Detrimental and Beneficial Diets Regulate Acute Pancreatitis Through Convergent Gut Microbiota Pathways

Abstract

Diet is a key factor in regulating gut microbiota homeostasis, thereby influencing the incidence, severity, and prognosis of acute pancreatitis (AP). This review categorizes common dietary patterns into harmful types (Western diet, high-fat diet, ketogenic diet, high-salt diet) and beneficial types (Mediterranean diet, high-fiber diet, plant-based diet, restricted diet). Unlike previous reviews that list dietary patterns one by one, this paper analyzes them within the framework of the four core pathological/protective pathways of AP. Harmful diets primarily exacerbate AP by inducing dysbiosis, reducing SCFAs (especially butyrate), impairing the gut barrier, promoting bacterial translocation and excessive inflammatory responses; beneficial diets alleviate AP progression by enriching probiotics, increasing SCFA synthesis, enhancing barrier integrity, and suppressing systemic inflammation. This paper particularly emphasizes that most current evidence comes from non-AP models such as obesity and inflammatory bowel disease, and AP-specific causal evidence remains very limited. By integrating clinical, animal, and cellular experimental evidence, this paper aims to elucidate the potential relationship between diet, gut microbiota, and AP, and to provide a theoretical basis for dietary intervention strategies targeting the gut microbiota.

Introduction

Acute pancreatitis (AP) is one of the common digestive system diseases in clinical practice. Approximately one-fifth of AP patients develop severe acute pancreatitis (SAP), with a mortality rate of about 20%.¹ In recent years, numerous studies have reported the important role of gut microbiota dysbiosis and bacterial translocation in the progression of AP. Using 16S rRNA technology, Li et al successfully identified DNA from multiple enteric pathogens (eg, E. coli and E. faecium) within the peripheral circulation of AP patients, with their distribution positively correlating with disease severity.² According to the observations of Zhu et al, AP severity correlates positively with a progressive rise in Acinetobacter and Pseudomonas, alongside a decline in beneficial genera such as Bacteroides and Blautia.³ Abnormal changes in gut microbiota and intestinal barrier function are considered key factors in AP complications (such as pancreatic necrosis and peripancreatic infection),^4,5 and are closely associated with poor prognosis.^6,7 Notably, microorganisms that cause sepsis and pancreatic infection usually originate from the gut.⁸

As a dietary regulator of the gut microbiota, diet directly shapes the composition and function of the microbial community. Of particular clinical relevance is the observation that AP inherently provokes rapid dysbiosis and barrier compromise via intestinal ischaemia and motility disturbances, forming a vicious cycle of “AP-intestinal injury-dysbiosis-worsening of AP”.⁹ Against this background, early enteral nutrition and other dietary interventions not only provide energy support,¹⁰ but also break this cycle by maintaining microbial homeostasis and barrier integrity.^11,12 This clinical paradigm shift from strict bowel rest (“pancreatic rest”) to early enteral nutrition (“gut nourishment”) underscores the crucial role of maintaining the intestinal barrier and regulating the microbiota in the management of AP, while also providing the most direct clinical basis for dietary interventions.

For the purpose of analysis, we have divided common dietary patterns into two major categories (Table 1): Among them, “harmful diets” primarily refer to dietary patterns that, when consumed long-term, are likely to induce metabolic endotoxemia and dysbiosis, including Western diets (WD), high-fat diets (HFD), ketogenic diets (KD), and high-salt diets (HSD); whereas “beneficial diets” refer to dietary patterns rich in dietary fiber, unsaturated fatty acids, and phytochemicals, which help maintain gut microbiota diversity and barrier integrity, such as the Mediterranean diet (MD), high-fiber diet, plant-based diet, and dietary restriction (DR).

Table 1.

Summary of How Different Dietary Patterns Influence AP Through the Gut Microbiota

