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Research ArticleGastroenterology
Open Access | 
10.1172/jci.insight.186745
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Wang, D. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
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1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Zhao, Q. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Zhao, B. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Ma, L. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
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1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Xu, L. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Gui, M. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Xu, D. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
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1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Zeng, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Shen, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Liu, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Jiang, C. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Ni, Q. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Cui, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Lu, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Lu, Q. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Dong, D. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Peng, Y. in: JCI | PubMed | Google Scholar
1Department of Emergency,
2Department of Laboratory Medicine, and
3Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Address correspondence to: Enqiang Mao, Yibing Peng, or Danfeng Dong, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai 200025, China. Phone: 86.13501747906; Email: maoeq@yeah.net (EM); Phone: 86.1375243560; Email: pyb9861@sina.com (YP); Phone: 86.13641860213; Email: ddf40688@rjh.com.cn (DD).
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Find articles by Mao, E. in: JCI | PubMed | Google Scholar
Authorship note: DW, SS, QZ, and BZ contributed equally to this work as co–first authors.
Published March 10, 2025 - More info
Published in Volume 10, Issue 5 on March 10, 2025
AbstractInfectious complications (ICs) in acute pancreatitis (AP) are primarily driven by intestinal bacterial translocation, significantly increasing mortality and hospital stays. Despite this, the role of the gut microenvironment, particularly its metabolic aspects, in AP remains poorly understood. In this study, we investigated a cohort of patients with AP, and conducted supplemental murine studies, to explore the relationship between the gut metabolome and the development of ICs. Metabolomic analysis revealed that disruptions in gut tryptophan metabolism — especially reductions in serotonin and indole pathways — are key features associated with IC occurrence. Additionally, elevated plasma levels of tryptophan metabolites within the kynurenine pathway were identified as valuable predictive biomarkers for ICs. Mechanistic studies in murine models demonstrated that an impaired intestinal Th17 response, modulated by these tryptophan metabolites, plays a critical role in IC development. Serotonin supplementation enhanced Th17 responses, reducing IC incidence, while administration of kynurenic acid, a kynurenine metabolite, exacerbated pancreatic infections, potentially through immunosuppressive effects. These findings highlight the pivotal role of tryptophan metabolites in AP pathogenesis, emphasizing their potential as both predictive markers and therapeutic targets in IC management.
Graphical Abstract
Introduction
Acute pancreatitis (AP) results from the abnormal activation of pancreatic enzymes, leading to self-digestion of pancreatic tissue and sudden abdominal pain (1). Common causes include gallstones, hyperlipidemia, and alcohol consumption (1). The revised Atlanta classification system categorizes severity as mild, moderate, or severe, with severe AP based on organ failure within the initial 48 hours (1). For severe acute pancreatitis (SAP) cases, infectious complications (ICs), particularly infected pancreatic necrosis (IPN), can result in rapid disease progression, leading to significantly longer hospital stays and increased mortality rates of 20%–40% (2–5). This highlights the importance of early prediction of ICs to guide prompt and effective clinical decision-making for patients with SAP. However, the search for sensitive and reliable biomarkers remains ongoing.
Intestinal bacterial translocation, a process where viable luminal microbes breach the compromised gut barrier and trigger infections in distant organs, is widely recognized as the primary instigator of ICs in AP (6, 7). With the hypothesis that indicators of IC occurrence may manifest in the gut lumen during the initial phases of AP, our current study focused on the alterations in the gut of AP. Although previous research has shed light on the role of the gut contents in manipulating AP progression (8–10), most studies concentrated on early inflammation, leaving their roles in bacterial translocation largely unexplored. Furthermore, the gut metabolites originating from diet, host metabolism, and microbiota metabolism play crucial roles in preserving gut barriers and antimicrobial defenses during critical illness (11–13), yet this aspect is less studied compared with the microbiome in AP. Therefore, our study aims to investigate the alterations in gut metabolic profiles in AP and their potential association with the development of ICs. The insights gained from this research provide valuable perspectives on the mechanisms underlying intestinal bacterial translocation in AP and may contribute to identifying biomarkers to predict ICs in this condition.
