Interleukin-37 protects against acinar cell pyroptosis in acute pancreatitis.

Acute pancreatitis (AP) is a local and/or systemic inflammatory disease that starts with acinar cell injury and necrosis; it has no effective medical treatment and thus remains a life-threatening condition. Interleukin-37 (IL-37), a natural immunomodulator, has demonstrated an antiinflammatory effect; however, the role of IL-37 in AP remains unknown. The serum IL-37 levels of 39 healthy controls and 94 patients with AP were measured. Cholecystokinin was applied to induce pancreatic acinar cell injury in vitro. Classical experimental AP models, such as caerulein, l-arginine, and taurolithocholic acid 3-sulfate disodium salt, were included in the in vivo study. A transgenic mouse model with the IL-37 gene and administration of recombinant IL-37 were used to further investigate the function of IL-37 in AP. Pancreas-specific gasdermin D-knockout (GSDMD-knockout) mice were used to explore the protective mechanism of IL-37. Our results showed that serum IL-37 levels in humans were negatively correlated with the severity of AP. Furthermore, IL-37-transgenic mice and supplementation with recombinant IL-37 could both protect against AP. Mechanistically, IL-37 was able to suppress pyroptosis of injured acinar cells, and specific depletion of GSDMD in the pancreas counteracted the protective effect of IL-37. Our study demonstrates that IL-37 protects against acinar cell pyroptosis in AP.

Early intravenous administration of tranexamic acid ameliorates intestinal barrier injury induced by neutrophil extracellular traps in a rat model of trauma/hemorrhagic shock.

BACKGROUND: Early intravenous administration of tranexamic acid has been shown to protect the intestinal barrier after a model of trauma-hemorrhagic shock in the rat, but the potential mechanism remains unclear. Our previous studies have demonstrated that neutrophil extracellular traps contribute to the intestinal barrier dysfunction during sepsis and other critical conditions. Meanwhile, there are high levels of neutrophil infiltration in the intestine during trauma-hemorrhagic shock. Here, we hypothesized that neutrophil extracellular trap formation played a vital role during trauma-hemorrhagic shock-induced intestinal injury and that tranexamic acid, a serine protease inhibitor, may inhibit neutrophil extracellular trap formation and protect intestinal barrier function in trauma-hemorrhagic shock. METHODS: A model of trauma-hemorrhagic shock in male rats was established. The rats were divided into 6 groups: (1) sham group; (2) trauma-hemorrhagic shock group; (3) trauma-hemorrhagic shock + DNase I group; (4) trauma-hemorrhagic shock + tranexamic acid group; (5) trauma-hemorrhagic shock + tranexamic acid (different time) group; and (6) trauma-hemorrhagic shock + tranexamic acid (different doses) group. The DNase I solution was injected intravenously to disrupt neutrophil extracellular traps immediately after the trauma-hemorrhagic shock model was completed. After 24 hours, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate or tranexamic acid, generation of reactive oxygen species, and key proteins expression were detected. RESULTS: Trauma-hemorrhagic shock induced the formation of intestinal neutrophil extracellular traps and disrupted the intestinal tight junction proteins. Clearing of neutrophil extracellular traps by DNase I resulted in increased expression of tight junction proteins and alleviated the intestinal injury. Early intravenous tranexamic acid administration (1 hour after trauma-hemorrhagic shock) decreased neutrophil extracellular trap formation and prevented tight junction protein disruption compared to the non-tranexamic acid group; however, after delayed administration of tranexamic acid (6 hours), there were no changes in neutrophil extracellular trap formation and intestinal injuries compared to the non-tranexamic acid group. Furthermore, tranexamic acid inhibited neutrophil extracellular trap formation and protected the intestinal barrier in a dose-dependent manner and high-dose (20 mg/kg) treatment of tranexamic acid showed a better effect compared with the therapeutic dose (10 mg/kg). The results of thromboelastography demonstrated that the R and K values in the high-dose group decreased (R, 1.85 ± 0.14 vs 3.87 ± 0.16 minutes, P < .001; K, 0.95 ± 0.04 vs 1.48 ± 0.07 minutes, P < .001), accompanied by a decrease in LY30, indicating that treatment with a high dose of tranexamic acid may cause hypercoagulability and shutdown of fibrinolysis. In addition, less neutrophil extracellular trap formation was detected in neutrophils incubated with neutrophils via an reactive oxygen species-dependent pathway. CONCLUSION: We first demonstrated a novel role of neutrophil extracellular traps in the pathophysiology of intestinal barrier dysfunction during trauma-hemorrhagic shock. Notably, early but not delayed intravenous administration of tranexamic acid effectively inhibits neutrophil extracellular trap formation and protects intestinal barrier function. Therefore, these results suggested a potential theoretic intervention for the protection of the intestinal barrier during trauma-hemorrhagic shock. In such a process, tranexamic acid appears to regulate neutrophil extracellular trap formation via the classic reactive oxygen species/mitogen-activated protein kinase pathway.