Dietary Pattern	Nutritional Composition	Gut Microbiota Changes	Effect on AP
Western diet	High saturated fat, high sugar, low fiber	Proteobacteria (especially Escherichia/Shigella)↑,13 Butyrate-producing bacteria (eg, Faecalibacterium prausnitzii)↓13	Worsens gut barrier, promotes bacterial translocation to pancreas and blood, increases necrosis and systemic infection; antibiotics may cause “substitute infections.”
High-fat diet	Fat provides >30% of energy	Bacteroides uniformis↓,14 Desulfovibrio↑, Staphylococcus↑, Ruminococcus↓15	Induces hypertriglyceridemia, promotes NETs, activates IL-17/NF-κB, aggravates acinar necrosis; LPS triggers TLR4/MyD88/NF-κB vicious cycle.
Ketogenic diet	Very high fat, very low carbohydrate	α-diversity↓, Spirochaetales, Erysipelotrichales↑,16,17 SCFA-producing bacteria↓18–20	Increases mortality (17%→58%), aggravates pancreatic necrosis, promotes bacterial translocation, enhances oxidative stress and pro-inflammatory cytokines (IL-1α, IL-5, IL-12).
High-salt diet	Sodium intake far above recommendation (WHO: <5 g salt/day)	Lactobacillus (especially L. murinus)↓21,22	Damages intestinal barriers, promotes bacterial translocation and secondary infections; reduces ILA, relieves Th17 inhibition, increases IL-17, worsens inflammation.
Mediterranean diet	Rich in dietary fiber, polyphenols (eg, hydroxytyrosol HT), ω-3 fatty acids	Butyrate-producing species↑ (Clostridium leptum, Eubacterium rectale, Faecalibacterium prausnitzii),23–26 Lactobacillus (especially L. johnsonii)↑27	HT upregulates ZO-1/Occludin, activates Nrf2/HO-1, inhibits NF-κB, reduces TNF-α, IL-6, iNOS; alleviates pancreatic and colonic inflammation.
High-fiber diet/Prebiotics	Soluble dietary fiber (lactulose, inulin, chitosan oligosaccharides, etc).	Akkermansia↑,28,29 SCFA-producing bacteria↑,28,30 Escherichia-Shigella, Enterococcus, Klebsiella↓28–30	Lactulose improves gut function and reduces endotoxin in AP patients; inulin via butyrate inhibits HDAC3, induces M2 macrophage polarisation, protects pancreas and gut; chitosan oligosaccharides inhibit TLR4/NF-κB and MAPK.
Plant-based diet	Primarily plant-based foods (high fiber, low animal fat)	Fiber-degrading and butyrate-producing bacteria (eg, Ruminococcaceae, Butyricicoccus) ↑31	Theoretically maintains mucus layer, reduces translocation and oxidative stress; linked to lower cardiometabolic risk (direct AP evidence lacking).
Dietary restriction	Caloric restriction (25–40%), intermittent fasting (5:2), time-restricted eating, fasting-mimicking diet, etc.	Lactobacillus↑, Bifidobacterium↑,Helicobacter↓,32 Lactobacillaceae, Bifidobacteriaceae↑,33 SCFA-producing bacteria (eg, Parabacteroides distasonis)↑34	CR reduces CRP and IL-6; FMD reduces intestinal immune cell infiltration; may protect barrier (very limited direct AP evidence).

Notes: The symbols ↑ and ↓ in the table indicate an increase or decrease in the abundance of intestinal microbiota.

However, previous reviews have mostly listed dietary patterns sequentially, resulting in fragmented content and overlapping descriptions of mechanisms; at the same time, these reviews extensively cited research data from non-AP models such as obesity and metabolic syndrome, but lacked sufficient focus on mechanisms unique to AP itself. To address this issue, this paper constructs a core analytical framework centered on AP pathological damage and protective pathways, systematically comparing how harmful and beneficial diets, through the gut microbiota, respectively affect bacterial translocation, intestinal barrier function, endotoxin-triggered inflammatory cascades, and immune regulatory responses during the AP process. Finally, we will summarize the existing gaps in the current evidence and provide prospects for future research directions.

Convergent Pathological Mechanisms Shared by Multiple Harmful Dietary Patterns

WD is characterized by a high intake of processed foods, refined carbohydrates, red meat and processed meats, and full-fat dairy products, along with an extremely low intake of dietary fiber, representing a contemporary dietary pattern.³⁵ Its key quantitative indicators include: saturated fat content exceeding 10% of total energy, a high proportion of simple sugars (especially fructose), abundant animal protein, excessive sodium intake, and dietary fiber intake below 20 g/day.^13,36

Generally, the fat intake of adults should account for 20%–30% of total energy. In relevant studies, HFD often refers to a dietary pattern where fat intake exceeds 30% of total energy.³⁷ It should be noted here that HFD mainly emphasizes excessive total fat intake, whereas WD is a more complex dietary pattern that, in addition to high fat, is also characterized by high sugar and low fiber.³⁸

KD is a dietary pattern characterized by high fat, very low carbohydrates, and moderate protein.^39,40 Its classic macronutrient ratio is approximately: 70–80% fat, 15–20% protein, and 5–10% carbohydrates.⁴¹ This extreme nutrient composition is designed to mimic a fasting state and induce ketone production.

