Exploring the mechanism and potential treatment of severe acute pancreatitis-associated lung injury based on the gut-lung axis

Abstract

Severe acute pancreatitis (SAP), a prevalent and life-threatening abdominal emergency, is characterized by its abrupt onset, rapid progression, and high mortality rate, frequently precipitating multiple organ dysfunction syndromes. Acute lung injury (ALI) represents the most common early complication of SAP. ALI may progress to acute respiratory distress syndrome, which constitutes the primary cause of mortality in patients with SAP. However, the precise pathogenesis underlying ALI in SAP remains incompletely elucidated. Notably, recent advances in gut-lung axis research have significantly advanced our understanding of SAP-associated ALI (SAP-ALI). The gut-lung axis, a sophisticated bidirectional communication network linking the intestines and lungs, facilitates crosstalk between the microbiota and their metabolites across both organs via lymphatic and circulatory systems alongside the mucosal immune system. Critically, research confirms that SAP induces severe gut microbiota dysbiosis. This dysbiosis disrupts the intestinal mucosal barrier, enabling bacterial and endotoxin translocation to the lungs through lymphatic and hematogenous routes. Concurrently, gut-derived immune cells migrate to the lungs via the bloodstream, directly contributing to pulmonary immune-inflammatory imbalance. Consequently, this review synthesized the central role of the gut-lung axis in SAP-ALI pathogenesis and explored emerging therapeutic strategies targeting this pivotal axis, aiming to provide novel insights for the clinical prevention and treatment of SAP-ALI.

Key Words: Severe acute pancreatitis-associated acute lung injury; Gut-lung axis; Intestinal microbiota; Bacterial translocation; Migration of immune cells

Core Tip: Severe acute pancreatitis (SAP)-associated acute lung injury is a pivotal determinant of mortality. The gut-lung axis plays a central role in its pathogenesis. SAP-induced gut microbiota dysbiosis compromises the intestinal barrier, facilitating bacterial/endotoxin translocation and gut-derived immune cell migration to the lungs. This process culminates in a profound pulmonary inflammatory response, thereby identifying the gut-lung axis as a promising therapeutic target for novel interventions against SAP-associated acute lung injury.

INTRODUCTION

Severe acute pancreatitis (SAP) is a serious inflammatory disease of the pancreas that is often accompanied by systemic inflammatory response syndrome and multiple organ dysfunction syndrome[1,2]. The incidence of SAP has been increasing in recent years with an estimated 110-140 cases per 100000 people and a mortality rate of at least 30%[3].

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) represents a severe complication of SAP with mortality rates reaching up to 50%[4,5]. However, the pathogenesis of SAP-associated ALI (SAP-ALI) remains incompletely understood, and effective, reliable treatment strategies are lacking. Consequently, further exploration of SAP-ALI pathogenesis is essential for developing targeted and personalized therapeutic approaches.

The gut-lung axis is a bidirectional regulatory system between the intestine and the lungs, operating through complex interactive pathways that involve host-microbial relationships, microbial community crosstalk, and immune response regulation[6]. In SAP gut microbiota dysbiosis, characterized by reduced diversity, correlates with disease severity, thus impairing intestinal mucosal immunity, increasing permeability, and facilitating bacterial translocation (BT)[3]. BT to the lungs activates inflammatory pathways, releasing proinflammatory cytokines and exacerbating lung injury. Patients with ARDS exhibit elevated levels of gut-associated bacteria (e.g., Bacteroidaceae and Enterobacteriaceae) in the lower respiratory tract[7]. Short-chain fatty acids (SCFAs) (e.g., butyrate and propionate), the main metabolites of the intestinal flora, act as key regulators that enhance the intestinal barrier function and inhibit the activation of inflammatory vesicles by inhibiting histone deacetylase (HDAC) activity or activating G protein-coupled receptors (GPCRs) and may directly affect lung tissues to reduce ALI[8,9]. In addition, gut-derived immune cells migrate to the lungs, modulating local inflammatory responses.