Clinical parameters and outcomes of necrotizing soft tissue infections secondary to gastrointestinal fistulas.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) is severe surgical infections which can occur following trauma or abdominal surgery. NSTIs secondary to gastrointestinal (GI) fistula is a rare but severe complication. METHODS: A retrospective cohort study was performed on all subjects presenting with GI fistulas associated NSTIs were included. Clinical characteristics, microbiological profile, operations performed, and outcomes of patients were analyzed. RESULTS: Between 2014 and 2017, 39 patients were finally enrolled. The mean age were 46.9 years and male were the dominant. For the etiology of fistula, 25 (64.1%) of the patients was due to trauma. Overall, in-hospital death occurred in 15 (38.5%) patients. Microbiologic findings were obtained from 31 patients and Klebsiella pneumoniae was the most common species (41.0%). Eight patients were treated with an open abdomen; negative pressure wound therapy was used in 33 patients and only 2 patients received hyperbaric oxygen therapy. Younger age and delayed abdominal wall reconstruction repair were more common in trauma than in non-trauma. Non-survivors had higher APACHE II score, less source control< 48 h and lower platelet count on admission than survivors. Multiple organ dysfunction syndrome, multidrug-resistant organisms and source control failure were the main cause of in-hospital mortality. CONCLUSIONS: Trauma is the main cause of GI fistulas associated NSTIs. Sepsis continues to be the most important factor related to mortality. Our data may assist providing enlightenment for quality improvement in these special populations.

Insulin-like growth factor-1 as a nutritional monitoring factor in patients with chronic intestinal failure.

BACKGROUND & AIMS: Nutritional monitoring plays an important role in optimizing nutritional support in patients with chronic intestinal failure (CIF) receiving long-term supplementation. Unlike initial nutritional assessment, however, there are no recommended guidelines for establishing a nutritional monitoring index. This study is to evaluate the suitability of insulin-like growth factor-1 (IGF-1) as a nutritional monitoring factor in CIF patients. METHODS: We retrospectively analyzed the correlation between serum nutritional indicators, including IGF-1 levels, and nutritional assessment, nutritional monitoring, and lean body mass in 197 patients with CIF. RESULTS: The mean age of the 197 enrolled patients was 47.22 ± 18.87 years old and; the mean BMI was 16.83 ± 3.31. The mean NRS-2002 score was 3.49 ± 0.83; and moreover, 76.3% of the patients were malnourished. The median length of hospital stay in hospital (LOS) was 18.5 days. IGF-1 was positively correlated with body mass index, hemoglobin, albumin, pre-albumin, retinol-binding protein (RBP), transferrin, serum creatinine (Scr) and cholesterol (p < 0.05 for all). Testing performed over 3 weeks post-admission showed that significantly different weekly changes were observed only in IGF-1, RBP, and Scr during the period of nutritional support (p < 0.05 for each). Multivariate linear regression analysis showed that IGF-1 and body mass index were independent factors influencing fat-free mass, skeletal muscle mass, and body protein mass (p < 0.05 for each). CONCLUSIONS: IGF-1 is suitable for monitoring short-term changes in the nutritional status in CIF patients. This may be attributed to its shorter half-life, greater sensitivity, and better correlation with lean body mass. ClinicalTrials.gov number, NCT03277014.

N-3 polyunsaturated fatty acids ameliorate hepatic steatosis via the PPAR-α/CPT-1α pathway in a mouse model of parenteral nutrition.