HSD generally refers to dietary patterns with sodium intake far exceeding the recommended standard (the World Health Organization recommends salt intake <5 g/day, approximately <2 g sodium/day).⁴² In experimental studies, 4% NaCl is commonly used to induce pathological effects.^21,22,43

Although harmful diets differ in macronutrient composition, they may collectively exacerbate AP through four interrelated pathways: ① promoting the growth of harmful gut bacteria and bacterial translocation; ② depleting SCFA-producing bacteria, damaging the gut barrier; ③ inducing metabolic endotoxemia and activating the TLR4/NF-κB pathway; ④ possibly disrupting the Th17/Treg immune balance.

Bacterial Translocation and Pancreatic Infection

During AP, intestinal motility disorders and mucosal ischemia themselves easily promote bacterial translocation. Harmful diets further increase the “source” and “scale” of translocation by altering the composition of the microbiota. In a mouse model of necrotizing pancreatitis, WD (high-fat, low-fiber) led to severe gut dysbiosis: overgrowth of Proteobacteria (particularly Escherichia/Shigella) and a marked reduction in beneficial butyrate-producing bacteria such as Faecalibacterium prausnitzii.¹³ Accompanied by impaired intestinal barrier function, these changes in the microbiota promote the translocation of pathogenic bacteria to the pancreas and bloodstream, thereby increasing the risk of pancreatic necrosis and systemic infection. It is noteworthy that although antibiotic treatment reduced the mortality of pancreatitis in WD-fed mice, it led to increased dissemination of Gram-positive bacteria such as Enterococcus. This “replacement infection” indicates that antibiotic intervention alone cannot correct the underlying dysbiosis and may even select for more problematic resistant bacteria.¹³

HFD primarily exacerbates AP indirectly by inducing hypertriglyceridemia (HTG). Data from prospective cohort studies show that HTG-AP patients have a high recurrence rate after discharge, especially those with triglycerides (TG) ≥5.65 mmol/L, whose risk of recurrence is twice that of patients with TG <5.65 mmol/L.⁴⁴ In the HTG-AP mouse model, gut microbiota dysbiosis (particularly the loss of Bacteroides uniformis) promotes the formation of neutrophil extracellular traps (NETs) by reducing taurine production and activating the IL-17/NF-κB pathway, which can block pancreatic microvessels and aggravate acinar cell necrosis.¹⁴ Meanwhile, bacterial lipopolysaccharides (LPS) entering the circulation activate the pancreatic TLR4/MyD88/NF-κB pathway, creating a vicious cycle.¹⁵

KD, although beneficial in certain diseases, shows a clear harmful effect in AP. In the experimental work of Xia et al, administration of caerulein or taurocholate revealed that KD feeding dramatically raised necrotizing pancreatitis mortality, escalating from 17% to 58%, and aggravated pancreatic necrosis.¹⁶ KD reduces intestinal microbiota α-diversity, promotes the proliferation of pathogenic bacteria such as Spirochaetales and Erysipelotrichales, and increases bacterial translocation to pancreatic tissue.^16,17

HSD directly damages the mechanical, chemical, and immune barriers of the gut,⁴³ promoting bacterial translocation and secondary infections in AP.⁴⁵ In particular, in SAP, activated regulatory T cells (Tregs) suppress gut immune barrier function, leading to dysbiosis of the duodenal microbiota, while dysbiosis further facilitates the translocation of gut bacteria to necrotic pancreatic regions, ultimately resulting in infected necrosis and disease progression.⁴⁶

Short-Chain Fatty Acid Depletion

SCFAs, particularly butyrate, are key molecules in maintaining intestinal barrier integrity and suppressing inflammation. Harmful diets almost universally lead to a reduction in SCFA-producing bacteria. Specifically, the WD, due to its low fiber content, significantly reduces butyrate production;¹³ the KD, with its extreme macronutrient composition, markedly decreases gut microbial diversity and depletes SCFA-producing bacteria;^16,18–20 HSD similarly reduces butyrate levels in cecal contents.^21,22

Butyrate shortage exerts several distinct effects during AP: it reduces the expression of intestinal tight-junction components (occludin and ZO-1), thus rendering the gut more permeable;^16,17 it renders epithelial cells more vulnerable to hypoxic and inflammatory insults;¹³ and it removes the brake on histone deacetylases (HDACs), which favours the polarization of macrophages towards a pro‑inflammatory M1 state.²⁸ However, supplementation with butyrate can significantly alleviate AP inflammation induced by WD and KD.^13,16,17 These findings suggest that butyrate depletion is a key central mechanism by which harmful diets exacerbate AP.

