In recent years, there has been a notable increase in the incidence of acute pancreatitis [25], with the risk of severe cases continuing to rise [26]. While factors such as gallstones, hyperlipidemia, and alcohol consumption are recognized as common etiologic factors [27, 28], a significant proportion of acute pancreatitis cases lack clear identifiable causes in clinical practice [29]. Recent research has increasingly highlighted the interconnected relationship between gut microbes and acute pancreatitis. Christoph et al. conducted a study involving 420 patients with acute pancreatitis, identifying a notable association between 16 gut microbiota and the severity of systemic inflammatory response syndrome [30]. Liu et al. demonstrated the potential therapeutic effects of gut microbiota-derived nicotinamide mononucleotide in alleviating acute pancreatitis through the activation of pancreatic SIRT3 signalling [31]. Li et al. observed that fecal microbiota transplantation (FMT) reactivates intestinal NLRP3 inflammatory vesicles, exacerbating disease in antibiotic treated (Abx) and germ-free (GF) mice [32]. Nevertheless, the precise relationship between AP and GM remains uncertain due to the small sample size of observational studies and the numerous confounding variables.
This study utilized two-sample Mendelian randomization analysis to investigate the potential causal relationship between two sets of samples, utilizing the most recent genome-wide association study data on 471 gut microbiota taxa as exposures. The analysis was conducted from a genetic perspective, revealing a significant causal relationship between three specific gut microbiota taxa (Coprobacillus, Holdemania sp900120005, Megamonas) and acute pancreatitis (AP). These findings offer novel therapeutic targets for the treatment of AP.
Imbalances in the gut microbiota have been closely associated with abnormal lipid metabolism and obesity [33]. Recent research has identified an overexpression of Coprobacillus in mice fed a high-fat diet, which may contribute to an increase in colon cancer multiplicity. However, treatment with non-steroidal anti-inflammatory drugs has been shown to significantly reduce these effects, potentially reversing some of the consequences of chronic obesity and tumor diversity [34]. Elena et al. observed a cumulative effect of a high-fat diet in 3xtg mice, wherein an increase in Coprobacillus abundance was concomitant with the overexpression of inflammatory metabolites such as unsaturated fatty acids, ketone bodies, lactate, and TMAO [35]. It is noteworthy that high lipid metabolism is significantly implicated in the pathogenesis of acute pancreatitis [36, 37]. Furthermore, the presence of Coprobacillus has been identified in various non-infectious inflammatory diseases [38]. The onset of acute pancreatitis (AP) is commonly associated with aseptic inflammation resulting from pancreatic tissue damage caused by excessive production of pancreatic enzymes, leading to self-digestion [39]. Nevertheless, Zhang et al. observed that baicalin administration decreased the expression of immune-related genes, such as Th1 and Th17, ameliorated intestinal inflammation, and promoted the proliferation of Coprobacillus in a murine model of high-dose antibiotic-induced intestinal inflammation [40]. This paradoxical outcome may be attributed to the disruption of microbial homeostasis in the initial gut environment caused by the extensive administration of antibiotics, leading to varying levels of mutations in the gut microbiota, thereby highlighting the diversity of Coprobacillus. Our research has revealed that Coprobacillus functions as a pathogenic bacterium that could potentially exacerbate the development of acute pancreatitis.
Holdemania sp900120005 belongs to Holdemania. Holdemania is a pathogenic bacterium that has been found in various environments and poses a potential threat to human health [41]. Studies have shown an elevated presence of Holdemania in inflammatory and psychiatric disorders, indicating its pathogenic nature [42–44]. In a study conducted by Bjørkhaug et al., the impact of alcohol on gut microbiota functioning was investigated by comparing 24 patients with alcohol overdose to 18 control subjects. The study revealed an increased expression of Holdemania in the alcohol overdose group, with no significant association observed with short-chain fatty acids (SCFA) [45]. Notably, alcohol is recognized as a primary causative agent in acute pancreatitis [46, 47]. Furthermore, Raimondi et al. demonstrated the involvement of Holdemania in mucin degradation, a crucial component of the intestinal barrier, with excessive degradation potentially exacerbating the systemic inflammatory response [48]. These findings suggest a potential mediating role of Holdemania in the relationship between alcohol consumption and acute pancreatitis.
Megamonas, a genus of beneficial bacteria belonging to the Firmicutes phylum [49], is involved in the metabolism of the organism through the fermentation of carbohydrates to produce short-chain fatty acids (SCFA) [50]. These SCFAs, such as acetate, propionate, and butyrate, are essential for maintaining intestinal homeostasis [51, 52]and have been shown to have significant anti-inflammatory effects in various inflammatory diseases [53–55]. Jing et al. demonstrated that supplementation with short-chain fatty acids (SCFA) led to the down-regulation of the NF-κB signaling pathway, resulting in decreased inflammation and improved neural tissue function [56]. In a separate study, Li et al. observed that oral anticoagulants (OACs) altered the composition of gut microbiota, specifically increasing the abundance of Megamonas and decreasing pro-inflammatory colonies in patients with atrial fibrillation (AF). This shift in microbiota was associated with reduced thrombosis and highlighted the potential modulatory role of Megamonas in abnormal lipid metabolism [ 57]. In conclusion, our findings reinforce the aforementioned conclusions and identify novel therapeutic targets for the management of acute pancreatitis.
Recent studies have highlighted a potential causal link between gut microbiota and AP [ 58,59]. However, due to the small sample size in previous research, further investigation is warranted. This study aims to delve deeper into this relationship by analyzing 471 updated gut microbiota samples, thus enhancing the reliability of our findings.
This study is subject to several limitations. While our research aligns with the MR hypothesis, it does not definitively establish a weak tool bias. Additionally, our findings would benefit from validation through additional experimental studies.