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Literature Review | Western Diet Disrupts Gut Microbiota and Increases Mortality in Necrotizing Pancreatitis

Introduction

The etiology and severity of acute pancreatitis (AP) are associated with bile acid stimulation, severe hypertriglyceridemia, ethanol consumption, and hemolysis.

Compared with healthy individuals, patients with acute pancreatitis are more susceptible to alterations in their gut microbiota, leading to increased intestinal permeability and dysbiosis, which may subsequently result in microbial infections. Obesity is a risk factor for adverse outcomes associated with increased pancreatic infection and inflammation, but its underlying mechanisms remain unclear.

In September 2020, the research team led by Fons F. van den Berg at the University of Amsterdam published a study titled “Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate” in the journal Gut (IF = 19.819). The paper elucidated how a Western diet disrupts the gut microbiota and its impact on mortality and bacterial translocation in necrotizing pancreatitis, as well as the critical roles of butyrate depletion and supplementation in the pathogenesis of this condition. The study employed a mouse model of necrotizing pancreatitis, along with multi-omics integration and regression analyses, offering valuable insights and methodologies that can inform future clinical research.

 

 

Research materials:

·Animal experiments

Six-week-old C57BL/6 mice were fed either a standard diet (SD) or a Western diet (WD) for 4 weeks to establish an acute necrotizing pancreatitis (ANP) model, with saline (VEH) serving as the control; cecal tissue samples (CE-T) and cecal contents (CE-C).

 

·Method for establishing a mouse model of necrotizing pancreatitis:

The mice were anesthetized and laparotomized. The descending portion of the duodenum was everted to the left and secured with sutures, exposing the Vater’s papilla at the duodeno‑pancreatic junction. A catheter equipped with an infusion tube and pump was inserted through the Vater’s papilla into the common bile duct, advancing approximately 1 mm into the duct and then ligated in place. Simultaneously, the bile duct at the hepatic hilum was clamped, and sodium taurocholate solutions of varying concentrations were infused retrogradely.

 

·Technology Methods: 16S rRNA sequencing, non-targeted metabolomics, targeted short-chain fatty acid metabolomics

·Experimental roadmap:

 

Research Findings:

1. Phenotypic analysis: A Western diet increases mortality and inflammation in ANP mice.

Infusion of taurocholic acid (TA) into the pancreatic duct can induce acute necrotizing pancreatitis (ANP) and mortality in WD‑fed mice, while blood and pancreatic culture results indicate a marked systemic infection in WD‑plus‑ANP mice.

Figure 1: A Western diet increases mortality and inflammation in ANP mice.

 

2.16S Sequencing Analysis: Analysis of the gut microbiota composition in ANP mice

Compared with WD+VEH and SD+ANP mice, WD+ANP mice exhibited significant alterations in the microbial composition of both cecal contents and cecal tissues; in contrast, mice fed a standard diet showed no significant differences following similar treatments.

The gut microbiota of WD+ANP mice is characterized by a loss of diversity and an overgrowth of Escherichia and Shigella.

Figure 2: Composition analysis of the gut microbiota in ANP mice

 

3. Phenotypic microarray + untargeted metabolomics + SCFA-targeted metabolomics analysis : The cecal microbiota is functionally disrupted in WD+ANP mice.

Further analysis using phenotypic microarray assays examined the capacity of cecal microbial communities to utilize carbon sources and their susceptibility to antimicrobial compounds. The results were consistent with 16S rRNA‑based compositional data, indicating that, under aerobic conditions, metabolic respiration was enhanced in the gut microbiota of WD+ANP mice.

Figure 3: Phenotypic microarray analysis of the gut microbiota in ANP mice

 

Targeting Targeted Metabolomics of Short-Chain Fatty Acids (SCFAs) Analysis indicates that, compared with SD pancreatitis mice, WD pancreatitis mice exhibit a marked reduction in acetate and butyrate levels in the cecum, accompanied by profound alterations in the composition and function of the cecal microbiota, characterized by significant decreases in butyrate, amino acids, and carbohydrates.

Figure 4: Targeted metabolomic analysis of SCFAs in cecal tissue from ANP mice.

 

4. Research on the Functions of Gut Microbiota

(1) Antibiotic treatment depleted Escherichia coli in the intestines of WD‑induced pancreatitis mice and reduced mortality in the WD+ANP group.

Figure 6: Antibiotic-depletion microbiota experiment

(2) Fecal microbiota transplantation (FMT) increases mortality and bacterial translocation in ANP mice.

(3) Oral administration and intraperitoneal injection of butyrate can reduce mortality and the dissemination of Escherichia coli in ANP mice.

 

5. Highlight of the article’s elevation: Returning to clinical analysis

16S rRNA sequencing of fecal microbiota from patients with pancreatitis and healthy individuals revealed that, compared with healthy subjects, patients with acute pancreatitis exhibited increased abundance of genera such as Shigella and Streptococcus, while butyrate-producing bacteria were reduced.

Figure 7: 16S rRNA sequencing analysis of clinical samples

 

Conclusion

This study established a pancreatitis model by retrograde infusion of sodium taurocholate into the pancreaticobiliary duct, a classic method for creating a severe acute pancreatitis model. Bile reflux into the pancreatic duct triggers activation of pancreatic zymogens, leading to autodigestion of pancreatic tissue and an inflammatory response, primarily characterized by pancreatic necrosis that extends to organs such as the kidneys, lungs, liver, and intestines. This model exhibits good stability and high reproducibility, closely mimicking the pathological and morphological changes observed in clinical patients.

Using 16S rRNA sequencing and both untargeted and targeted metabolomics, we demonstrate that diet and its interactions with the gut microbiota can profoundly influence the disease course and prognosis of ANP. Western‑diet feeding exacerbates experimental acute necrotizing pancreatitis by promoting bacterial translocation and alters intestinal metabolic profiles through depletion of short-chain fatty acids. In the gut microbiota of pancreatitis‑prone mice fed a Western diet, Escherichia coli predominates; selective decontamination with Gram‑negative agents reduces the proliferation of Gram‑negative bacteria but, conversely, increases the dissemination of Gram‑positive species. In a mouse model of acute necrotizing pancreatitis, fecal microbiota transplantation enhances bacterial translocation and elevates mortality. By contrast, butyrate supplementation attenuates disease progression in mice, suggesting that prophylactic butyrate therapy in patients with acute pancreatitis may represent a promising strategy to prevent the progression of this potentially life‑threatening condition.

 

 

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