The gastrointestinal microbiome, consisting of over 1,000 bacterial species, has been reported to contain a gene pool approximately 100 times larger than that of the human genome. More than 99% of these bacteria are classified into five predominant phyla: Firmicutes, Bacteroidetes, Proteobacteria, Verrucomicrobia, and Actinobacteria (Lupu et al., 2023). With the rapid advancement of microbiological research, increasing attention has been directed toward the role of gut dysbiosis in pancreatic diseases. In patients with AP, gut dysbiosis has been observed in comparison to healthy controls, characterized by an elevated abundance of opportunistic pathogens and a reduction in beneficial bacteria such as Firmicutes and Actinobacteria. Stratified analyses of AP cases have demonstrated that the composition of the gut microbiota varies according to disease severity, indicating a contributory role of intestinal microbes in the pathogenesis and progression of AP (Zhang et al., 2018; van den Berg et al., 2021; Yu et al., 2021; Yu et al., 2020).

Further investigations have indicated distinct gut microbial profiles in patients with HLAP compared to other forms of AP. In HLAP, more substantial reductions in both microbial abundance and diversity have been reported when compared to non-HLAP cases (Hu et al., 2021). These changes are primarily characterized by an increased prevalence of Enterococcus and Escherichia, accompanied by decreased levels of Bacteroides and Faecalibacterium. Correlation analyses have indicated a negative association between the abundance of Faecalibacterium and Bacteroides and the severity of disease, indicating a potential pathophysiological relationship between gut microbiota composition and HLAP (Li et al., 2023).

A bidirectional relationship has been identified between the gut microbiota, their metabolites, and the host. Among microbial metabolites, SCFAs represent the most abundant group in the gastrointestinal tract. As the principal end products of bacterial fermentation, SCFAs have been recognized as a key component in mediating host–microbiota interactions (Gentile and Weir, 2018). The primary SCFA-producing microorganisms are anaerobic bacteria, including genera such as Bacteroides, Bifidobacterium, Clostridium, and Streptococcus (Marchesi et al., 2016). These bacteria predominantly secrete acetic and lactic acids, which reduce intestinal pH and inhibit the proliferation of pathogenic microbes. In addition, they are known to degrade cellulose effectively, enabling the fermentation of dietary fiber and the subsequent production of SCFAs (Zhu et al., 2019).

In the context of HLAP, a decline in the abundance of these commensal intestinal bacteria has been usually observed, accompanied by an increase in opportunistic pathogens (Li et al., 2023). The reduction in SCFA-producing bacteria tends to become more pronounced with disease progression. Zhu et al. reported significantly lower levels of Bacteroides, Alloprevotella, Blautia, and Gemella in patients with severe acute pancreatitis (SAP) compared to those with mild and moderately severe (MSAP) forms (Zhu et al., 2019). These microbial taxa have previously facilitated dietary fiber fermentation and SCFA production (Chen et al., 2018; Liu et al., 2018; Kellingray et al., 2018). Furthermore, Eubacterium hallii, a known butyrate-producing bacterium, was identified by Yu et al. as one of the most significantly reduced genera in both MSAP and SAP patients (Yu et al., 2020). The reduction or disruption of these beneficial bacterial populations has been identified as a primary contributor to the decreased production of SCFAs in patients with HLAP.

Acute intestinal dysfunction is frequently observed as a complication in patients with HLAP and is strongly associated with unfavorable clinical outcomes (Ding et al., 2020). As SCFAs are primarily synthesized within the intestine, most current research on their mechanisms of action has focused on their role in maintaining gut homeostasis. Gut homeostasis refers to a dynamic and integrated equilibrium involving gut microbiota, intestinal epithelial barrier, and mucosal immune barrier. The protective effects of SCFAs can be broadly classified according to their influence on these three components.

First, SCFAs contribute to the correction of gut dysbiosis. Clostridium butyricum, an anaerobic bacterium capable of fermenting dietary fiber to produce SCFAs increases the abundance and diversity of intestinal microbiota when administered orally in HLAP rat models. This intervention promoted the proliferation of beneficial bacteria such as Lactobacillus, Coprococcus, and Allobaculum, while reducing the levels of pathogenic bacteria (Zhao et al., 2020). Direct supplementation with butyrate enhances the relative abundance of SCFA-producing bacteria within the intestinal tract (Gao et al., 2021; Xiong et al., 2022).

