Gut-derived infection is among the most common complications in patients who underwent severe trauma, serious burn, major surgery, hemorrhagic shock or severe acute pancreatitis (SAP). It could cause sepsis and multiple organ dysfunction syndrome (MODS), which are regarded as a leading cause of mortality in these cases. Gut-derived infection is commonly caused by pathological translocation of intestinal bacteria or endotoxins, resulting from the dysfunction of the gut barrier. In the last decades, the studies regarding to the pathogenesis of gut-derived infection mainly focused on the breakdown of intestinal epithelial tight junction and increased permeability. Limited information is available on the roles of intestinal microbial barrier in the development of gut-derived infection. Recently, advances of next-generation DNA sequencing techniques and its utilization has revolutionized the gut microecology, leading to novel views into the composition of the intestinal microbiota and its connections with multiple diseases. Here, we reviewed the recent progress in the research field of intestinal barrier disruption and gut-derived infection, mainly through the perspectives of the dysbiosis of intestinal microbiota and its interaction with intestinal mucosal immune cells. This review presents novel insights into how the gut microbiota collaborates with mucosal immune cells to involve the development of pathological bacterial translocation. The data might have important implication to better understand the mechanism underlying pathological bacterial translocation, contributing us to develop new strategies for prevention and treatment of gut-derived sepsis.

Increased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

Introduction: Dysbiosis of intestinal microbiota likely plays an important role in the development of gut-derived infections, making it a potential therapeutic target against sepsis. However, experience with fecal microbiota transplantation (FMT) in the treatment of sepsis and knowledge of the underlying mechanisms are extremely lacking. In this article, we describe a case of a patient who developed sepsis after a vagotomy and later received an infusion of donor feces microbiota, and we report our findings. Methods: A 44-year-old woman developed septic shock and severe watery diarrhea 4 days after undergoing a vagotomy. Antibiotics, probiotics and supportive treatment strategies were used for about 30 day after surgery, but the patient’s fever, bacteremia and watery diarrhea persisted. Considering the possibility of intestinal dysbiosis, we evaluated the structure and composition of the patient’s fecal microbiota using 16S rDNA-based molecular techniques. As expected, the gut microbiota was extensively disrupted; therefore, a donor fecal suspension was delivered into the patient by nasoduodenal tube. The patient’s clinical outcomes and shifts of the gut microbiota following the treatment were also determined. Results: Dramatically, the patient’s septic symptoms and severe diarrhea were successfully controlled following FMT. Her stool output markedly declined after 7 days and normalized 16 days after FMT. A significant modification in her microbiota composition was consistently seen, characterized by a profound enrichment of the commensals in Firmicutes and depletion of opportunistic organisms in Proteobacteria. Furthermore, we identified a reconstituted bacterial community enriched in Firmicutes and depleted of Proteobacteria members that was associated with fecal output, plasma markers of inflammation and T helper cells. Conclusions: In this report, we describe our initial experience with FMT, in which we successfully used it in the treatment of a patient with sepsis and severe diarrhea after a vagotomy. Our data indicate an association between repaired intestinal microbiota barrier and improvement of clinical outcomes. Our patient’s surprising clinical benefits from FMT demonstrate the role of intestinal microbiota in modulating immune equilibrium. It represents a breakthrough in the clinical management of sepsis and suggests new therapeutic avenues to pursue for microbiota-related indications.

Infectious complications are a leading cause of death for patients with severe acute pancreatitis (SAP). Yet, our knowledge about details of the blood microbial landscape in SAP patients remains limited. Recently, some studies have reported that the peripheral circulation harbors a diverse bacterial community in healthy and septic subjects. The objective of this study was to examine the presence of the blood bacterial microbiome in SAP patients and its potential role in the development of infectious complications. Here we conducted a prospective observational study on a cohort of 50 SAP patients and 12 healthy subjects to profile the bacterial composition in the blood. The patients were subgrouped into uninfected (n = 17), infected (n = 16), and septic (n = 17) cases. Applying 16S rDNA-based next-generation sequencing technique, we investigated blood and neutrophil-associated microbiomes in SAP patients, and assessed their connections with immunological alterations. Based on the sequencing data, a diverse bacterial microbiota was found in peripheral blood and neutrophils from the healthy and SAP subjects. As compared to healthy controls, the blood and neutrophil-associated microbiomes in the patients were significantly altered, with an expansion in Bacteroidetes and Firmicutes as well as a decrease in Actinobacteria. Variations in the microbiome composition in patients were associated with immunological disorders, including altered lymphocyte subgroups, elevated levels of serum cytokines and altered proteomic profiles of neutrophils. However, no significant compositional difference was observed between the patient subgroups, implying that the microbiota alterations might not be linked to presence/absence of infectious complications in SAP. Together, we present an initial description of the blood and neutrophil-associated bacterial profiles in SAP patients, offering novel evidence for the existence of the blood microbiome. Identification of the blood microbiome provides novel insights into characteristics and diagnostics of bacteremia in the patients. Further study is required to assess the possible implications of the blood microbiome in health and diseases.

