Shotgun metagenomics reveals significant gut microbiome features in different grades of acute pancreatitis
Introduction
Acute pancreatitis (AP) is the most common gastrointestinal disease that requires acute admission and causes tremendous pain and socioeconomic burden [1]. The worldwide incidence of AP ranges from 4.9 to 80 cases per 100,000 individuals annually [2]. According to the Revised Atlanta Classification, AP is stratified into mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis (SAP) [3]. The outcome of AP patients with different severity is widely divergent. For instance, patients with MAP only need supportive care such as fluid and analgesia and recover within a few days. But in the non-mild form of AP, an inflammatory cascade leads to local and systemic complications, claims remarkable morbidity and mortality, and makes the management of AP challenging [4]. The pathogenetic mechanism underlying the progression of AP severity is yet to be elucidated [5].
Gut microbiota plays an essential role in maintaining immune homeostasis and the biological barrier of the intestine [6]. Under pathological conditions such as AP, perturbations to the gut microbiota could disrupt gut barrier, increase the intestinal permeability, and lead to bacterial translocation, which in turn triggers secondary infectious complications [7]. Several bacteria, including Escherichia, Shigella, Enterococcus, and Enterobacteriaceae family, have been found in the pancreas, indicating that their translocation from the gut could lead to infected pancreatic necrosis in non-mild AP [8]. Indeed Li et al. reported that the abundance of potentially pathogenic bacteria such as Enterococcus and Enterobacteriaceae is significantly increased, and that of beneficial bacteria such as Bifidobacterium is significantly decreased in gut microbiota of patients with MAP and SAP [9]. Our previous work revealed different gut bacteria composition in AP patients with different grades of severity. To be specific, Bacteroides, Escherichis-Shigella, and Enterococcus was the dominant gut microbiota species in MAP, MSAP, and SAP, respectively. Besides, Anaerococcus and Enterococcus were significantly increased and Eubacterium hallii decreased in non-mild AP patients [10]. Similar findings were also reported by Zhu Y et al. [7]. These studies together indicated a potential association between gut microbiota dysbiosis and AP progression. However, what remains obscure is what functional effects gut microbiota may exert upon the worsening of AP.
Shotgun metagenomic sequencing of the whole DNA provides valuable information about the functions of the microbial community [11]. The sequencing technology is used to obtain the entire genomic content of the microbiome and achieve accurate taxonomic classification and functional assignments. Also, it is able identify novel functional genes, antibiotic resistance genes, microbial pathways, and functional dysbiosis of the gut microbiome [12]. In our previous study, we performed 16S rRNA sequencing to find potential pathogenic microorganisms in patients with different severity of AP [10]. In order to further evaluate the composition and functional effects of gut microbiota in different grades of AP severity, we conducted a metagenomic shotgun survey on intestinal microbiota of MAP, MSAP, SAP patients and healthy controls, in order to characterize the AP-related composition and functional changes.
Section snippets
Subjects recruitment
The 2012 revised Atlanta classification stratified the clinical severity of AP patients into three categories: mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP) [3]. All the patients with a diagnosis of AP based on the 2012 Revised Atlanta Classification and admitted to Peking Union Medical College Hospital, Beijing, China were eligible for inclusion if they were enrolled within 48 h of the onset of symptoms from June to December 2019. A total of three MAP, three MSAP, and three
Clinical characteristics of patients and healthy subjects
A total of 9 AP patients (3 MAP, 3 MSAP, and 3 SAP) and 3 NOR were enrolled in this study. The NOR group were all women and they were 42.0 ± 14.2 years old with a BMI of 20.9 ± 2.3. The multivariate test showed that there was no individual selection bias in age and gender (supplementary Figure 3). The clinical characteristics of AP groups were shown in Table 1. Age (p = 0.473) and gender (p = 0.99) were comparable between the AP groups and the NOR group. Among the AP patients statistically
Discussion
In this study, we performed the Shotgun metagenomic sequencing approach to a cohort of 12 individuals, including 9 AP patients (3 MAP, 3 MSAP, and 3 SAP) and 3 NOR. We found remarkably different outcomes (Table 1) and significant dysbiosis of microbiome composition and function in the AP patients. Moreover, the composition and function of microbiota in SAP were different from MAP and MSAP, implying the possible association of the dysbiosis of microbial composition and function to AP severity.
Conclusions
We conducted a shotgun metagenomics survey on the gut microbiome of AP patients with three different severity grades for the first time. We identified several new AP-related bacteria and functional gene pathways, which extend the current knowledge about the role of gut microbiota in AP. Our findings may be useful for future studies investigating the mechanism of AP worsening and developing strategies for the treatment of AP.
Author statement
YSS, XYY and FYY contributed to collection of clinical data and fecal samples, and interpretation of data, and drafting of the article. WD, MX, and XJ contributed to the concept and design of the study, interpretation of data, and the critical revision of the study methods. CGR contributed to the critical revision of the article for relevant intellectual content. ZHD made critical review of the article for valuable intellectual content. WD and XJ contributed to the drafting of the article, and
Funding
This work was supported by the Beijing Natural Science Foundation (No. 7192162) and Grants from Peking Union Medical College (2019XK320036, 2019zlgc0503).
Declaration of competing interest
None.
Acknowledgments
The authors want to thank Dr. Zhang Yan for the editing of this paper.
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Shanshan Yu, Yangyang Xiong, and Yangyang Fu contributed equally and should be regarded co-first authors.