Systematic research on the role of the gut–lung axis in SAP-ALI pathogenesis remains limited. This mini-review summarized gut microbiota alterations, the bidirectional regulatory mechanisms of the gut-lung axis, and advancements in SAP-targeted interventions, offering insights for future clinical applications.

DYSREGULATION OF GUT MICROBIOTA DURING SAP

Growing evidence highlights the pivotal role of the gut microbiota in acute pancreatitis (AP) progression. In healthy individuals Bacillota dominate the intestinal microbiota, followed by Bacteroidota, Actinomycetota, and Pseudomonadota. Compared with healthy controls, patients with AP exhibited increased levels of Bacteroidota and Pseudomonadota (e.g., Escherichia and Streptococcus) and reduced levels of Bacillota and Actinomycetota[10-13]. AP-associated bacteria replaced the host-specific microbial community (Table 1)[10-19]. Previous studies have shown that the microbial composition of fecal samples from patients with early-stage AP is different from that of healthy controls[17-19].

Table 1 Summary of gut microbiota alterations in acute pancreatitis.

Ref.	Type of sample	Subjects	Sequencing methods	Phylum	Genus	Species
Zhang et al[10]	Fecal	AP (n = 45) vs healthy volunteers (n = 44)	16S rRNA sequencing	Increase: Bacteroidota, Pseudomonadota. Decrease: Bacillota, Actinomycetota	-	-
Gong et al[11]	Fecal	AP (n = 12) vs healthy controls (n = 12)	Metagenomics and culturomics	Increase: Bacillota, Pseudomonadota. Decrease: Bacteroidota	Increase: Enterococcus, Klebsiella. Decrease: Bacteroides, Eubacterium	Increase: Enterococcus faecium, Enterococcus faecalis, unclassified Enterococcus, Escherichia coli. Decrease: Unclassified Bacteroides, Eubacterium rectale, Prevotella copri
Xie et al[12]	Fecal	AP (n = 86) vs healthy controls (n = 46)	16S rRNA sequencing	-	Increase: Enterococcus, Pseudomonas, Escherichia-Shigella. Decrease: Akkermansia, Lachnoclostridium, Ruminococcus	-
Hu et al[13]	Fecal	AP (n = 65) vs healthy volunteers (n = 20)	16S rRNA gene sequencing	Increase: Pseudomonadota, Bacteroidota	Increase: Escherichia-Shigella, Bacteroides, Enterococcus. Decrease: Bifidobacterium	Increase: Clostridium ramosum. Decrease: Bifidobacterium longum
He et al[14]	Fecal	SAP (n = 73) vs healthy volunteers (n = 28)	-	Increase: Pseudomonadota. Decrease: Bacillota, Actinomycetota	Increase: Escherichia-Shigella, Enterococcus, Klebsiella. Decrease: Blautia, Bifidobacterium, Romboutsia	-
Wang et al[15]	Fecal	SAP vs mild AP	16S rRNA sequencing	Increase: Pseudomonadota, Planctomycetota	Increase: Stenotrophomonas, Enterobacter	Increase: Cloacibacillus evryensis
Ammer-Herrmenau et al[16]	Fecal	SAP (n = 28) vs non-SAP (n = 363)	Metagenomic sequencing	-	-	Increase: Parabacteroides distasonis, Enterocloster bolteae, Flavonifractor plautii, Dysosmobacter welbionis, Anaerobutyricum hallii, Roseburia hominis, Clostridium CCN A10. Decrease: Lachnospiraceae sp., Lachnospira GAM79, Lachnospira eligens, Finegoldia magna, Peptostreptococcus anaerobius, Porphyromonas asaccharolytica, Lawsonella clevelandensis, Streptococcus pyogenes, Anaerococcus mediterraneensis
Zhao et al[17]	Ileum tissues	AP mice (n = 15) vs control group (n = 10)	16S rRNA sequencing	Increase: Verrucomicrobiota. Decrease: Deferribacterota, Actinomycetota, Campylobacterota	Increase: Muribaculum, Akkermansia, Parabacteroides, Oscillospiraceae_unclassified, Bacteroides. Decrease: Helicobacter, Dietzia	-
Fu et al[18]	Cecal contents	AP mice vs control group	16S rRNA sequencing	Increase: Pseudomonadota, Bacillota. Decrease: Bacteroidota	Increase: Escherichia-Shigella, Bacteroides, Helicobacter. Decrease: Blautia	-
Zhang et al[19]	Colonic contents	SAP mice vs sham-operated group	RNA and assay for transposase accessible chromatin sequencing	Increase: Pseudomonadota. Decrease: Bacillota	Increase: Escherichia-Shigella, Morganella, Flagellated bacteria. Decrease: Lactobacillus	-