Metabolic Endotoxemia and the TLR4/NF-κB Inflammatory Pathway

After intestinal barrier damage, LPS enters the portal vein and systemic circulation, triggering “metabolic endotoxemia.” LPS is a classical ligand of TLR4, which is widely expressed in pancreatic tissue; a deficiency of TLR4 can reduce acinar cell necrosis and alleviate the severity of AP.^47–50 Harmful diets activate this pathway through multiple mechanisms: the high saturated fats, trans fats, refined sugars, and advanced glycation end products in WD can activate TLR4 at the cellular level;³⁵ free fatty acids (FFA, especially saturated fatty acids) induced by HFD can also activate TLR4-mediated pro-inflammatory signaling pathways;^51,52 additionally, HFD increases serum nitric oxide and free radicals,⁵³ and reactive oxygen species promote auto-phosphorylation of receptor-interacting protein 1 (RIP1), thereby facilitating RIP3 recruitment to the necrosome, leading to necrotic death of pancreatic acinar cells.⁵⁴ In HTG-AP, dysbiosis (such as an increase in the abundance of Desulfovibrio and Staphylococcus and a decrease in the abundance of Ruminococcus) elevates endotoxin levels, activates the TLR4/MyD88/NF-κB pathway, and promotes the release of TNF-α and IL-6.¹⁵

An important caveat is the absence of natural antioxidants (vitamins C/E and polyphenols) in the WD, which compromises cellular redox defence, leading to oxidative damage, dysfunction, and apoptosis.⁵⁵ Similarly, KD also enhances pancreatic oxidative stress and upregulates pro-inflammatory factors such as IL-1α, IL-5, and IL-12.^16,17

Immune Regulation: Dietary-Microbiota Regulation of Th17/Treg Balance

HSD provides a typical example of the diet-microbiota-immune interaction. In a trial involving 12 healthy male participants, after a two-week high-salt challenge, the survival rate of gut Lactobacillus plummeted by nearly 42%, accompanied by an increase in pro-inflammatory Th17 cells in peripheral blood.²¹ Mechanistically, HSD reduces the levels of Lactobacillus murinus and its metabolite indole-3-lactic acid (ILA), relieving the inhibition on Th17 differentiation;^21,22 meanwhile, decreased butyrate also weakens the suppression of Th17. Elevated IL-17 can synergize with other cytokines to amplify systemic inflammation.^56,57 Although this inference originates from non-AP models, IL-17 levels have been confirmed to be positively correlated with disease severity in AP patients.^45,58 Therefore, HSD may exacerbate the severity of AP through the IL-17/Th17 axis.

Interestingly, KD reduces gut Th17 cells in certain disease models,⁵⁹ but aggravates inflammation in AP models,^16,17 suggesting that dietary effects on immunity are highly disease-specific. Furthermore, high salt can induce mitochondrial dysfunction in Tregs in vitro,⁶⁰ potentially reducing Treg-mediated suppression of the intestinal immune barrier.

Although the above harmful diets act through different initial pathways, they ultimately converge on a common core pathway (Figure 1): in the case of dysbiosis, the drastic reduction of SCFA-producing bacteria further damages the intestinal barrier, leading to LPS/bacterial translocation, which in turn activates the TLR4/NF-κB or Th17 pathways, ultimately causing pancreatic necrosis and exacerbating systemic inflammation. Among them, butyrate depletion is the core hub molecule linking harmful diets to the worsening of AP.

Figure 1.

Harmful diets disrupt gut microecology, reduce microbial diversity and butyrate-producing bacteria, damage the gut barrier (leaky gut), and promote LPS and bacterial translocation. LPS activates the TLR4/NF-κB pathway, releasing TNF-αand IL-6; in high-fat diets (HFD), free fatty acids (FFA) induce calcium overload and ROS, activating RIP1/RIP3-mediated necroptosis; high-salt diets (HSD) reduce Lactobacillus and indole-3-lactic acid (ILA), relieving inhibition on Th17 and increasing IL-17; ketogenic diets (KD) exacerbate oxidative stress and multiple pro-inflammatory factors. Collectively, these factors aggravate pancreatic necrosis and systemic inflammation. An upward arrow indicates an increase in the abundance of the microbiota, the expression of inflammatory mediators or metabolites, and the aggravation of related pathological phenomena, whereas a downward arrow indicates a decrease in the abundance of the microbiota, the expression of inflammatory mediators or metabolites, and the mitigation of related pathological phenomena.

Unified Protective Pathways Activated by Various Beneficial Dietary Components

As a traditional dietary habit of the Mediterranean region, MD is one of the most widely researched and recognized dietary patterns in the world.⁶¹ It is rich in dietary fiber, polyphenols, omega-3 fatty acids, and prebiotics. It primarily uses olive oil as the main source of fat, includes moderate consumption of fish and seafood, as well as moderate amounts of dairy products and poultry, while reducing the intake of red meat and processed foods.^23,62,63

A high-fiber diet, as the name implies, is a type of dietary pattern rich in dietary fiber, which is divided into soluble and insoluble fiber. Among them, insoluble fiber is not fermentable,⁶⁴ while soluble dietary fiber is fermented by gut bacteria into SCFAs, such as acetate, propionate, and butyrate.

