Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can cause severe local and systemic complications (Boxhoorn et al., 2020). Approximately 15–20% of patients with AP develop acute necrotizing pancreatitis (ANP) (Iannuzzi et al., 2022). One of the most common causes of death in patients with AP is infected pancreatic necrosis (IPN), a severe complication of ANP with a mortality of 20–30% (Baron et al., 2020). Previous studies have reported the microbiological profile of organisms in IPN. However, the results were not entirely consistent among studies due to different hospitals, clinical practices, and practices of antibiotic usage (Garret et al., 2020; Jiang et al., 2020; Wolbrink et al., 2020). In a retrospective study, Mowbray et al. compared their findings with eight other studies evaluating pathogens that caused IPN (Mowbray et al., 2018). They revealed a predominance of gut bacteria in IPN, including Escherichia coli (20%), which was also confirmed in our previous studies (24-29%) (Ning et al., 2019; Li et al., 2022). Notably, Escherichia coli was one of the most frequently cultured microorganisms in IPN.

Recently, studies have reported that several pathogenic microorganisms were identified as independent risk factors for increased mortality in IPN, including fungal infection, Carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumanii infection as well as candidemia and multidrug-resistant organisms (MDROs) infection (Moka et al., 2018; Rasch et al., 2018; Ning et al., 2019; Würstle et al., 2019; Moran et al., 2022). However, as one of the most frequently cultured microorganisms in IPN, Escherichia coli has never been investigated for its impact on the prognosis of patients with IPN. Therefore, we conducted this study from the prospective database of patients with IPN at a large Chinese tertiary hospital and attempted to identify the impacts of Escherichia coli infection on the outcomes of patients with IPN.

To the best of our knowledge, this was the first and largest post-hoc study ever conducted in a tertiary hospital that evaluated the impacts of Escherichia coli infection on the outcomes of patients with IPN. This study demonstrated a significantly lower occurrence of SAP, fewer step-up surgical interventions, lower rate of MOF, and lower mortality in patients with IPN complicated with Escherichia coli infection. Additionally, this study revealed that MOF and hemorrhage were independent predictors of higher mortality in patients with IPN, and that the occurrence of Escherichia coli infection was a significant predictive factor for favorable prognosis in patients with IPN. These findings suggested that the prognosis of patients with IPN was significantly associated with the microbial culture results, which might help clinicians stratify patients based on microbial culture results.

IPN is considered a late-phase complication of AP, usually occurring two weeks after the onset of the disease. Although gut-derived bacteria cause most infections, the development of secondary necrotic collection infection is not fully understood (Liu et al., 2019; Thomas and Jobin, 2020). Significant gut barrier dysfunction has been observed in approximately 60% of patients with SAP (Wu et al., 2014). Gut barrier dysfunction and bacterial translocation from the gut are considered the central mechanisms underlying the development of peripancreatic infections (Li et al., 2020; Thomas and Jobin, 2020). Escherichia coli is one of the most frequently cultured microorganisms in the IPN and it is also an opportunistic pathogen derived from the gut (Mowbray et al., 2018). However, data regarding its role in IPN are still lacking. Li et al. (Li et al., 2013) conducted a prospective controlled study in patients with AP as revealed using 16S recombinant deoxyribonucleic acid (rDNA)-based molecular approaches, and they observed that translocated bacteria in patients with AP primarily consisted of opportunistic pathogens derived from the gut, including Escherichia coli, Shigella flexneri, Enterobacteriaceae bacterium, Acinetobacter lwoffii, Bacillus coagulans, and Enterococcus faecium. They also observed an association between the translocated bacterial spectrum of bacteremia and the severity of AP. Additionally, they revealed that more than half (60.4%) of the patients with AP encountered polymicrobial flora, which is consistent with our study’s results in that the polymicrobial infection rate was approximately 68.4% in IPN patients. An experimental animal study on the effects of Escherichia coli reported that Escherichia coli MG1655, a commensal belonging to Escherichia, increased intestinal injury and aggravated ANP in rats (Zheng et al., 2019), which seems to contradict our study’s conclusions. However, that study was concerned with the separate effects of Escherichia coli, whereas our this study focused on the role of Escherichia coli in polymicrobial infection of patients with IPN.