AP: Acute pancreatitis; SAP: Severe acute pancreatitis.

Compared with that in patients with mild AP, the diversity of the gut microbiome was significantly lower in patients with SAP, particularly with an increase in pathogenic bacteria and a decrease in beneficial bacteria such as Blautia, Enterococcus, Faecalicatena contorta, and Ruminococcaceae. Specifically, at the phylum level Pseudomonadota and Planctomycetota were significantly enriched in the SAP group. At the family level, Enterobacteriaceae, Veillonellaceae and Pseudonocardiaceae were more abundant in the SAP group. At the genus level, the abundance of Stenotrophomonas and Enterobacter was significantly increased in the SAP group. At the species level, the abundance of Cloacibacillus evryensis was significantly increased in the SAP group[15]. Therefore, there is a significant correlation between the composition of the gut microbiome and the severity of pancreatitis. Changes in specific microbial communities may reflect the severity of the disease and the corresponding physiological state.

In a prospective multicenter European study, the rectal and oral microbiomes of 450 patients with AP were collected at the time of admission to the hospital; unexpectedly, the abundance of 10 known SCFA-producing bacteria was greater in the SAP group than in the control group[16]. One explanation is that rectal swabs represent a relatively large mucosa-associated microbiome, and the differences observed in this study may be a result of niche-specific changes in the SAP group. This spatial variation in dysbiosis is a common phenomenon in patients with other diseases associated with an altered intestinal microbiome[20,21]. Evidence suggests that SCFA-producing species and strains may also be harmful[22,23]. However, compared with those in SAP non-survivors, the levels of SCFAs in SAP survivors were found to be increased and is likely due to the rejuvenation of SCFA-producing bacteria[14]. At present, we can only speculate whether SCFA-producing bacteria are the cause of SAP or a consequence of SAP. Therefore, it is necessary to explore the characteristics of species that produce SCFAs and the dynamics and functions of targeted metabolomics during the pathogenesis of SAP.

TRANSLOCATION OF INTESTINAL BACTERIA ALONG THE ENTEROPULMONARY AXIS TO THE LUNG

In healthy individuals the lung flora is dominated by Bacteroidota and Bacillota with Streptococcus, Prevotella and Veillonella being the most common[24]. A study revealed that the proportion of gut-associated bacteria, especially Bacteroidota and Enterobacteriaceae, increased in the lower respiratory tracts of patients with ARDS[25]. Further studies have shown that a predominance of Enterobacteriaceae in the gut and its enrichment in the lungs of patients with ALI/ARDS are major drivers of lung microbiota dysbiosis, are positively correlated with serum interleukin-6 (IL-6) and alveolar tumor necrosis factor alpha levels, and are highly valuable in predicting the development of ALI/ARDS[26-28]. Even transient translocation of such bacteria can alter the lung microbiota[29].