Parenteral nutrition (PN) is one of the basic therapies for patients with intestinal failure; however, hepatic steatosis associated with PN limits the long-term use of PN. N-3 polyunsaturated fatty acids (PUFAs) have been used to improve clinical outcomes of patients receiving PN; however, the mechanisms by which n-3 PUFAs ameliorate hepatic steatosis remain unclear. In the present study, C57BL/6J mice were randomly assigned to three treatment groups, namely, enteral nutrition (EN), n-3 PUFAs, and n-6 PUFAs. Additionally, MK 886 was used to inhibit PPAR-α. After 7 days of intervention, mice were sacrificed, and liver tissue and serum samples were collected. Results from liver weight and liver triglyceride measurements and Oil Red O staining showed that n-3 PUFAs significantly reduced the liver triglyceride levels. In addition, treatment with n-3 PUFAs resulted in a greater decrease in serum triglyceride and low-density lipoprotein cholesterol levels compared to n-6 PUFAs. The key enzymes involved in FA oxidation, namely, PPAR-α and CPT-1α, were significantly restored at both the mRNA and protein levels in the n-3 PUFAs group. However, the benefits of n-3 PUFAs in improving serum and liver TG levels were abolished when the PPAR-α/CPT-1α pathway was blocked by MK 886. The results of this study indicated that n-3 PUFAs ameliorated the PN-associated hepatic steatosis by activating the PPAR-α/CPT-1α pathway. The present study provided a reliable scientific basis supporting the potential beneficial effects of n-3 PUFAs for improving hepatic steatosis in patients receiving long-term parenteral nutrition.

Efficacy and safety of pectin-supplemented enteral nutrition in intensive care: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Enteral nutrition (EN) can improve clinical outcomes as an important treatment in critically ill patients. However, when patients suffer from gastrointestinal function disorders, intestinal intolerance occurs and EN administration may be delayed and even fails to perform. Pectin, a structural heteropolysaccharide, could protect gastrointestinal function from disorders in many gastrointestianl diseases. The present study aimed to determine whether pectin-supplemented EN was safe and improved clinical outcomes in intensive care unit (ICU) patients. METHODS AND STUDY DESIGN: Patients enrolled in ICU from August 2014 to January 2015 were randomized to EN group and pectin-supplemented EN group (PEC/EN group). Both group received isonitrogenous, isocaloric EN support within 36 hours after ICU admission, and last for 6 days. The primary endpoints were 30-day mortality and gastrointestinal intolerance. RESULTS: There were 125 patients included in this study (63 in EN group, and 62 in PEC/EN group). The results showed that the 30-day mortality was 4.8% in EN group and 1.61% in PEC/EN group (p=0.317). PEC/EN group had a smaller gastrointestinal intolerance rate than EN group (41.3% vs 27.4%, p=0.04). Furthermore, there were shorter times to reach full EN (13.0±5.12 vs 9.99±1.91, p=0.05), length of ICU stay (17.9±9.72 vs 13.8±8.59, p<0.001), and length of hospital stay (32.9±19.0 vs 23.4±13.2, p<0.001) in EN group than those in PEC/EN group. CONCLUSIONS: These results revealed that pectin- supplemented EN was safe, and could improve clinical outcomes in ICU patients.

Lipid-rich enteral nutrition controls intestinal inflammation, improves intestinal motility and mucosal barrier damage in a rat model of intestinal ischemia/reperfusion injury.

BACKGROUND: It has been reported that lipid-rich enteral nutrition (EN) could ameliorate inflammation in various diseases. In this study, we investigated whether lipid-rich EN could control intestinal inflammation, improve intestinal motility and mucosal barrier injury after intestinal ischemia/reperfusion (I/R) injury. METHODS: Male adult rats received saline, conventional EN, or lipid-rich EN via gavage before and after intestinal I/R injury. The superior mesenteric artery was occluded for 60 min. The sham group underwent laparotomy without superior mesenteric artery occlusion and was administrated saline. Intestinal motility was measured 4 h after intestinal I/R injury by fluorescein isothiocyanate-dextran transit assay; the intestinal and systemic inflammation were assessed by analyzing intestinal and serum concentrations of tumor necrosis factor α, interleukin (IL)- 6, and IL-10, separately. The intestinal mucosal barrier injury was assessed by analyzing the serum levels of intestinal fatty acid-binding protein (I-FABP) and intestinal mucosal tight junction (TJ) proteins. RESULTS: The intestinal I/R injury decreased intestinal motility and intestinal mucosal TJs expression significantly when compared with the sham group (P < 0.05). The intestinal and systemic inflammatory parameters and the serum I-FABP were also significantly higher in the I/R groups than those in the sham group (P < 0.05). Both conventional and lipid-rich EN increased the intestinal motility and the intestinal mucosal TJs expression and decreased the intestinal and systemic inflammatory parameter and serum I-FABP levels to different degrees when compared with the I/R group (P < 0.05). However, lipid-rich EN significantly improved the negative alterations in these biochemical parameters when compared with the conventional EN (P < 0.05). CONCLUSIONS: These results suggest that lipid-rich EN might be able to control intestinal inflammation, improve intestinal motility and mucosal barrier injury after intestinal I/R injury. Thus, the administration of lipid-rich EN may be an effective treatment for promoting gastrointestinal function recovery after intestinal I/R injury.