It has been established that many higher organisms harbor various complex microbial communities. Although interactions between microbial species in these communities can be cooperative, competitive interactions appear to be more common (Hibbing et al., 2010), which includes interference competition and exploitative competition. Interference competition is one of the modes of microbial competition, and it involves the disruption of quorum sensing (i.e., cell-cell communication in bacteria) by competitors (Raffatellu, 2018). Prior studies have reported that enteric bacteria such as Escherichia coli consume the quorum-sensing molecule autoinducer-2 so that inhibiting light production by V. harveyi (Xavier and Bassler, 2005). Another experimental study revealed that Lactobacillus salivarius UCC118, a strain of Lactobacillus, decreased dissemination from the gut to the spleen and liver of mice infected with the gram-positive pathogen Listeria monocytogenes, due to the benefits of the production of a bacteriocin termed Abp11849 (Corr et al., 2007), and bacteriocin production was also reported to mediate competition between Enterococcus faecalis strains of the gut in a follow-up study (Kommineni et al., 2015).

Furthermore, in some infectious and non-infectious colitis in mice, it has been demonstrated that Enterobacteriaceae compete for nutrients (Winter and Bäumler, 2014). In these settings, exploitative competition is essential determinants of which enteric strains predominate. For instance, intestinal clearance of the mouse gut pathogen Citrobacter rodentium can be achieved when a mouse is colonized with Escherichia coli. Similar to the growth of Citrobacter rodentium, Escherichia coli grows on carbohydrates (Kamada et al., 2012).

It is generally accepted that the gut microbiota can provide ‘colonization resistance’ by stimulating the host immune system and engaging in interference, and exploitative competition, which could provide a barrier against pathogens through colonization resistance (Kim et al., 2017). Similar competition mechanisms have been demonstrated at other body sites colonized by microbes, such as the skin and upper airways (Sassone-Corsi and Raffatellu, 2015). The results of this study showed a lower occurrence of several pathogenic bacteria in patients with IPN and Escherichia coli infection than in those without Escherichia coli infection, including Klebsiella pneumoniae infection (33.8% vs. 38.3%, P = 0.471) and Acinetobacter baumannii infection (23.8% vs. 29.0%, P = 0.372), although the difference was not significant. We speculated that Escherichia coli infection improved the outcomes of patients with IPN by colonization resistance and by conducting its competitive inhibition effect with other pathogenic bacteria of greater virulence.

Nevertheless, further studies, such as prospective studies with larger samples and animal experiments, are required to confirm the role of Escherichia coli infection in the disease process of IPN. Interestingly, in the present study, the prognosis remained unchanged even if the Escherichia coli infection became multidrug-resistant. There was no significant difference in the clinical outcomes of patients with IPN between the MDRO-Escherichia coli infection group and the non-MDRO-Escherichia coli infection group. This study demonstrated for the first time, to our knowledge, that females are more likely to develop the MDRO-Escherichia coli infection than males, but this conclusion requires verification in a larger sample size.

This study had some limitations. As the study was performed in a single center with a multidisciplinary team of specialists, it would be prudent to extrapolate the results, which may not apply to every institution. Additionally, despite this series representing one of the largest published to date addressing IPN with Escherichia coli infection, the sample size was still relatively small. Therefore, large-scale, multicenter, and prospective studies are needed to provide more precise conclusions and to reduce potential confounding results.

This study showed a significantly lower occurrence of SAP, more frequent occurrence of polymicrobial infection, fewer step-up surgical interventions, lower rate of MOF, and lower mortality in IPN patients with Escherichia coli infection than in those without Escherichia coli infection. Additionally, this study revealed that MOF and hemorrhage were independent predictors of higher mortality in patients with IPN and that Escherichia coli infection was a significant factor associated with decreased mortality. These findings have vital implications for future antibiotic regimens in patients with IPN. However, more research is required to understand how opportunistic microbes compete with pathogens in the IPN and investigate bacterial metabolites with antimicrobial functions. As more is learned about specific mechanisms of microbial competition in the host, this knowledge can be leveraged to identify and deploy new opportunistic microbes and introduce these specific microbes or their metabolites to inhibit pathogenic strains, thus improving the prognosis.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional Review Board of Xiangya Hospital. The patients/participants provided their written informed consent to participate in this study.

HH conceived the study. HH, JP, DS and GH participated in the study design. CN, QW, JL, CL, ZS, LC and SZ collected the data. HH and DS performed the statistical analyses. HH drafted the manuscript. DS and GH edited and checked the manuscript. All authors contributed to the article and approved the submitted version.