Prior to ARDS onset in patients with SAP, the gut microbiota already exhibits ARDS-associated characteristics with Escherichia-Shigella identified as a key predictive biomarker. Compared with patients with SAP but without ARDS, those with ARDS have increased abundances of Pseudomonadota, Enterobacteriaceae, Escherichia-Shigella, and Enterococcus but reduced abundances of Bifidobacterium. At the species level, potentially pathogenic bacteria such as Klebsiella pneumoniae, Prevotella copri, and Clostridium ramosum are significantly elevated in patients with SAP-associated ARDS[13]. Additionally, increased abundance of Escherichia coli in the pulmonary tract has been linked to increased mortality in patients with ARDS[30]. The similarity between alterations in the gut microbiota in patients with SAP-ALI and previously reported changes in the lung microbiota suggests that microbial translocation from the gut may contribute to pulmonary dysbiosis.

The impact of BT on SAP is widespread. BT refers to the entry of enteric pathogens into the lungs through a compromised intestinal barrier, which may lead to gut-derived infection and other related complications that can exacerbate SAP[5,31,32]. Dysbiosis of the gut microbiota leads to intestinal barrier damage, disrupts the balance between gut and pulmonary bacteria, and increases BT. Pathogen-associated molecular patterns enter the lymphatic and blood circulation, thereby activating the innate immune response in distant lungs[33]. Moreover, the lungs are particularly vulnerable as they are the first organs exposed to mesenteric lymph, which drains via the thoracic duct into the subclavian vein and subsequently enters the cardiopulmonary circulation, explaining why pulmonary failure is often the earliest clinical manifestation[34]. Once bacteria and endotoxins enter systemic circulation through intestinal epithelial disruption, they bind specific receptors and activate intracellular signaling pathways, including those involving nuclear factor kappa B (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), signal transducer and activator of transcription 3, extracellular signal-regulated kinase, mitogen-activated protein kinase, and AP-1. This activation triggers the release of inflammatory mediators, amplifies the cytokine cascade, and promotes systemic inflammatory response syndrome and multiple organ dysfunction syndrome (Figure 1)[35].

Figure 1 Pathways of intestinal bacterial translocation. Created in BioRender. PAMPs: Pathogen-associated molecular patterns; SIRS: Systemic inflammatory response syndrome.

Clinical evidence further links intestinal bacterial load to the severity of lung injury in patients with SAP. A hydrogen breath test study revealed a significant correlation between bacterial counts and the progression from ALI (PaO₂/FiO₂ ≤ 200) to more severe ARDS (PaO₂/FiO₂ < 300), indicating that early organ failure is associated with gut-derived bacteria[36]. This pulmonary injury is exacerbated by impaired oxidative stress defense and marked by decreased superoxide dismutase and glutathione peroxidase activities and elevated malondialdehyde levels[37].

Tang et al[38] by constructing a model of antibiotic-induced imbalance of intestinal bacteria found that the dysbiosis would damage the intestinal mucosal barrier and induce lipopolysaccharide (LPS) translocation to the systemic circulation. Hashimoto et al[39] showed that antibiotic-induced microbiota depletion could improve LPS-induced ALI and significantly reduce the increase of IL-6 levels.

SAP promotes an expansion in the abundance of flagellated bacteria and disrupts metabolite homeostasis, leading to the activation of toll-like receptor 5 (TLR5) on lamina propria dendritic cells[27]. This signaling impairs the intestinal barrier and alters helper T cell differentiation, ultimately facilitating BT. Thus, the flagellin-TLR5 axis represents a promising therapeutic target for mitigating gut-derived complications in patients with SAP. Although the mechanisms underlying microbiota dysbiosis require further elucidation, restoring intestinal barrier integrity remains crucial for improving SAP-ALI.