ResultsStudy population. To investigate the relationship between metabolic features and the occurrence of ICs in AP, we recruited a cohort of 92 patients with AP from the emergency intensive care units (ICUs) at Ruijin Hospital, Shanghai, China, during our clinical observation period. The clinical and demographic characteristics of the patients can be found in Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.186745DS1 The most common causes of AP in this cohort were bile and hyperlipidemia, with 49 cases categorized as SAP. During the course of the disease, 43 patients developed ICs. The median interval between infection diagnosis and hospital admission was 5 days. The primary types of infections included pulmonary (n = 35), urinary (n = 14), and abdominal (n = 14). The primary pathogens included Acinetobacter baumannii (n = 16) and Klebsiella pneumoniae (n = 12). Additionally, 12 patients developed IPN, and 19 patients developed infections in more than 2 sites. Importantly, those who developed infections or specifically IPN experienced significantly longer hospital and ICU stays, along with higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, Bedside Index for Severity in Acute Pancreatitis (BISAP) scores, and serum procalcitonin (PCT) levels (Supplemental Tables 2 and 3). Patients with infections in multiple sites had even longer hospital and ICU stays compared with those with infections in a single site (Supplemental Table 4). These findings emphasized the more severe disease progression in patients with AP who developed ICs.
Dysregulation of gut tryptophan metabolism is associated with AP disease progression. We initially employed untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomics to identify potentially significant intestinal metabolic pathways in AP using a randomly selected discovery group. Compared with healthy controls (HCs), we observed a significant reduction in the levels of the majority of gut metabolites in AP (Figure 1A). These altered metabolites were primarily associated with tryptophan metabolism, purine metabolism, and the biosynthesis of plant secondary metabolites, with tryptophan metabolism displaying the most significant P value (Figure 1B). The tryptophan metabolism involves 3 pathways: the kynurenine (Kyn) and serotonin (Ser) pathways, which are metabolized by the host, and the indole (Ind) pathways, primarily managed by the gut microbiota (Figure 1C) (14). Notably, we found that the reduced intestinal tryptophan metabolites in AP were mainly involved in the Ser and Ind pathways (Figure 1D). To validate the dysregulation of tryptophan metabolism in human AP, we utilized a sodium taurocholate acid–induced (TCA-induced) AP mouse model and performed a targeted metabolomic analysis of mouse stool samples, accurately quantifying 33 common tryptophan metabolites. Our results revealed that AP mice exhibited significant depletions in tryptophan as well as several Ser and Ind metabolites, including Ser, N-acetyl-serotonin (NAS), tryptophol, and 3-indoleproponic acid (IPA), compared with HC mice (Figure 1E). Due to the depletion of tryptophan substrate, we also utilized the relative abundance of these metabolites, calculated as the ratio of metabolite concentration to tryptophan concentration, as an indicator for pathway assessment. Through this analysis, we noted a decrease in the relative abundance of 2 Ser metabolites, Ser and NAS, in AP mice as well (Figure 1F). Conversely, both the concentration and relative abundance of nicotinamide, a Kyn metabolite, increased in AP mice compared with that in HC mice (Figure 1, E and F).
Figure 1Alterations in fecal tryptophan metabolism in human AP patients and mouse models. (A) Volcano plot of differential metabolites between patients with AP (n = 33) and healthy controls (HCs; n = 19). Depleted (blue) and enriched (red) metabolites are highlighted based on P < 0.05 and variable importance in projection (VIP) > 1. (B) Bubble diagram showing Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differential gut metabolites between patients with AP (n = 33) and HCs (n = 19). Bubble size indicates the number of enriched metabolites, while the color gradient reflects enrichment significance. (C) Schematic of host and microbial tryptophan metabolism pathways. (D) Heatmap showing the relative abundance of tryptophan (Trp) metabolites across human study groups. (E) Volcano plot of differential fecal metabolites between TCA-induced AP mice (n = 11) and HC mice (n = 5). Depleted (blue) and enriched (red) metabolites were identified using a significance threshold of P < 0.05 (Student’s t test) and VIP > 0.1. (F) Relative abundance (Metabolite/Trp) of significant Trp metabolites in fecal samples from AP (n = 11) and HC mice (n = 5). (G) Bubble diagram of KEGG enrichment analysis of differential gut metabolites between AP patients with and without IC (IC, n = 16; non-IC, n = 17) and between AP patients with or without IPN (IPN, n = 5; non-IPN, n = 28). Enriched and depleted Trp metabolites are indicated by upward or downward arrows, respectively. (H) Correlation heatmap showing the relationships between clinical severity parameters and fecal Trp metabolites in patients with AP (n = 33). Box plots display medians and quartiles. Statistical analyses: Mann-Whitney test (A and D), Fisher’s exact test (B and G), Student’s t test (E and F), and Spearman’s correlation (H). *P < 0.05, **P < 0.01, ***P < 0.001.