The scope of a plant-based diet is relatively broad, including but not limited to vegetarianism. It mainly focuses on plant-derived foods (such as vegetables, fruits, whole grains, legumes, nuts, and seeds) and may include or exclude some animal-derived foods.⁶⁵

In this review, we define DR as a collective term for several strategies that limit either food intake timing or energy intake, such as caloric restriction (CR), intermittent fasting (IMF), and fasting-mimicking diet (FMD). CR refers to reducing a certain percentage of daily energy intake, usually by 25–40%.^66,67 IMF is a dietary pattern based on fasting or fixed proportion of energy intake during specified periods. Common IMF patterns used in studies include alternate-day fasting and 5:2 intermittent fasting.^34,68,69 FMD is a low-calorie, plant-based diet characterized by moderate carbohydrates, low protein, and high fat.⁷⁰

Although beneficial dietary patterns differ in specific nutrient compositions, they jointly alleviate the severity of AP through four interrelated pathways: ① enhancing intestinal barrier function and reducing bacterial translocation; ② increasing SCFA (especially butyrate) production, exerting metabolic and immune regulation through HDAC inhibition; ③ inhibiting the TLR4/NF-κB pathway, thereby reducing endotoxemia and oxidative stress; ④ regulating immune balance, possibly promoting the Treg/IL-10 anti-inflammatory axis, and inhibiting excessive Th17 activation.

Enhancing the Intestinal Barrier and Reducing Bacterial Translocation: The Key Role of Butyrate

During AP, “leaky gut” is the prerequisite for bacterial translocation to the pancreas and bloodstream. Beneficial diets maintain barrier integrity by enriching butyrate-producing bacteria and upregulating tight junction proteins.

Hydroxytyrosol (HT), a key component of the MD, significantly increased the expression of tight junction proteins ZO-1 and Occludin in pancreatic and colonic tissues and reduced mast cell recruitment in a caerulein-induced AP mouse model, thereby alleviating AP-associated intestinal injury.⁷¹ This effect is related to HT’s activation of the Nrf2/HO-1 pathway and reduction of oxidative stress.^72,73

High-fiber diets/prebiotics have the most direct evidence for barrier protection in AP. In a clinical study, lactulose treatment in patients with moderate to severe AP accompanied by intestinal dysfunction not only improved gastrointestinal function but also reduced endotoxin translocation by increasing SCFA production and inhibiting Escherichia coli and Shigella.³⁰ In animal experiments, inulin supplementation significantly inhibited the overgrowth of intestinal pathogens (Escherichia-Shigella, Enterococcus, Klebsiella) in high-fat diet-fed mice while increasing the abundance of beneficial Akkermansia; mechanistically, butyrate reduced LPS translocation by upregulating tight junction proteins through HDAC3 inhibition.²⁸ Additionally, chitosan oligosaccharide pretreatment similarly alleviated pancreatic inflammation in SAP mice, accompanied by upregulation of intestinal Akkermansia and downregulation of Enterococcus.²⁹

Despite a paucity of direct evidence linking plant‑based diets to AP outcomes, their high-fibre and low-animal-fat characteristics can reduce mucinase activity and maintain the integrity of the mucus layer.⁷⁴ Large-scale cohort studies have shown that vegan diets promote the growth of fiber-degrading and butyrate-producing bacteria (such as Ruminococcaceae and Butyricicoccus),³¹ which is theoretically beneficial for maintaining the intestinal barrier.

The gut microbiota is remodeled through calorie restriction or intermittent fasting. In CR mice, the abundance of Lactobacillus and Bifidobacterium increased, while Helicobacter decreased;³² FMD enriched Lactobacillaceae and Bifidobacteriaceae and reduced infiltration of intestinal immune cells.³³ Although these studies were mainly conducted in obese or healthy models, the enhancement of the intestinal barrier may reduce the risk of bacterial translocation in AP.

Enhancing SCFA Production and HDAC Inhibition: Butyrate as a Metabolic Immune Regulatory Hub

Butyrate is not only an energy substrate but also an important signaling molecule that regulates gene transcription through HDAC inhibition. Various beneficial diets significantly increase the abundance of butyrate-producing bacteria and SCFA levels.

It has been robustly demonstrated by multiple RCTs that sustained MD intervention elicits profound compositional shifts in the human gut microbiome, notably enriching SCFA-producing taxa, including butyrate producers such as Clostridium leptum, Eubacterium rectale, and Faecalibacterium prausnitzii.^23–26 Research conducted on HFD-fed obese animals revealed that HT elevates Lactobacillus counts (particularly L. johnsonii).²⁷ Although this study was not conducted in an AP model, Lactobacillus itself is an SCFA-producing bacterium.