High Prevalence of Suboptimal Vitamin D Status and Bone Loss in Adult Short Bowel Syndrome Even After Weaning Off Parenteral Nutrition.

BACKGROUND: Previous studies have noticed the high incidence of suboptimal vitamin D (VtD) status and bone loss in short bowel syndrome (SBS) with parenteral nutrition (PN) dependence. However, limited data have focused on adult SBS without PN dependence. Therefore, our objective was to investigate the incidence and risk factors of suboptimal VtD status and bone loss in adult SBS even after weaning off PN. MATERIALS AND METHODS: We performed a prospective study of 60 adult patients with SBS. Serum 25-hydroxyvitamin D (25-OHD) was measured by radioimmunoassay. Bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry (DEXA). Medical records and various laboratory parameters were collected in all participants. RESULTS: Suboptimal VtD status was identified in all individuals, including 3 (5.0%) with VtD insufficiency and 57 (95.0%) with VtD deficiency. Residual small bowel length (B, 0.072, P = .001) and duration of SBS (B, -0.066, P = .020) were both significantly correlated with suboptimal VtD levels. Overall, only 2 patients presented a normal BMD; osteopenia and osteoporosis were noted in 41 (68.3%) and 17 (28.3%) individuals, respectively. Low 25-OHD concentration was associated with a decreased BMD (B, 0.065, P = .029). There were no other demographic characteristics or clinical examinations associated with suboptimal VtD levels and bone loss. CONCLUSION: Suboptimal VtD status and bone loss were common in adult SBS even after weaning off PN. Despite routine oral VtD supplementation, most patients did not achieve satisfactory status. This emphasizes the critical importance of routine surveillance of 25-OHD and BMD, as well as consideration of alternative methods of supplementation after weaning off PN.

Soluble Dietary Fiber Ameliorates Radiation-Induced Intestinal Epithelial-to-Mesenchymal Transition and Fibrosis.

BACKGROUND: Intestinal fibrosis is a late complication of pelvic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue fibrosis. The aim of this study was to examine the effect of soluble dietary fiber on radiation-induced intestinal EMT and fibrosis in a mouse model. MATERIALS AND METHODS: Apple pectin (4% wt/wt in drinking water) was administered to wild-type and pVillin-Cre-EGFP transgenic mice with intestinal fibrosis induced by a single dose of abdominal irradiation of 10 Gy. The effects of pectin on intestinal EMT and fibrosis, gut microbiota, and short-chain fatty acid (SCFA) concentration were evaluated. RESULTS: Intestinal fibrosis in late radiation enteropathy showed increased submucosal thickness and subepithelial collagen deposition. Enhanced green fluorescent protein (EGFP)+/vimentin+ and EGFP+/α-smooth muscle actin (SMA)+ coexpressing cells were most clearly observed at 2 weeks after irradiation and gradually decreased at 4 and 12 weeks. Pectin significantly attenuated the thickness of submucosa and collagen deposition at 12 weeks (24.3 vs 27.6 µm in the pectin + radiation-treated group compared with radiation-alone group, respectively, P < .05; 69.0% vs 57.1%, P < .001) and ameliorated EMT at 2 and 4 weeks. Pectin also modulated the intestinal microbiota composition and increased the luminal SCFA concentration. CONCLUSION: The soluble dietary fiber pectin protected the terminal ileum against radiation-induced fibrosis. This effect might be mediated by altered SCFA concentration in the intestinal lumen and reduced EMT in the ileal epithelium.