In addition, SCFAs serve as a primary energy source for intestinal epithelial cells and exert direct effects in maintaining the structural integrity of the intestinal barrier (Xiao et al., 2022). In rat models of SAP, treatment with butyrate resulted in decreased pathological severity scores of intestinal injury and reduced plasma concentrations of inflammatory markers. When compared to untreated controls, increased expression of tight junction proteins such as zonula occludens-1, claudin-1, and occludin were observed, along with decreased expression of claudin-2 and matrix metallopeptidase-9, indicating repair of the intestinal mucosal barrier (Zhao et al., 2020). Butyrate restores goblet cells responsible for mucin secretion, thereby contributing to mucosal protection (Gao et al., 2021).

Regarding the mucosal immune barrier, SCFAs modulate both colonic epithelial cells and immune cells to exert anti-inflammatory effects. Pretreatment with butyrate has been associated with attenuation of intestinal inflammation and injury through the suppression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Findings from immunofluorescence staining and flow cytometry analyses have further demonstrated increased expression of forkhead box protein 3 at both the mRNA and protein levels, supporting the role of butyrate in enhancing the proportion of regulatory T cells. These effects contribute to the prevention of excessive innate and adaptive immune responses and the preservation of gut homeostasis in SAP (Xiao et al., 2022; Fan et al., 2024).

Hyperlipidemia (HL) is a major contributing factor in the development of HLAP, with the incidence of HLAP having surpassed that of alcoholic pancreatitis, making it the second most common cause of AP (Chinese Pancreatic Surgery Association, and Chinese Society of Surgery, Chinese Medical Association, 2021). HL is a pathological condition resulting from disruptions in lipid metabolism caused by various internal and external factors. In this context, SCFAs have been identified as key regulators of host energy metabolism, influencing the balance of lipid degradation, fatty acid oxidation, and synthesis (Komaroff, 2017).

Diets high in fat and carbohydrates have been shown to reduce both the diversity and abundance of gut microbiota, particularly leading to a marked decline in SCFA-producing bacteria such as Bacteroides and Bifidobacterium. This microbial imbalance contributes to increased lipid accumulation and the onset of hyperlipidemia (Wang et al., 2020; Gallardo-Becerra et al., 2020; Ziętek et al., 2021). Experimental studies have demonstrated that continuous administration of fructooligosaccharides in mice significantly increases SCFA levels, lowers serum total cholesterol, triglycerides, and low-density lipoprotein levels induced by high-fat and high-carbohydrate diets. Furthermore, reductions in chronic inflammation, oxidative stress, and lipid deposition were observed, along with improved lipid profiles in the circulatory system (Schachter et al., 2018). Additional research has indicated that direct dietary supplementation with SCFAs promotes triglyceride hydrolysis, enhances FA oxidation, and facilitates the formation of brown adipose tissue, thereby reducing blood lipid levels in mice that were fed a high-fat diet (Lu et al., 2016). In summary, direct or indirect supplementation of SCFAs can significantly improve lipid metabolism. Previous studies have indicated that in severe hyperlipidemia, a large amount of lipoproteins and chylomicrons can lead to elevated plasma viscosity, which is believed to hinder blood flow in pancreatic tissue, leading to ischemia and tissue injury, and ultimately, acute pancreatitis (Adiamah et al., 2018). Furthermore, the easy availability of pro-inflammatory free fatty acids (FFAs) in plasma and the potential accumulation of FFAs in pancreatic tissue can contribute to the exacerbation of disease progression (Hansen et al., 2019; Hansen et al., 2023). Therefore, SCFA may prevent the onset and progression of HLAP by lowering blood lipid levels.

The mechanisms by which SCFAs regulate hyperlipidemia remain under active investigation. SCFAs have been found to serve dual roles in lipid metabolism, acting both as metabolic substrates through conversion into acetyl coenzyme A and as signaling molecules. SCFAs have been shown to activate the 5′-AMP-activated protein kinase (AMPK) signaling pathway, leading to increased expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase, thereby enhancing lipolysis (Tang et al., 2020). In addition, SCFAs downregulate the expression of peroxisome proliferator-activated receptor-γ and increase the expression of mitochondrial uncoupling protein 2 by activating AMPK and elevating the AMP/ATP ratio. These changes collectively contribute to enhanced FA oxidation in hepatic and adipose tissues (den Besten et al., 2015).