INTESTINAL FLORA ACT ON THE ENTEROPULMONARY AXIS THROUGH THEIR METABOLITES

SCFAs, primarily acetate, propionate, and butyrate, are organic fatty acids (≤ 6 carbon atoms) produced by the gut microbiota through the anaerobic fermentation of dietary fiber and resistant starch. Under physiological conditions SCFAs are absorbed by colonic cells via monocarboxylate transporters (e.g., monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1) and metabolized to meet the energy demands of intestinal epithelial cells. The surplus SCFAs enter the systemic circulation either via the portal vein or directly through the basolateral membrane into the inferior vena cava, thereby exerting regulatory effects on distant organs[40].

SCFAs function primarily through two pathways: Inhibition of HDAC activity to exert epigenetic effects and activation of GPCRs to modulate immunity. By binding to GPCRs on intestinal and lung cells, SCFAs activate the AMPK pathway while suppressing NF-κB and NLRP3 inflammasome activities. These actions enhance epithelial barrier integrity, attenuate proinflammatory responses, and ultimately ameliorate histopathological damage in SAP-ALI[9,41].

Receptors for SCFAs, FFAR2 and FFAR3, are expressed on alveolar macrophages and type 2 epithelial cells with their levels modulated by LPS exposure[42]. This finding supports a direct role for SCFAs in lung protection as they significantly mitigate LPS-induced ALI by inhibiting HMGB1 release and NF-κB activation. Consequently, SCFAs reduce proinflammatory cytokine production, oxidative stress, immune cell infiltration, vascular permeability, and histological damage[43,44].

As a natural HDAC inhibitor, butyrate modulates inflammatory gene expression, suppressing the expression of proinflammatory cytokines (e.g., tumor necrosis factor alpha, IL-1β, and IL-6) while promoting anti-inflammatory IL-10 release[45]. In hypoxic models butyrate attenuated pulmonary vascular edema and leakage, reduced macrophage infiltration, and enhanced lung endothelial barrier integrity by upregulating the expression of tight junction proteins (occludin, cingulin, and claudin-1) and increasing histone H3 acetylation[46]. Similarly, in murine AP models, butyrate supplementation strengthened the intestinal barrier function via tight junction upregulation and HDAC inhibition, thereby reducing BT, systemic inflammation, and secondary infection risk.

Acetate and propionate, which are likely derived from the gut and transferred to the lungs, are present in human lung tissue at varying levels. They exert anti-inflammatory effects by activating GPCR41/43 and inhibiting the NLRP3 inflammasome, thereby reducing the maturation and release of IL-1β and IL-18 and mitigating local inflammation in the intestine and pancreas. Tian et al[47] demonstrated that enrichment of propionate-producing bacteria, particularly Lachnospiraceae, attenuated lung inflammation following pulmonary ischemia-reperfusion injury in vivo.

In SAP mice propionate and butyrate mitigate lung injury by inhibiting macrophage M1 polarization and neutrophil infiltration via suppression of the mitogen-activated protein kinase pathway, thereby modulating inflammation and restoring the intestinal barrier function[8]. Conversely, succinate, a bacterial metabolite, activates the phosphoinositide 3-kinase/protein kinase B/hypoxia-inducible factor 1 alpha pathway by binding to SUCNR1 on pulmonary macrophages, promoting their polarization toward a reparative M2 phenotype to alleviate injury[48].

To overcome the low bioavailability of SCFAs, chitosan-protocatechuic aldehyde/calcium alginate/sodium butyrate microspheres were developed by encapsulating sodium butyrate in a chitosan-based carrier, offering a targeted approach for intestinal barrier repair[49]. This delivery system represents a promising strategy for SCFA application. Although existing studies have suggested that SCFA supplementation has beneficial effects on SAP-ALI, the available evidence remains limited and somewhat controversial, warranting further investigation[50,51].

