Study on the pathogenesis of idiopathic pediatric acute pancreatitis by combining intestinal microbiome and metabolome.

Abstract

Background: Idiopathic pediatric acute pancreatitis (IPAP) represents a significant health threat to children and adolescents, yet its underlying pathogenesis remains poorly understood, necessitating further research to elucidate its mechanisms. This study aims to explore the roles of intestinal microbiota, short-chain fatty acids (SCFAs), and serum metabolites in the pathogenesis of IPAP, as well as to assess the therapeutic potential of acetic acid intervention in this condition.

Methods: Fecal and serum samples from 22 cases of IPAP (excluding biliary origin) and 10 healthy controls were collected and analyzed. Intestinal microbial was characterized using 16S ribosomal RNA (16S rRNA) sequencing, while SCFAs and serum metabolites were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Omics analysis was employed to identify microbial-metabolite regulation and regulatory networks and potential disease biomarkers. To evaluate the therapeutic efficacy of acetic acid in acute pancreatitis (AP), AP was induced in animal models by intraperitoneal injection of caerulein (50 µg/kg; once daily for seven days), followed by oral administration of acetic acid (10 mL/kg, once daily) in 4-, 6-, and 8-week models. Pancreatic and ileum tissues were examined for histopathological changes, serum enzymes levels, and intestinal barrier integrity.

Results: The results of 16S rRNA sequencing revealed significant differences in the composition and abundance of intestinal microbial communities between the control (Con) and IPAP groups. Pathogenic bacteria, such as f_Tannerellaceae and c_Bacteroidia, as well as certain symbiotic bacteria, were significantly enriched in the IPAP group. SCFAs metabolome analysis indicated that acetic acid, as a key intermediate metabolite, may play a regulatory role in the pathogenesis of IPAP. The construction of a microbial-metabolite regulatory network demonstrated that microorganisms such as g_Monoglobus and g_Morganella were closely associated with SCFAs, including acetic acid, suggesting that the development of IPAP is influenced by upstream and downstream regulatory mechanisms. Furthermore, significant associations were identified between serum metabolites and gut microbes. For instance, (4E,15E)-bilirubin and creatinine showed significant positive correlations with g_Bacteroides (P<0.01). Similarly, 1,2-ethanediol monoricinoleate was significantly positively correlated with g_Hungatella (P<0.01), while pubescenol and tecastemizole were significantly positively correlated with g_Parabacteroides (P<0.01). Animal experiments demonstrated that pancreatic and intestinal tissue damage was alleviated to varying degrees following treatment. Compared to the disease model group, the acetic acid treatment group exhibited significantly reduced serum levels of D-lactic acid, amylase, and lipase, along with a significantly increased positive staining surface density of intestinal barrier proteins (occludin, claudin-1, and ZO-1).

Conclusions: Intestinal flora, SCFAs and serum metabolites were significantly altered in IPAP, and the interaction regulated the development of IPAP. Acetic acid can effectively intervene the occurrence of IPAP.