Further findings suggest that SCFAs inhibit peroxisome proliferator-activated receptor-α while concurrently activating AMPK and extracellular signal-regulated kinase 1/2 pathways, resulting in suppression of FA synthesis and promotion of FA catabolism and oxidation, thereby reducing lipid accumulation (Liu et al., 2019). Additionally, SCFAs impair ATP synthesis via activation of uncoupling proteins, leading to increased thermogenesis and lipid metabolic expenditure, thus improving overall lipid metabolism (He et al., 2020).

The pathogenesis of HLAP is multifactorial, with several mechanisms contributing simultaneously and often intersecting. Among these, the inflammatory response plays a central role in both the initiation and progression of the disease. In the early stages of HLAP, pancreatic inflammation initiated a cytokine cascade that manifested clinically as SIRS (Methods in Medicine CAM, 2023). The excessive activation and amplification of inflammatory pathways represent key factors in HLAP development, making the prevention or timely interruption of SIRS essential for early disease management.

SCFAs have been identified as potential mediators of the regulatory effects of gut microbiota on both intestinal and systemic inflammatory responses. SCFAs not only exert local effects in the gut but also modulate immune cell function and regulate systemic inflammation via multiple inflammatory signaling pathways. According to evidence, a reduction in butyrate-producing bacterial strains disrupts SCFA synthesis and metabolism, thereby exacerbating HLAP progression and contributing to altered gut metabolic profiles. Butyrate exerts anti-inflammatory effects through inhibition of histone deacetylase 1 (HDAC1) and modulation of the signal transducer and activator of transcription 1 (STAT1)/AP1-NLRP3 signaling pathway (van den Berg et al., 2021). Additionally, Parabacteroides have been reported to produce acetate that alleviates heparanase-aggravated acute pancreatitis by reducing neutrophil infiltration (Lei et al., 2021). Bifidobacterium and its metabolite lactic acid suppress systemic inflammation and attenuate acute pancreatitis by modulating the Toll-like receptor 4 (TLR4)/MyD88 and NLRP3/Caspase-1 signaling pathways (Li et al., 2022). Furthermore, butyrate has been shown to reduce pancreatic injury in acute pancreatitis by downregulating inflammatory mediators and inhibiting activation of the NLRP3 inflammasome (Pan et al., 2019).

SCFAs exert diverse immunomodulatory effects on various immune and inflammatory cells. These metabolites have been shown to influence leukocyte function by promoting leukocyte migration and suppressing the production of pro-inflammatory cytokines (Vinolo et al., 2009; Park et al., 2007). In addition, SCFAs induce apoptosis in lymphocytes, macrophages, and neutrophils (Kurita-Ochiai et al., 2001; Bailón et al., 2010; Ramos et al., 2002; Aoyama et al., 2010). The mechanisms underlying SCFA activity are complex, with two primary pathways extensively studied: inhibition of HDAC activity to produce epigenetic effects and activation of GPCRs to initiate signal transduction.

SCFAs exhibit anti-inflammatory properties by inhibiting the release of pro-inflammatory mediators such as interleukin-1β (IL-1β), TNF-α, IL-6, and nitric oxide, while promoting the expression of the anti-inflammatory cytokine interleukin-10 (IL-10) (Ferreira et al., 2014; Cox et al., 2009). Butyrate inhibits the activation of nuclear factor kappa B (NF-κB) and STAT1 contributing to its anti-inflammatory effects (Belizário et al., 2018). Moreover, butyrate activates PPAR-γ, which is abundantly expressed in colonic epithelial cells, and suppresses interferon-γ signaling (Liu et al., 2018). As inhibitors of HDAC, SCFAs also influence gene expression by promoting protein hyperacetylation, facilitating chromatin remodeling, and modulating transcriptional activity, ultimately leading to cell cycle arrest and apoptosis (Chen et al., 2019). Collectively, these findings support the immunoregulatory potential of SCFAs in maintaining a balanced inflammatory response.