Hypothalamic activation is essential for endotoxemia-induced acute muscle wasting.

Growing evidence suggests acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in critical patients. Previously, plenty of studies of muscle wasting focused on the peripheral pathway, little was known about the central role. We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process. In lipopolysaccharide (LPS) treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of nuclear factor kappa-B (NF-κB) pathway activation by infusion of an inhibitor (PS1145) can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide proopiomelanocortin (POMC) expression with a lentiviral vector containing shRNA can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected. Taken together, these results suggest activation of hypothalamic POMC is pivotal for acute muscle wasting caused by endotoxemia. Neuropeptide POMC expression may have mediated the contribution of hypothalamic inflammation to peripheral muscle wasting. Pharmaceuticals with the ability of inhibiting hypothalamic NF-κB pathway or POMC activation may have a therapeutic potential for acute muscle wasting and nutritional therapy in septic patients.

Pectin enhances the effect of fecal microbiota transplantation in ulcerative colitis by delaying the loss of diversity of gut flora.

BACKGROUND: Fecal microbiota transplantation (FMT) induces remission in ulcerative colitis (UC). However, the treatment effect of FMT diminishes over time. Maintaining the diversity of the gut flora for long periods may improve the effects of FMT in UC. Pectin, which can be fermented by gut microbiota into short-chain fatty acids, is postulated to shape the composition and maintain the balance of gut microbiota following transplantation. This study investigated whether pectin could enhance the effects of FMT in UC patients. RESULTS: Three FMT patients and four FMTP patients achieved the primary outcome. The Mayo scores of the FMTP group were lower than those of the FMT group at weeks 4 and 12 (P = 0.042 and P = 0.042, respectively). There were no differences in the diversity of the gut flora between the two groups at weeks 4 and 12; however, the composition of the gut flora of the FMTP group was more similar than the FMT group to that of the donor at all-time points post-treatment. CONCLUSIONS: Pectin decreased the Mayo score by preserving the diversity of the gut flora following FMT for UC. TRIAL REGISTRATION: Current Controlled Trial NCT02016469 . Registered 10 November 2013.

Mucosal MicroRNAs Expression Profiles before and after Exclusive Enteral Nutrition Therapy in Adult Patients with Crohn's Disease.

MicroRNAs (miRNAs) have been shown to be important for the pathogenesis of Crohn's disease (CD). Exclusive enteral nutrition (EEN) is an effective therapy for inducing remission in CD. We aimed to investigate the alteration of miRNAs expression profile in the terminal ileal mucosa of CD patients before and after EEN. Twenty-five patients and ten healthy individuals were included. MiRNAs expression profile was firstly assessed using microarray technology and then validation was performed by qRT-PCR. The correlations between miRNAs and CD activity index (CDAI) score and serum C-reactive protein (CRP) level were also evaluated. Microarray analysis showed that mucosal miRNAs expression profile after EEN therapy was significantly changed compared with inflamed mucosa before treatment, and was most similar to the healthy one among all CD groups. Altered expressions of hsa-miR-192-5p, hsa-miR-423-3p, hsa-miR-99a-5p, hsa-miR-124-3p, hsa-miR-301a-5p, hsa-miR-495-5p, and hsa-let-7b-5p were confirmed by qRT-PCR. hsa-let-7b-5p was significantly correlated with serum CRP levels before and after EEN treatment (r = -0.518, p = 0.008, and r = -0.569, p = 0.003). Our study showed EEN induction therapy was associated with a trend for normalizing of the mucosal miRNAs expression profile, and expression of mucosal hsa-let-7b-5p was correlated with serum CRP level in patients with CD.

N-3 Polyunsaturated Fatty Acids Improve Liver Lipid Oxidation-Related Enzyme Levels and Increased the Peroxisome Proliferator-Activated Receptor α Expression Level in Mice Subjected to Hemorrhagic Shock/Resuscitation.