MIGRATION OF IMMUNE CELLS VIA THE GUT-LUNG AXIS

Immune cells are pivotal for maintaining the proinflammatory and anti-inflammatory balance during SAP-ALI (Figure 2)[52,53]. Immune cells originating from the bone marrow trigger immune responses in the lungs while intestinal immune cells migrate directly from the intestine to the lungs via the bloodstream, influencing pulmonary immune activity[54]. Group 2 innate lymphoid cells (ILC2s) rapidly migrate from the intestine to the lungs following helminth infection, and circulating ILC2s have been observed in the blood in experimental settings. These early responders enhance type 2 immunity and barrier repair[55]. Specific populations, including ILC2s, ILC3s, and T helper 17 cells (Th17) cells, can migrate from the gut to the lungs via circulation, a process in which ILCs depend on sphingosine-1-phosphate signaling, and directly participate in dysregulated immune responses[56,57]. Furthermore, gut Pseudomonadota facilitate ILC2 trafficking along the gut-lung axis. While IL-33 and CXCL16 guide natural ILC2 accumulation in the lungs, the IL-25 and CCL25 axis promotes inflammatory ILC2 migration to the intestine, collectively modulating axis-specific inflammation[58].

Figure 2 Pathogenesis of acute lung injury resulting from gut immune cell translocation. Created in BioRender. AKT: Protein kinase B; ALI: Acute lung injury; AMs: Alveolar macrophages; DAMPs: Damage-associated molecular patterns; DC: Dendritic cells; γδ T: Gamma delta T cells; HIF-1α: Hypoxia-inducible factor 1 alpha; HMGB1: High mobility group box 1; IL: Interleukin; ILC2s: Group 2 innate lymphoid cells; MAPK: Mitogen-activated protein kinase; NETs: Neutrophil extracellular traps; NF-κB: Nuclear factor kappa B; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; PI3K: Phosphoinositide 3-kinase; SCFAs: Short-chain fatty acids; TNF-α: Tumor necrosis factor alpha; Th17: T helper 17 cells; Treg cells: Regulatory T cells.

In ALI/ARDS regulatory T cells (Treg cells) provide protection by suppressing pulmonary inflammation, whereas Th17 cells exacerbate pulmonary injury. Additionally, gamma delta T cells (γδ T cells), antibody-secreting cells, and ILCs play roles in pulmonary immune responses and are important for ALI/ARDS[59]. Notably, SCFAs entering the peripheral blood influence the development of immune cells[54]. Shaping adaptive immune responses, particularly the development and differentiation of CD4+ and CD8+ T cells, is another function of the gut microbiota. Dysbiosis triggers and activates Tregs, promoting the proliferation and differentiation of Tregs and Th17 cells, leading to the production of IL-17 by intestinal Th17 cells and prompting B cells to produce and secrete secretory immunoglobulin A[60].

The intestinal mucosal immune barrier orchestrates immune cell migration along the gut-lung axis by activating immune cells, delivering microbial metabolites, maintaining barrier integrity, and regulating immune polarization[61]. For instance, during sepsis alveolar macrophages activate the Wnt/β-catenin-Lef1 pathway, upregulate CCL1, and recruit intestinal γδ T17 cells via CCR8. These lung-infiltrating γδ T17 cells exacerbate injury through the secretion of IL-17A, which promotes neutrophil infiltration, M1 polarization, and NETosis[62]. Although gut-derived immune cells are clearly important in AP-ALI, their migration pathways require further elucidation. A deeper understanding of their precise roles will facilitate the development of targeted immunotherapies for SAP-ALI.

POTENTIAL STRATEGIES AND INTERVENTIONS FOR THE TREATMENT OF SAP-ALI

Probiotics and prebiotics

Defined as live microorganisms that colonize the gut and maintain intestinal homeostasis[63,64], probiotics such as Bifidobacterium and Lactobacillus species protect against SAP-ALI through multiple mechanisms[65,66]: Remodeling the microbiota to increase SCFA production; enhancing intestinal barrier integrity; inhibiting pathogenic bacteria; and reinforcing mucosal immunity[67-70]. Specific mixtures can also promote anti-inflammatory M2 macrophage polarization via elevation of butyrate levels[71]. Clinical evidence includes a randomized trial showing that a Bacillus subtilis and Enterococcus faecium blend reduced hospitalization duration in patients with AP and reports indicating that strains such as Lactobacillus reuteri and Saccharomyces boulardii lower BT and SAP-ALI incidence[72-75].