Direct evidence for high-fiber diets is the most substantial. In a SAP mouse model with inulin intervention, butyrate regulated macrophage polarization toward the M2 phenotype by inhibiting HDAC3 and subsequent histone H3K27 acetylation, thereby alleviating pancreatic and intestinal damage.²⁸ This represents the current direct validation of the butyrate-HDAC-macrophage polarization axis in AP. Furthermore, lactulose significantly increased fecal SCFA levels in AP patients.³⁰

A plant-based diet promotes fiber fermentation by increasing microbial carbohydrate-active enzymes (CAZymes), thereby enhancing SCFA production.⁷⁴ Among DR, 5:2 intermittent fasting in healthy adults significantly enriches SCFA-producing bacteria (such as Parabacteroides distasonis) and improves metabolic markers.³⁴ CR mice also exhibit increased SCFA levels.³²

One must acknowledge that most DR-related investigations have not been performed specifically within AP cohorts; nevertheless, given that butyrate’s protective effect in AP has been confirmed in multiple AP models (WD,¹³ KD^16,17), increasing butyrate endogenously through diet is undoubtedly an ideal strategy.

Inhibition of the TLR4/NF-κB Pathway: Antioxidant and Anti-Endotoxemic Effects

Beneficial diets alleviate excessive inflammation in AP by reducing LPS translocation into the bloodstream and directly inhibiting the TLR4 signaling pathway.

HT in MD can directly reduce the degradation of IκB-α, inhibiting NF-κB nuclear translocation, thereby decreasing the expression of pro-inflammatory factors (TNF-α, IL-6) and inducible nitric oxide synthase (iNOS).⁷³ In AP mice, NF-κB activation in the pancreas and colon tissues is significantly reduced in the HT-treated group.⁷¹

High-fiber diet reduces the production of intestinal LPS by decreasing the abundance of Proteobacteria (especially Escherichia-Shigella). In SAP mice, inulin intervention significantly lowered serum LPS levels, accompanied by downregulation of pancreatic TLR4 and downstream MyD88 expression.²⁸ Chitosan oligosaccharides similarly inhibited the TLR4/NF-κB and MAPK pathways.²⁹ At the cellular level, various prebiotics can alleviate the adverse effects of inflammatory cytokines and reactive oxygen species on pancreatic acinar cells by regulating the TLR4/NF-κB and Nrf2/HO-1 signaling pathways.^75,76

Plant-based diet increases antioxidant polyphenols and fiber, reducing systemic oxidative stress. Although direct evidence for AP is lacking, plant-based diets are associated with lower risks of cardiovascular disease and diabetes,^77–79 which often coexist with low-grade inflammation.

In healthy non-obese populations, adherence to a 25% CR regimen for two consecutive years resulted in marked reductions in inflammatory markers such as serum CRP and IL-6.⁸⁰ FMD also reduces systemic inflammation in subjects with elevated CRP.³³ Fasting itself has been established as a fundamental treatment for AP patients, with its anti-inflammatory effects potentially partially mediated by the gut microbiota.

Regulating Immune Balance: Treg/IL-10 Axis and Th17 Inhibition

Beneficial diets can promote the differentiation of regulatory T cells (Treg) through microbial metabolites and inhibit excessive Th17 activation, which has been indirectly demonstrated in the harmful effects of HSD.

Although direct evidence is limited, butyrate produced by a high-fiber diet is known to promote Treg differentiation and IL-10 production.^81,82 In SAP mice with inulin intervention, butyrate inhibited HDAC3, which not only regulated macrophage polarization but also potentially affected Treg function.²⁸ The anti-inflammatory effects of MD are partly attributed to the regulatory effects of microbial metabolites on immune cells.

Under dietary restrictions, FMD reduced gut immune cell infiltration and systemic inflammation in mice.³³ CR did not impair cellular immunity in humans but reduced inflammatory markers.⁸⁰ Given that Th17/IL-17 levels are positively correlated with disease severity in AP patients,^45,58 dietary upregulation of the Treg/IL-10 axis may be an effective strategy for mitigating AP immunopathology.

Corresponding to harmful diets, although the beneficial diets mentioned above vary in composition, they ultimately converge on a common protective pathway: increasing butyrate-producing bacteria → elevated SCFAs (butyrate) → enhanced gut barrier, inhibited HDAC3/NF-κB, promoted Treg/IL-10, activated Nrf2/HO-1 → reduced bacterial translocation and systemic inflammation → and alleviated pancreatic injury (Figure 2). This commonality highlights the key role of butyrate as a central hub molecule and provides a theoretical basis for developing diet-based interventions targeting the gut microbiota.