Introduction: Recent studies have demonstrated the presence of a circulating microbiome in the blood of healthy subjects and chronic inflammatory patients. However, our knowledge regarding the blood microbiome and its potential roles in surgical patients remains very limited. The objective of this study was to determine the blood microbial landscape in surgical patients and to explore its potential associations with postoperative sepsis.Materials and Methods: 2825 patients who underwent surgical treatments were screened for enrollment and 204 cases were recruited in this study. The patients were sub‐grouped into noninfected, infected, sepsis, and septic shock according to postoperative clinical manifestations. A total of 222 blood samples were obtained for neutrophil isolation, DNA extraction and high‐throughput sequencing, quantitative proteomics analysis, and flow cytometric analyses.Results: Blood and neutrophils in surgical patients and healthy controls contained highly diverse microbiomes, mainly comprising Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. The majority (80.7%–91.5%) of the microbiomes were composed of gut‐associated bacteria. The microbiomes in septic patients were significantly distinct from those of healthy controls, and marked differences in microbiome composition were observed between sepsis and septic shock groups. Several specific bacterial genera, including Flavobacterium, Agrococcus, Polynucleobacter, and Acidovorax, could distinguish patients with septic shock from those with sepsis, with higher area under curve values. Moreover, Agrococcus, Polynucleobacter, and Acidovorax were positively associated with the sequential (sepsis‐related) organ failure assessment scores and/or acute physiology and chronic health examination scores in septic shock patients. The proteins involved in bactericidal activities of neutrophils were downregulated in septic patients.Conclusions: We present evidence identifying significant changes of blood and neutrophil‐specific microbiomes across various stages of sepsis, which might be associated with the progression of sepsis after surgical treatments. Several certain bacterial genera in blood microbiome could have potential as microbial markers for early detection of sepsis.

Introduction: The pathogenesis of inflammatory bowel disease (IBD) has not yet been clarified and is closely related to several pro‐inflammatory factors. MicroRNA‐233 (miR‐223) might be involved in the development of IBD; however, the mechanism underlying its pathogenesis is unclear. In this study, we attempted to determine the role of miR‐223 in dextran sodium sulfate (DSS)‐induced colitis and explore the involvement of the IL‐6/STAT3 pathway in the development of intestinal mucosal inflammation.Materials and Methods: Except control (WT) group, male C57BL/6 mice were provided DSS, then treated for with miR‐223 agomir or antagomir including DSS group, DSS + miR‐223 agomir (DSS + A) group, and DSS + miR‐223 antagomir (DSS + AN) group. The colitis symptoms were observed, the disease activity index (DAI) score were recorded daily, and colonic inflammation was evaluated by histopathological scoring. The expression of myeloperoxidase (MPO), cytokines and IL‐6/STAT3 pathway‐related proteins were measured.Results: miR‐223 expression in the terminal ileum and colon was increased in the DSS group compared with the WT group. Colitis symptoms were significantly alleviated in the DSS + A group and exacerbated in the DSS + AN group after administration of the miR‐223 agomir and antagomir, respectively. MPO, tumor necrosis factor‐α, IL‐6, and IL‐17 were decreased and IL‐10 was increased in the DSS + A group, but these changes were reversed in the DSS + AN group. Gp130, p‐STAT3, Bcl‐2, and Bcl‐xl in the colon declined in the DSS + A group, but these levels increased in the DSS + AN group.Conclusions: The upregulation of miR‐223 by agomir administration alleviated colonic inflammation in a DSS‐induced colitis model, which was likely mediated by inhibiting the production of pro‐inflammatory cytokines via the IL‐6/STAT3 signaling pathway. These findings provide evidence that miR‐223 might have potential therapeutic implications in IBD.