Prebiotics, defined as non-digestible food ingredients that selectively stimulate beneficial gut bacteria, confer health advantages to the host[76]. For instance, inulin suppresses pathogenic bacteria such as Shigella and Klebsiella while enriching the probiotic Akkermansia[77]. Shi et al[78] further demonstrated that fritillary polysaccharides modulate the gut–lung immune axis by regulating the differentiation and migration of CCR6+ Th17/CCR6+ Treg cells while also enhancing intestinal barrier integrity and immunoglobulin A production. Although generally safe, the application of probiotics and prebiotics requires careful safety monitoring and should be tailored to disease severity and variations in individual patients. Future studies must focus on optimizing strain selection, dosage, and treatment duration and elucidating the precise mechanisms to validate the efficacy of probiotics and prebiotics in SAP-ALI.

Mesenteric lymphatic vessel ligation

The intestinal lymphatic system serves as a major route for transporting gut-derived bacteria and toxins to distant organs with the lungs being the primary target because of their direct drainage from the mesenteric lymph via the thoracic duct[34]. Animal studies have consistently demonstrated that interrupting mesenteric lymph flow through ligation in models of shock, trauma, burns, or ischemia/reperfusion effectively attenuates lung injury[79,80]. This protective effect is mediated through the inhibition of key inflammatory pathways, including HMGB1/RAGE/NF-κB signaling, leading to reduced proinflammatory cytokine release and the downregulation of NF-κB, iNOS, ICAM-1, and TLR4 expression[81]. These findings suggest that mesenteric lymphatic ligation could represent a novel therapeutic strategy for SAP-ALI.

Traditional Chinese medicine

Several Chinese herbal compounds and monomers, often acting via the gut-lung axis following oral administration, have been shown to have clinical utility in patients with SAP. For instance, multiple studies have shown that rhubarb-derived rhubarbin alleviates SAP (SAP-ALI)[82-84]. Qingyi decoction, a common multi-herb formula, exerts multi-target effects; it has been shown to reduce systemic inflammation and restore the intestinal barrier function via the SCFA-mediated AMPK/NF-κB/NLRP3 pathway[41,85]. Chaihuang Qingfu Pills, a traditional Chinese medicine formula modified from Qingyi decoction, was able to reduce matrix metalloprotease 9 and NLRP3 to inhibit sepsis in alveolar macrophages and protect against SAP-ALI[86]. Other active ingredients, such as those from Zingiber officinale, ameliorate pancreatic and lung injury by reducing oxidative stress and inflammation, and the injectable formulation hemopexin has also been shown to be effective against SAP-ALI/ARDS[87,88].

CONCLUSION

The increasing recognition of the gut–lung axis in SAP-ALI prompted this review. We summarized how SAP-induced gut microbiota dysbiosis impairs intestinal barrier function, facilitating BT, and how gut immune imbalances drive the migration of immune cells along the gut-lung axis, thereby amplifying pulmonary inflammation. Special attention should be given to SCFAs and their role in preserving barrier integrity and attenuating lung injury. Finally, we discussed potential interventions targeting these pathways, offering new strategies for clinical management.

Despite recent advances, several limitations and unanswered questions remain. The molecular mechanisms governing gut-lung cross talk in SAP-ALI require further elucidation, and current evidence, largely derived from animal studies, necessitates clinical validation. Future research should focus on delineating the migration routes and precise functions of immune cells along the gut-lung axis, revealing novel diagnostic and therapeutic targets. A deeper understanding of these pathways will undoubtedly open new avenues for preventing and treating SAP-ALI.