Figure 2.

A beneficial diet increases microbial diversity and butyrate-producing bacteria. Butyrate enhances the gut barrier, inhibits NF-κB, and promotes the Treg/IL-10 axis; hydroxytyrosol (HT) in the Mediterranean diet activates Nrf2/HO-1; a high-fiber diet induces M2 macrophage polarization through HDAC3 inhibition; a plant-based diet upregulates carbohydrate-active enzymes; dietary restriction regulates leptin and insulin. These factors jointly block the vicious cycle of AP. An upward arrow indicates an increase in the abundance of the microbiota, the expression of inflammatory mediators or metabolites, and the aggravation of related pathological phenomena, whereas a downward arrow indicates a decrease in the abundance of the microbiota, the expression of inflammatory mediators or metabolites, and the mitigation of related pathological phenomena.

Discussion

Core Findings and Evidence Gaps

After reviewing the existing literature, a consistent pattern emerges: diets themselves vary greatly, but ultimately they affect AP by altering the “functional direction” of the gut microbiota—harmful diets push the microbiota toward the “pro-inflammatory, barrier-disrupting” side, thereby worsening the condition; beneficial diets push the microbiota toward the “anti-inflammatory, barrier-maintaining” side, thereby exerting a protective effect (Figure 3). In other words, the effect of diet on AP essentially reflects a shift in the overall functional state of the gut ecosystem, rather than the action of a single nutrient or a specific pathway.

Figure 3.

Diet influences AP by regulating the composition and function of the gut microbiota, altering microbial metabolites (SCFAs, LPS, ILA, etc), immune signaling (TLR4/NF-κB, Th17/Treg), and intestinal barrier integrity, thereby affecting pancreatic inflammation, acinar cell necrosis, infectious complications, and the repair process.

It must be frankly pointed out that among the references cited in this article, more than 60% of the evidence comes from non-AP models (obesity, metabolic syndrome, IBD, colitis, cardiovascular diseases, etc). Although these studies provide an important foundation for understanding the diet-microbiota-inflammation axis, the unique pathophysiological processes of AP (such as pancreatic self-digestion, peripancreatic necrosis, abdominal compartment syndrome, etc.) do not exist in other diseases. Therefore, directly extrapolating mechanisms from non-AP models to AP carries certain risks.

From Structure to Function: Paradigm Shifts in Microbiome Research

In recent years, research on the AP microbiome has been shifting from species composition to functional activity.^83,84 Traditional 16S rRNA sequencing can only observe the types of microbiota, making it difficult to reflect functional differences among different strains within the same species, and it cannot capture the dynamic changes in gene expression of the microbiota. In the future, more use should be made of metagenomic shotgun sequencing, starting from the genes of the microbial community, to identify functional modules that are truly associated with the severity of AP. On this basis, the integration of multi-omics technologies such as metatranscriptomics, metabolomics, proteomics, and even spatial transcriptomics can more comprehensively reveal the differences between microbial potential and actual activity.^82,85–87

At the mechanistic level, the research perspective also needs to shift from single-pathway analysis to networked regulatory thinking.^86,88,89 Various metabolites produced by microbes (short-chain fatty acids, secondary bile acids, branched-chain amino acids, indole derivatives, etc.) are often interrelated and mutually restraining, forming a dynamically changing metabolic network that jointly affects intestinal barrier function, immune and inflammatory responses, and pancreatic pathological processes on multiple levels.^90–93

From Individual Interventions to Synergistic Strategies: Integrating Diet, Microbiota, and Clinical Management

At the level of therapeutic strategy, microbial interventions for AP are evolving from a single approach toward a “diet-microbiota-host” coordinated regulation.^94,95 Fecal microbiota transplantation (FMT) has been preliminarily explored in AP,⁹⁶ but it still faces challenges related to safety and uncertain efficacy.^97,98 Notably, some studies indicate that dietary interventions are superior to the use of FMT alone in driving microbiota recovery, because diet not only provides nutritional support but also promotes microbiota “self-repair” by reshaping microbial niches and restoring metabolic network functions.^99–101 Based on this, diet should be considered a first-line approach for microbial intervention in AP, while strategies such as FMT may be viewed as adjunct treatments for specific refractory cases, such as recurrent refractory HTG-AP or severe antibiotic-associated dysbiosis.^28,97

