data regarding clinically relevant treatment windows remain limited. Without rigorous evaluation of administration timing, clinical translation may be affected. The dose-exposure-response relationship of resveratrol remains incompletely established due to several limitations: i) Effective doses observed in animal models may not be safely achievable in humans; ii) effective concentrations observed in vitro may not be reached in target tissues; and iii) pre-treatment animal models do not fully represent clinical scenarios involving post-onset intervention. Addressing these translational gaps requires improved experimental strategies, including pathological models that improved reflect clinical conditions, pharmacokinetic/pharmacodynamic (PK/PD)-integrated trial designs, validation of molecular targets in human tissues and rational dose-finding approaches based on achievable human exposure. In addition, well-designed studies reporting both positive and negative findings are necessary to objectively evaluate the clinical potential of resveratrol. Furthermore, the biological effects of resveratrol may depend on the dynamic immune environment during sepsis.

Early proinflammatory (M1-type) macrophage overactivation contributes to cytokine release and inflammatory amplification, whereas later stages may involve immune suppression and M2-associated responses. Therefore, resveratrol may require precise temporal regulation of macrophage polarization, including early suppression of excessive M1 activation and avoidance of excessive M2 polarization during later stages. Inappropriate administration timing may potentially disturb immune balance, such as impairing tissue repair through excessive inhibition of M2-associated responses. The pathological environment of sepsis may also influence the efficacy of resveratrol. Reduced intestinal mucosal perfusion and oxidative stress may limit antioxidant activity and potentially alter its biological effects under highly oxidative conditions. Meanwhile, gut microbiota dysbiosis, including expansion of pathogenic bacteria, may continuously activate M1 macrophages through TLR/NF-κB signaling, potentially interfering with the immunomodulatory effects of resveratrol. Sepsis-associated capillary leakage and impaired liver and kidney function may alter resveratrol pharmacokinetics, including distribution and clearance, thereby affecting local intestinal exposure (130). Intestinal mucosal edema and disruption of TJ integrity may further influence drug absorption, highlighting the potential need for advanced delivery systems, such as mucosal adhesive nanoparticles or exosome-based platforms. Additionally, liver dysfunction during sepsis may affect resveratrol metabolism through alterations in CYP450 enzyme activity, whereas bacterial translocation following intestinal barrier disruption may increase hepatic burden and contribute to a pathological feedback loop. Different pathogens (gram-negative bacteria, gram-positive bacteria and fungi) and infection sites may induce distinct macrophage responses, suggesting that individualized therapeutic strategies may be required for future clinical applications of resveratrol.

Resveratrol can exert comprehensive protective effects, including antioxidant, anti-inflammatory, barrier repair, inhibition of programmed cell death and microbiota regulation, in sepsis-induced intestinal mucosal injury through multi-target and multi-pathway synergistic mechanisms. However, limitations remain in in vitro studies, animal experiments, clinical studies and clinical trials, as summarized in Table SVII.

Current models for sepsis-induced intestinal injury exhibit significant inconsistencies in experimental conditions and outcomes, alongside notable limitations: as summarized in Table SVIII, LPS-induced models, varying in dosage, administration routes and animal strains, only activate the TLR4 pathway and fail to replicate the immune complexity of human sepsis (131), leading to divergent intestinal injury severities and time points across studies. The 'gold standard' CLP model suffers from poor inter-laboratory reproducibility due to variations in cecal ligation ratios, puncture techniques and post-operative care, with intestinal injury severity closely tied to sepsis grading but complicated by operational uncertainty (132). Intestinal ischemia/reperfusion models show marked individual differences in injury susceptibility due to factors such as ischemia duration and animal strains, making uniform evaluation challenging (133). Cell models, while useful for studying cellular-level damage, are limited by diverse preparation methods and an inability to recapitulate the in vivo intestinal structure and microenvironment (134). Collectively, these models have inherent shortcomings in simulating pathophysiological mechanisms, suffer from physiological differences between animals and humans, lack consistency and reproducibility and struggle to mimic clinical complexities, all of which severely restrict their translational value.

In the future, gene editing technologies such as CRISPR may be applied to develop high-yield strains and address the challenges associated with low extraction rates (<1%) and high levels of impurities during chemical synthesis of plant-derived resveratrol (149). Current global efforts focus on optimizing metabolic pathways to increase fermentation yields to industrial production levels (150). Emerging technologies, including supercritical fluid extraction and enzymatic hydrolysis, may improve the utilization of resveratrol raw materials, reduce residual organic solvents and facilitate the production of pharmaceutical-grade resveratrol (>98% purity) (151). Carrier-based technologies, such as liposomes and polymer nanoparticles, may overcome the poor water solubility and rapid metabolism of resveratrol, thereby prolonging its biological activity (152). Experimental studies have shown that nanoencapsulation can increase oral bioavailability by 3-5-fold (153). Methylation and glycosylation modifications may also improve resveratrol stability, with tetramethyl resveratrol exhibiting an ~8-fold longer half-life than the natural form (154). Additionally, integration of single-cell sequencing and metabolomics may facilitate the identification of novel targets involved in resveratrol-mediated regulation of the SIRT1/AMPK pathway (155), while combined formulations containing resveratrol, nicotinamide nucleoside and quercetin may provide synergistic biological effects.

Furthermore, future studies may explore real-time adjustment of dosing regimens based on biomarkers such as IL-6 and M1/M2-associated surface markers CD86/CD206 (156). The development of intelligent responsive drug delivery systems, such as ROS-responsive nanoparticles, may enable targeted drug release at inflammatory sites (157). The combined effects of resveratrol with other organ-protective agents, including mitochondrial antioxidants, also warrant further investigation. In experimental studies, humanized mouse models and organoid systems may help improved simulate sepsis-induced intestinal injury and improve translational relevance.

Resveratrol, a natural plant polyphenol, has attracted increasing attention due to its diverse biological activities, including anti-inflammatory, antioxidant and immunoregulatory effects. It may regulate immune responses during sepsis by influencing M1/M2 macrophage polarization. Through modulation of macrophage functional states, resveratrol may contribute to the attenuation of intestinal inflammation, preservation of intestinal barrier integrity and reduction of intestinal permeability. These effects may limit bacterial and toxin translocation and alleviate systemic inflammatory responses associated with sepsis. However, current evidence remains insufficient to support routine clinical use of resveratrol in sepsis. Therefore, although resveratrol represents a promising experimental compound with potential immunomodulatory and barrier-protective properties, further mechanistic studies and well-designed clinical investigations are required before therapeutic conclusions can be established in patients with sepsis.

The M1/M2 framework, while historically valuable, has limitations in fully representing macrophage biology. Single-cell sequencing has revealed substantial complexity among macrophage states across different tissues, disease conditions and temporal stages. In sepsis research, considering this complexity rather than relying solely on binary classification may facilitate more precise diagnosis, patient stratification and targeted therapeutic strategies. Future macrophage research will likely require systems-level approaches to characterize dynamic, context-dependent and ontogenically diverse macrophage populations, ultimately supporting the development of more effective immunomodulatory strategies for critical illness.