Next, we investigated the association between the gut metabolome and the future progression of AP in patients. Intriguingly, comparison of patients with AP who developed ICs during the disease course (AP-IC group) with those who did not (AP-non-IC group) revealed that the differential metabolites were predominantly enriched in the tryptophan metabolism pathway (Figure 1G). This pathway was also identified as the metabolic pathway most significantly associated with the occurrence of IPN (Figure 1G). Specifically, AP patients with ICs, or IPN specifically, exhibited marked reductions in the Ser and Ind pathways, accompanied by a potential augmentation of the Kyn pathway, compared with AP patients without ICs or IPN (Figure 1G). Furthermore, we found significant negative correlations among the abundance of Ser and Ind metabolites and disease outcomes, including ICU stay duration and serum PCT levels (Figure 1H). This observation suggests potential alleviating impacts of gut Ser and Ind metabolites in the progression of AP. In summary, our findings underscored the presence of dysregulated tryptophan metabolism in the intestine during AP that was characterized by diminished Ser and Ind pathway activities and closely linked to disease progression.
The AP gut microbiota and its association with ICs. We also assessed the microbial alterations in AP using 16S rRNA sequencing. Evaluation of the gut microbiome health index (GMHI) (15) revealed significantly lower values in patients with AP upon admission and AP mice compared with those in the corresponding HC groups, indicating dysregulation in the gut microbiota of AP (Supplemental Figure 1, A and B). Specifically, we observed increased abundances of opportunistic pathogens, including Enterococcaceae and Enterobacteriaceae, with decreased abundance of Lachnospiraceae, specifically Blautia spp., in both patients and mice with AP (Supplemental Figure 1, C and D). We further evaluated the association between the gut microbiota and the development of ICs, which revealed that patients with ICs exhibited a significantly lower GMHI and a notably higher abundance of Enterobacteriaceae (Supplemental Figure 1, E and F). Enterobacteriaceae was also more abundant in patients with IPN than those with AP without IPN (Supplemental Figure 1G). Furthermore, we found that higher levels of Enterobacteriaceae in AP were significantly associated with longer hospital stays (Supplemental Figure 1H). Overall, these findings indicate that the initial microbial composition upon admission, particularly the heightened presence of Enterobacteriaceae, can also serve as a potential predictor for subsequent secondary infections in the setting of AP.
Plasma Kyn metabolite levels predict future IC occurrence in AP. In the process of tryptophan metabolism, the Ser and Ind pathways mainly occur within the gut, whereas the Kyn pathway takes place in various locations throughout the host (14, 16). To capture the full tryptophan metabolic landscape, we then conducted an analysis of the plasma untargeted metabolomic data from the discovery group of patients with AP. Among the annotated tryptophan metabolites, kynurenic acid (KA), a vital metabolite of the Kyn pathway, significantly increased in the plasma of AP compared with HCs (Supplemental Figure 2A). Moreover, KA level was much higher in AP patients with IPN and showed significant correlations with the length of stay in the ICU (Supplemental Figure 2, B and C).
Given the precision limitations of untargeted metabolomic tools, we proceeded to perform a targeted analysis of plasma tryptophan metabolites in a validation group comprising 56 patients with AP (Figure 2A). Compared with the HC group, we found significant depletion of plasma tryptophan levels in AP, along with elevated Kyn levels and an increased kynurenine/tryptophan (Kyn/Trp) ratio (Figure 2B and Supplemental Figure 3A). Notably, this elevation in Kyn levels and the Kyn/Trp ratio was even more pronounced in the SAP group (Supplemental Figure 3, B and C). In the AP mouse model, AP resulted in decreased plasma tryptophan levels but an increased relative abundance of several Kyn metabolites, including 3-hydroxy-dl-kynurenine (3-HK) and KA (Figure 2C and Supplemental Figure 3D). These findings suggest that alterations in tryptophan metabolism may extend beyond the gut environment and manifest in the circulating plasma during AP. Integrating those metabolomic analyses, we conclude that the downregulation of the Ser and Ind pathways in the intestine, combined with the upregulation of the Kyn pathway in the plasma, represents a key metabolic feature of tryptophan metabolism in AP.