Conclusion and Future Perspectives

Core Conclusion

In summary, this review, using the four core pathological/protective pathways of AP as a framework, systematically reveals the convergent mechanisms by which harmful and beneficial diets exert bidirectional regulation on AP through the gut microbiota. Although harmful diets differ in macronutrient composition, they commonly exacerbate acute pancreatitis by inducing a core cascade: causing dysbiosis → depleting SCFA-producing bacteria (especially butyrate producers) → impairing the intestinal barrier → promoting LPS/bacterial translocation → activating TLR4/NF-κB pathway and Th17 immune imbalance, thereby intensifying pancreatic necrosis and systemic inflammation. Conversely, beneficial diets attenuate acute pancreatitis severity by inversely regulating the same core pathway: enriching butyrate-producing bacteria → increasing SCFA synthesis → enhancing barrier integrity → inhibiting TLR4/NF-κB and promoting the Treg/IL-10 anti-inflammatory axis. This “convergent mechanism” suggests that the effect of diet on AP does not rely on some specific food “magic component,” but rather on reshaping the functional profile of the gut microbiota (particularly butyrate production capacity and endotoxin generation ability) to alter host susceptibility and damage responses in AP.

Clinical Implications and Research Prospects

The above findings suggest that dietary management of AP should focus on maintaining the butyrate-producing capacity of the gut microbiota and inhibiting the sources of endotoxin production. Diets high in dietary fiber, rich in polyphenols, and low in saturated fat are recommended as a priority, while strictly limiting high-fat, high-salt, and extremely low-carbohydrate dietary schemes. Promoting public policies that encourage healthy eating patterns is expected to become an effective primary prevention strategy for reducing the incidence of AP.^61,102

Due to the lack of AP-specific evidence, there is an urgent need for future multicenter prospective AP cohort studies to systematically collect fecal samples and dietary records at various stages of the disease course, and to use metagenomics and targeted metabolomics to clarify the patterns of microbial functional changes under different etiologies. On this basis, randomized controlled trials should be designed to verify the safety and preliminary efficacy of high-fiber dietary formulations or butyrate supplements, and to screen microbial biomarkers that predict dietary responsiveness. At the same time, whether specific probiotic strains can provide additional protection based on optimized diets needs to be validated in large-scale, AP-specific trials.

Given the diverse etiology of AP and the significant individual differences in microbiota, it is necessary to explore personalized strategies based on etiology, microbial characteristics, and metabolic phenotypes—specific enterotypes or microbial biomarkers are expected to become targets for predicting dietary responses and guiding interventions.^103,104 Moreover, the integration of emerging technologies presents opportunities for personalized management, and the rapid development of minimally invasive treatments and artificial intelligence technologies opens new avenues for AP management,^105–108 which can be deeply integrated with microbiome research. By using machine learning to integrate microbiome composition, metabolite profiles, and inflammatory markers,¹⁰⁹ it is expected to identify combinations of microbial biomarkers associated with AP severity and dietary responses, and predict individual responses to specific dietary interventions, thereby achieving microbiome-guided personalized nutrition.

In the long term, if the theoretical framework of this review can be validated in clinical studies, it is expected to promote substantial revisions of AP diagnosis and treatment guidelines, adding content on microbiota-targeted modulation on the basis of existing nutritional support recommendations, and clarifying dietary principles for different stages of the disease. Integrating gut microbiota monitoring into routine clinical pathways for AP could elevate dietary interventions from supportive measures to treatment strategies with specific targets, potentially improving both the short-term prognosis and long-term quality of life of AP patients.

Funding Statement

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82270665, 82400751, 82470672); the Natural Science Foundation of Heilongjiang Province (Grant Nos. PL2024H037); the National Key Research and Development Program of China (Grant Nos. 2024ZD0525500, 2024ZD0525503); Outstanding Master’s and Doctoral Theses of New Era Heilongjiang in 2023(LJYXL2023-024).

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Jiafu Wu: Conceptualization, Data Curation, Investigation, Visualization, Writing-Original Draft, Writing-Review & Editing.

Rui Bai: Investigation, Methodology, Writing-Original Draft, Writing-Review & Editing.

Zehua Zhong: Resources, Visualization, Methodology, Writing-Review & Editing.

Can Zhang: Data Curation, Investigation,Writing-Review & Editing.

Tianqi Liu: Formal Analysis,Writing-Original Draft.

Tianqi Lu:Conceptualization, Resources, Writing-Review & Editing.

Yiqin Song: Conceptualization,Investigation, Writing-Review & Editing.

Zhihan Miao: Investigation, Data Curation, Writing-Review & Editing.

Duoyi Zhang: Writing-Original Draft, Resources.

Ziqi Wang: Writing-Original Draft, Resources.

Guanqun Li: Conceptualization, Writing-Review & Editing, Supervision.

Bei Sun:Conceptualization, Supervision, Funding Acquisition, Writing-Review & Editing.

All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

All authors declared that there are no conflicts of interest in this study.