In recent years, the incidence of HLAP has continued to rise, accompanied by a trend toward increased clinical severity and a higher prevalence of complications, including ARDS, AKI, and MODS (Li et al., 2018). SCFAs prevent or alleviate organ failure through the restoration of intestinal barrier integrity and inhibition of systemic inflammatory responses, with their effects extending to organs such as the lungs and kidneys.

Acute lung injury and ARDS are observed in approximately one-third of patients with SAP. The underlying pathogenesis of lung injury involves increased pulmonary microvascular permeability, resulting in the accumulation of protein-rich exudates within the alveolar spaces and the formation of hyaline membranes (Shields et al., 2002; Yehia Kamel et al., 2023). SCFAs produced by gut microbiota have been shown to reduce the expression of pro-inflammatory cytokines and reactive oxygen species, lower immune cell infiltration, and attenuate lipopolysaccharide-induced microvascular permeability and histological lung damage. These effects are mediated through the inhibition of high-mobility group box 1 protein release and NF-κB activation (Li et al., 2018; Verma et al., 2024). In hypoxic models, administration of butyrate reduces macrophage accumulation in alveolar and interstitial tissues, prevents hypoxia-induced pulmonary vascular edema and leakage, and upregulates tight junction protein expression in pulmonary microvascular endothelial cells (Karoor et al., 2021). In patients with acute pancreatitis and ARDS, an increased abundance of Proteobacteria, Enterobacteriaceae, Escherichia-Shigella, and Klebsiella pneumoniae, along with a decreased abundance of Bifidobacterium, has been reported in comparison to those without ARDS (Hu et al., 2023). These findings indicate that gut microbiota and SCFAs may play a key role in the development of pancreatitis-associated lung injury.

AKI is another common complication of SAP, with pathogenic mechanisms involving increased vascular permeability, hypovolemia, inflammatory responses, vasoconstriction, intravascular coagulation, and direct nephrotoxic damage (Nassar and Qunibi, 2019). SCFAs have demonstrated anti-inflammatory and immunomodulatory effects in AKI, contributing to improved renal function (Andrade-Oliveira et al., 2015). SCFA therapy has been shown to reduce pro-inflammatory cytokine and chemokine levels in renal tissue and serum by downregulating TLR4 mRNA expression and inhibiting NF-κB pathway activation. Concurrently, reductions in apoptotic cell counts in renal tissue and increased proliferation of renal epithelial cells have been observed, facilitating tissue repair (Andrade-Oliveira et al., 2015; Huang et al., 2017). Additional studies have reported that high-fiber diets confer similar protective effects in AKI. Dietary fiber improves AKI-associated gut dysbiosis by promoting the growth of SCFA-producing bacteria such as Bifidobacterium and Prevotella. Inhibition of renal HDAC activity has also been observed in mice that have been fed a high-fiber diet (Liu et al., 2021).

Evidence shows that SCFAs contribute to the mitigation of pancreatic injury in AP (Sun et al., 2015). In murine models of AP, pretreatment with sodium butyrate has been shown to reduce macrophage and neutrophil infiltration into pancreatic tissue and decrease pro-inflammatory cytokine levels in the intestine. These effects may be mediated via inhibition of HDAC1 in the pancreas or activation of G protein-coupled receptor 109A in the colon, leading to suppression of NLRP3 inflammasome activation (Pan et al., 2019). Another study demonstrated that sodium butyrate supplementation significantly reduced the proportions of neutrophils, macrophages, and M2-type macrophages in pancreatic tissue, along with decreased expression of IL-1β, TNF-α, and C-X-C motif chemokine ligand 1 (Xiong et al., 2022).

The persistence of systemic inflammation or local pancreatic complications markedly increases the risk of infectious events in patients with acute pancreatitis, including pancreatic abscesses, bloodstream infections, and pulmonary infections (Besselink et al., 2009). Given the ability of SCFAs to protect intestinal barrier function and reduce pancreatic injury, their supplementation as part of early enteral nutrition may offer a promising strategy for lowering the incidence of systemic infectious complications in individuals with HLAP (see Figure 2).