Appropriate metabolic interventions after hemorrhagic shock/resuscitation injury have not yet been identified. We aimed to examine the effects of fish oil on lipid metabolic intervention after hemorrhagic shock/resuscitation. Firstly, 48 C57BL/6 mice were assigned to six groups (n = 8 per group). The sham group did not undergo surgery, while mice in the remaining groups were sacrificed 1-5 days after hemorrhagic shock/resuscitation. In the second part, mice were treated with saline or fish oil (n = 8 per group) five days after injury. We determined serum triglyceride levels and liver tissues were collected and prepared for qRT-PCR or Western blot analysis. We found that triglyceride levels were increased five days after hemorrhagic shock/resuscitation, but decreased after addition of fish oil. After injury, the protein and gene expression of carnitine palmitoyltransferase 1A, fatty acid transport protein 1, and peroxisome proliferator-activated receptor-α decreased significantly in liver tissue. In contrast, after treatment with fish oil, the expression levels of these targets increased compared with those in the saline group. The present results suggest n-3 polyunsaturated fatty acids could improve lipid oxidation-related enzymes in liver subjected to hemorrhagic shock/resuscitation. This function is possibly accomplished through activating the peroxisome proliferator-activated receptor-α pathway.

High-fat enteral nutrition controls intestinal inflammation and improves intestinal motility after peritoneal air exposure.

BACKGROUND: Peritoneal air exposure is a common phenomenon in abdominal surgery, but long-term exposure could induce intestinal inflammatory responses, resulting in delayed recovery of gastrointestinal motility after surgery. High-fat enteral nutrition has been reported to ameliorate inflammation in many diseases. In the present study, we investigated whether high-fat enteral nutrition could control intestinal inflammation and improve intestinal motility after peritoneal air exposure. METHODS: Male adult rats were administrated saline, low-fat enteral nutrition, or high-fat enteral nutrition via gavage before and after peritoneal air exposure for 3 h. Control rats underwent anesthesia without laparotomy and received saline. Intestinal motility was assessed 24 h after surgery by charcoal transport assay; systemic inflammation was assessed by analyzing serum levels of tumor necrosis factor α, interleukin (IL)-1ß, IL-6, and IL-10; and intestinal inflammation was assessed by analyzing myeloperoxidase activity and concentrations and gene expression of tumor necrosis factor α, IL-1ß, IL-6, and IL-10 in the intestinal tissue. RESULTS: Peritoneal air exposure decreased intestinal motility significantly compared with the control group (P < 0.05). The systemic and intestinal inflammatory parameters were also much higher in the peritoneal air exposure groups than in the control group. Both low-fat and high-fat enteral nutrition increased intestinal motility and reduced systemic and intestinal inflammatory parameter levels to different degrees. However, high-fat enteral nutrition significantly improved the negative alterations in these biochemical parameters compared with low-fat enteral nutrition (P < 0.05). CONCLUSIONS: These results suggest that high-fat enteral nutrition might be able to control intestinal inflammation and improve intestinal motility after peritoneal air exposure. Thus, the perioperative administration of high-fat enteral nutrition may be a promising treatment to enhance the recovery of intestinal motility after surgery.

Preoperative Nutritional Therapy Reduces the Risk of Anastomotic Leakage in Patients with Crohn's Disease Requiring Resections.

Background. The rate of anastomotic leakage is high in surgeries for Crohn's disease, and therefore a temporary diverting stoma is often needed. We conducted this study to investigate whether preoperative nutritional therapy could reduce the risk of anastomotic leakage while decreasing the frequency of temporary stoma formation. Methods. This was a retrospective study. Patients requiring bowel resections due to Crohn's disease were reviewed. The rate of anastomotic leakage and temporary diverting stoma was compared between patients who received preoperative nutritional therapy and those on a normal diet before surgery. Possible predictive factors for anastomotic leakage were also analyzed. Results. One hundred and fourteen patients undergoing 123 surgeries were included. Patients in nutritional therapy (NT) group had a significantly lower level of C-reactive protein on the day before surgery. Patients in NT group suffered less anastomotic leakage (2.3% versus 17.9%, P = 0.023) and less temporary diverting stoma (22.8% versus 40.9%, P = 0.036). Serum albumin of the day before surgery ≤35 g/L and preoperative nutritional therapy were identified as factors which independently affected the rate of anastomotic leakage. Conclusion. Preoperative nutritional therapy reduced the risk of anastomotic leakage and the frequency of temporary diverting stoma formation in patients with Crohn's disease requiring resections.

n-3 Polyunsaturated Fatty Acids Improve Inflammation via Inhibiting Sphingosine Kinase 1 in a Rat Model of Parenteral Nutrition and CLP-Induced Sepsis.

The sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) pathway plays a key role in inflammation. Parenteral nutrition containing n-3 polyunsaturated fatty acids (n-3 PUFA) may regulate inflammatory reactions. The aim of this study is to determine whether n-3 PUFA may improve inflammatory responses by neutralizing SphK1 signaling. Rat models of parenteral nutrition, cecal ligation and puncture (CLP)-induced sepsis were generated. Male Sprague-Dawley rats were operated for CLP on day 2 after venous catheterization. The rats were randomized to receive normal saline (NS; n = 20), parenteral nutrition (PN; n = 20), or PN + fish oil (FO; n = 20) for 5 days. The daily intake of fish oil (1.25-2.82 g EPA and 1.44-3.09 g DHA per 100 ml) in the FO group was approximately 1.8 g/kg body weight/day. Rats in the control group (n = 10) were subjected to sham operation and received a chow diet. Spleen tissues were collected for SphK1 and S1P receptor expression analysis. Our data showed that n-3 PUFA ameliorated the survival rate. SphK1 expression and its enzymatic activity were significantly upregulated in sepsis rats. Furthermore, mRNA and protein levels of S1PR3, but not S1PR1, were also facilitated after CLP. However, PN + FO dramatically decreased SphK1 mRNA level and its enzymatic activity. S1PR3 expression was also attenuated by FO addition. In conclusion, the anti-inflammatory effect of n-3 PUFA may be linked to the inhibition of the SphK1/S1P pathway in a rat model of parenteral nutrition and CLP-induced sepsis.

Tripterygium wilfordii Hook F as Maintenance Treatment for Crohn's Disease.

BACKGROUND: The traditional Chinese medicine, Tripterygium wilfordii Hook F (TwHF) is widely used to treat Crohn's disease (CD) in China. METHODS: The authors compared different doses of TwHF with mesalazine in 198 patients with CD over a 52-week period. Subjects were randomized to receive mesalazine (3 g/d), low-dose TwHF (1.5 mg·kg·d), or high-dose TwHF (2.0 mg·kg·d). RESULTS: A total of 137 patients completed the study. At week 52, a significant lower proportion of patients in the high-dose TwHF group (7/71) had clinical recurrence compared with patients in the low-dose TwHF (15/68, P = 0.047) or mesalazine group (17/59, P = 0.006), whereas the difference between the low-dose TwHF group and the mesalazine group was not significant (P = 0.503). Patients receiving mesalazine experienced less adverse events than those receiving high-dose TwHF (P = 0.029) and those receiving low-dose TwHF (P = 0.048), but no significant difference was found about drug adverse events resulted withdrawal in the 3 groups (P > 0.05). In addition, compared with low-dose TwHF and mesalazine, the authors also detected significant superiority of high-dose TwHF arm in the decrease of CDAI and SESCD (P < 0.05). CONCLUSION: A 2.0 mg/kg daily TwHF was well tolerated and prolonged remission in patients with CD.

Cordyceps sinensis preserves intestinal mucosal barrier and may be an adjunct therapy in endotoxin-induced sepsis rat model: a pilot study.

BACKGROUND: Cordyceps sinensis (C. sinensis), a traditional Chinese medicine, exhibits various pharmacological activities such as reparative, antioxidant, and apoptosis inhibitory effects. Intestinal barrier dysfunction plays a vital role in the progression of sepsis. We aimed to explore the effect of C. sinensis on the gut barrier and evaluate its efficacy in sepsis. METHODS: A murine model of gut barrier dysfunction was created by intraperitoneal injection of endotoxin. C. sinensis or saline was administered orally after the induction of sepsis. Alterations of intestinal barrier were evaluated and compared in terms of epithelial cell apoptosis, proliferation index (PI), intercellular tight junction (TJ) and proliferating cell nuclear antigen (PCNA). RESULTS: C. sinensis significantly decreased the percentage of apoptotic cells and promoted mucosal cells proliferation indicated by enhanced PI and PCNA expression in the intestinal mucosa compared to control group. The TJs between epithelial cells which were disrupted in septic rats were also restored by treatment of C. sinensis. In survival studies, C. sinensis was demonstrated to confer a protection against the lethal effect of sepsis. CONCLUSION: These results suggest that C. sinensis has gut barrier-protection effect in endotoxin-induced sepsis by promoting the proliferation and inhibiting the apoptosis of intestinal mucosal cells, as well as restoring the TJs of intestinal mucosa. C. sinensis may have the potential to be a useful adjunct therapy for sepsis.