Figure 2Plasma tryptophan profiling in relation to ICs in AP. (A) Flow chart outlining the study design for identifying meaningful tryptophan metabolites in patients with AP. (B) Heatmap showing the abundance of tryptophan metabolites in the validation group. Significant differences were evaluated between AP (n = 56) and HC (n = 14), AP-non-IC (n = 32) and IC (n = 24), and AP-non-IPN (n = 49) and IPN (n = 7). Differential metabolites were identified as P < 0.05 with VIP > 0.1 and are labeled. AP-IC-M, AP with multisite IC; AP-IC-S, AP with single-site IC. (C) Relative abundance (Metabolite/Trp) of significant tryptophan metabolites in plasma from AP-induced mice (n = 11) and HC mice (n = 5). (D–F) Plasma levels of kynurenic acid (KA) and 3-hydroxy-dl-kynurenine (3-HK) in AP subgroups. (D) KA levels in AP-non-IC (n = 32), AP-IC-S (n = 12), AP-IC-M (n = 12), and HC (n = 14). (E) 3-HK levels in the same groups. (F) KA levels in AP-IPN (n = 7), AP-non-IPN (n = 48), and HC (n = 14). (G) Distribution of multisite IC, single-site IC, and non-IC, as well as IPN and non-IPN, among AP patients with KA levels above or below 30 ng/mL (2-fold HC levels). (H) Correlation heatmap of clinical severity parameters and plasma tryptophan metabolites in patients with AP (n = 55). (I) Correlation between plasma KA levels (log, ng/mL) and total hospital stay (n = 55). One patient who was discharged early was excluded from H and I. Box plots display medians and quartiles. Statistical analyses: Mann-Whitney test (B); Student’s t test (C); Kruskal-Wallis with 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli (D–F); χ2/Fisher’s exact test (G); or Spearman’s (H) or Pearson’s (I) correlation. *P < 0.05, **P < 0.01, ***P < 0.001. See also Supplemental Figures 3 and 4.
We next assessed the associations between plasma metabolites and AP progression. We observed that patients with AP who developed ICs had significantly elevated levels of Kyn metabolites, specifically 3-HK and KA, upon admission (Figure 2B). This trend was particularly pronounced in patients with multisite infections (Figure 2, D and E). Patients with IPN showed significantly higher levels of KA compared with other patients with AP (Figure 2F). We also compared each specific infection type — pulmonary, urinary, and abdominal infections — with the non-IC group and observed that increases in Kyn metabolites, including KA, quinolinic acid, and 3-HK, were consistently present across these infection types (Supplemental Figure 4, A–C). When stratifying patients with AP into 2 groups based on whether their metabolite levels exceeded a 2-fold increase relative to HCs, we found that patients with markedly elevated levels of KA and 3-HK were significantly more likely to develop ICs, including multisite infections (Figure 2G and Supplemental Figure 4D). Additionally, elevated KA levels were associated with an increased likelihood of developing IPN (Figure 2G). In summary, these findings suggest that elevated Kyn metabolites, such as KA and 3-HK, may serve as indicators of a heightened risk for developing ICs in AP.
We then conducted a correlation analysis, which revealed significant positive associations between specific Kyn metabolites, particularly KA, and prolonged hospital and ICU stays, while Ser metabolites exhibited weak negative correlations (Figure 2H). On average, a 0.1 log increase in KA was associated with an additional 4.2 days of hospitalization (Figure 2I). Integrating these findings with fecal metabolomic data further reinforced the strong association between altered tryptophan metabolism and the progression of AP. The distinct distribution and correlation patterns of Kyn and Ser metabolites highlighted their contributions to the development of ICs in AP (Figure 3A).
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