Leucine supplementation improves acquired growth hormone resistance in rats with protein-energy malnutrition.

BACKGROUND: Protein-energy malnutrition (PEM) can lead to growth hormone (GH) resistance. Leucine supplementation diets have been shown to increase protein synthesis in muscles. Our study aimed at investigating if long-term leucine supplementation could modulate GH-insulin-like growth factor (IGF)-1 system function and mammalian target of rapamycin (mTOR)-related signal transduction in skeletal muscles in a rat model of severe malnutrition. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague-Dawley rats (n = 50; weight, 302 ± 5 g) were divided into 5 treatment groups, including 2 control groups (a normal control group that was fed chow and ad libitum water [CON, n = 10] and a malnourished control group [MC, n = 10] that was fed a 50% chow diet). After undergoing a weight loss stage for 4 weeks, rats received either the chow diet (MC-CON, n = 10), the chow diet supplemented with low-dose leucine (MC-L, n = 10), or the chow diet supplemented with high-dose leucine (MC-H, n = 10) for 2 weeks. The muscle masses of the gastrocnemius, soleus, and extensor digitorum longus were significantly reduced in the MC group. Re-feeding increased muscle mass, especially in the MC-L and MC-H groups. In the MC group, serum IGF-1, IGF-binding protein (IGFBP)-3, and hepatic growth hormone receptor (GHR) levels were significantly decreased and phosphorylation of the downstream anabolic signaling effectors protein kinase B (Akt), mTOR, and ribosomal protein S6 kinase 1 (S6K1) were significantly lower than in other groups. However, serum IGF-1 and IGF binding protein (IGFBP)-3 concentrations and hepatic growth hormone receptor (GHR) levels were significantly higher in the MC-L and MC-H groups than in the MC-CON group, and serum IGFBP-1 levels was significantly reduced in the MC-L and MC-H groups. These changes were consistent with those observed for hepatic mRNA expression levels. Phosphorylation of the downstream anabolic signaling effectors Akt, mTOR, and S6K1 were also significantly higher in the MC-L and MC-H groups than in the MC-CON group. CONCLUSION/SIGNIFICANCE: Our data are the first to demonstrate that long-term supplementation with leucine improved acquired growth hormone resistance in rats with protein-energy malnutrition. Leucine might promote skeletal muscle protein synthesis by regulating downstream anabolic signaling transduction.

Role of exclusive enteral nutrition in the preoperative optimization of patients with Crohn's disease following immunosuppressive therapy.

We conducted a study to evaluate the impact of the exclusive enteral nutrition (EEN) on perioperative outcome in Crohn's disease (CD) patients following immunosuppressive therapy. Patients with CD followed at a referral center between January 2001 and March 2014 who underwent abdominal surgery were identified. Patients were divided into 4 groups: patients not exposed to immunosuppressive agents in the previous 8 weeks before surgery (group 1); patients received immunosuppressive medications without preoperative drug-free interval (group 2); patients had preoperative immunosuppressants-free interval (group 3); patients treated with adding EEN to preoperative immunosuppressants-free interval regimen (group 4). Urgent operation requirement, stoma creation, postoperative complications, readmission, and reoperation were compared in patients among groups. Overall, 708 abdominal surgeries performed in 498 CD patients were identified. Three hundred seventy-six (53.11%) surgeries performed in those receiving preoperative immunosuppressive medications. Compared with other groups, group 2 had increased postoperative complications, more frequent urgent operation, and higher rate of stoma creation. Patients in group 4 were found to have better outcome including lower rate of stoma creation (P < 0.05), and decreased incidence of postoperative complications (P < 0.05) compared with group 2 and group 3. Additionally, decreased urgent operation requirement (P < 0.05) and extended preoperative drug-free interval (P < 0.001) were observed in the group 4 than those in the group 3. Preoperative optimization of CD following immunosuppressive therapy by EEN prolongs the immunosuppressants-free interval, reduces the risk of urgent surgery and reoperation, and most importantly, decreases complications after abdominal surgery.