Lugen Zuo

A Practical Predictive Index for Intra-abdominal Septic Complications After Primary Anastomosis for Crohn's Disease: Change in C-Reactive Protein Level Before Surgery.

BACKGROUND: Postoperative intra-abdominal septic complications are difficult to manage in Crohn’s disease, which makes prevention especially important. OBJECTIVE: The purpose of this study was to examine the risk factors for intra-abdominal septic complications after primary anastomosis for Crohn’s disease and to seek a practical predictive index for intra-abdominal septic complications. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Based on a computerized database of 344 patients with Crohn’s disease who underwent primary anastomosis between 2004 and 2013, the patients were placed into an intra-abdominal septic complications group and a group without intra-abdominal septic complications. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors, and the predictive accuracy of possible predictors was assessed using receiver operating characteristic curves. RESULTS: Overall, 39 patients (11.34%) developed intra-abdominal septic complications. Preoperative C-reactive protein level >10 mg/L was found to be an independent risk factor (p < 0.01) for intra-abdominal septic complications. For prediction of intra-abdominal septic complications, receiver operating characteristic curve analysis showed that a C-reactive protein cutoff of 14.50 mg/L provided negative and positive predictive values of 96.84% and 34.07%. In addition, the change in C-reactive protein levels over the 2 weeks before surgery was greater in the intra-abdominal septic complications group than the group with no intra-abdominal septic complications (p < 0.01), and the directions of change were opposite, upward in the former and downward in the latter. Apart from being a risk factor for intra-abdominal septic complications (p < 0.01), receiver operating characteristic curve analysis showed that the change in C-reactive protein levels before surgery had a negative predictive value for intra-abdominal septic complications of 98.66% and a positive predictive value of 76.09%. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Changes in C-reactive protein before surgical treatment of Crohn’s disease could serve as a practical predictive index for postoperative intra-abdominal septic complications.

Bifidobacteria may be beneficial to intestinal microbiota and reduction of bacterial translocation in mice following ischaemia and reperfusion injury

The aim of the present study was to determine the effect of peroral bifidobacteria on the intestinal microbiota, barrier function and bacterial translocation (BT) in a mouse model of ischaemia and reperfusion (I/R) injury. A total of twenty-four male BALB/c mice were randomly allocated into three groups: (1) sham-operated, (2) I/R and (3) I/R injury and bifidobacteria pretreatment (109 colony-forming units/d). Bifidobacteria were administered daily intragastrically for 2 weeks before induction of I/R. Subsequently, samples of caecal content, intestinal mucosa, ileal segments, blood, mesenteric lymph nodes (MLN) and distant organs (liver, spleen and kidney) were prepared for examination. In the I/R model, barrier dysfunction (caecal microbiota dysbiosis, disruption of tight junction (TJ), increased epithelial cell apoptosis, disruption of mucosa and multiple erosions) in the intestine was observed, associated with increased BT to extraintestinal sites. The ratio of BT to MLN and distant organs in mice exposed to I/R injury was 62·5 %, which was significantly higher than the sham-operated group. However, pretreatment of animals with bifidobacteria prevented I/R-induced BT, reduced pro-inflammatory cytokine release, the levels of endotoxin, intestinal epithelial cell apoptosis, disruption of TJ and increased the concentration of SCFA, resulting in recovered microbiota and mucosal integrity. Bifidobacteria may be beneficial in reducing BT in I/R injury of mice. Therefore, peroral administration of bifidobacteria is a potential strategy to prevent I/R-induced BT and intestinal barrier dysfunction.

Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy.

BACKGROUND Celastrol had been proved effective in the treatment for IBD, probably with the modulation of oxidative stress, inflammatory cytokines and intestinal homeostasis. This study was aimed to investigate whether celastrol could ameliorate the inflammation of IL-10 deficient mice, a murine model of Crohns disease (CD) with the induction of autophagy. MATERIAL AND METHODS The mice included were divided into four groups, ##WT group, IL-10(-/-) group, Cel group and Control group (celastrol+3-Methyladenine). Celastrol (2 mg/kg) treatment by gavage was administered to mice daily over one week. 3-Methyladenine (autophagy inhibitors) was administered at a dose of 30 mg/kg by intraperitoneal injection. The histological evaluation of the colon, tissue myeloperoxidase (MPO), and colon inflammation of mice in the four groups was evaluated and compared. Furthermore, the PI3K/Akt/mTOR pathway and the status of autophagy in intestine affected by celastrol were also assessed. RESULTS The one-week administration of celastrol ameliorated established colitis in IL-10 deficient mice, associated with a reduction of marked histological inflammation, a decreased colon MPO concentration and suppression of colonic proinflammatory cytokine. Furthermore, the decreased neutrophil infiltration in proximal colon and improvement of inflammation in the Cel group was much more obvious than that in the Control group. The Western blotting analysis of the PI3K/Akt/mTOR pathway and autophagy showed that celastrol treatment up-regulated the autophagy of colon tissue by suppressing the PI3K/Akt/mTOR signaling pathway. CONCLUSIONS Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy by suppressing the PI3K/Akt/mTOR signaling pathway.

Cigarette smoking is associated with intestinal barrier dysfunction in the small intestine but not in the large intestine of mice

AIMS To observe the effect of cigarette smoke (CS) on the small bowel and colon in mice and to attempt to explain the potential mechanisms that account for these effects. METHODS Male BALB/c mice age 6-8 weeks were randomly divided into a CS group and a control group (n=10 per group). CS mice were exposed to CS (five cigarettes each time, four times a day for 5 days a week using Hamburg II smoking machine and CS was diluted with air at a ratio of 1:6) for 10 weeks, and control mice were exposed to room air. After 10 weeks, mice were sacrificed for analysis (colon and small bowel). RESULTS CS exposure impaired the intestinal barrier of the small bowel, based on evidence that CS mice exhibited increased intestinal permeability, bacterial translocation, intestinal villi atrophy, damaged tight junctions and abnormal tight junction proteins. These changes were partly mediated through the activated NF-κB (p65) signalling pathway. However, no obvious changes associated with the intestinal barrier were identified in the small bowel of control mice or the colons of control or CS mice. CONCLUSIONS CS is associated with intestinal barrier dysfunction in the small intestine but not in the large intestine of mice.

Oral treatment with SEW2871, a sphingosine-1-phosphate type 1 receptor agonist, ameliorates experimental colitis in interleukin-10 gene deficient mice

SEW2871, a selective sphingosine‐1‐phosphate type 1 receptor (S1P1) agonist, has been shown to be effective in protecting kidneys against ischaemia–reperfusion injury by reducing CD4+ T cell infiltration in mice. However, the effects of SEW2871 on colitis remain unclear. The aim of this study was to investigate the effects of SEW2871 on established colitis in interleukin (IL)‐10 gene‐deficient (IL‐10–/–) mice, a murine model of Crohns disease (CD). SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL‐10–/– mice. Severity of colitis, serum amyloid A, tissue myeloperoxidase (MPO), T cells in blood and colon lamina propria (LP) and proinflammatory cytokine productions were evaluated. Furthermore, the phospho‐signal transducer and activator of transcription (STAT)‐3 (p‐STAT‐3) expression in lymphocytes isolated from colon LP was also assessed. The 2‐week administration of SEW2871 ameliorated established colitis in IL‐10–/– mice, associated with a reduction of serum amyloid A concentration, a decreased colon MPO concentration, a depletion of the peripheral CD4+CD45+ T cells and a reduction of the homing of T cells into colon LP. Moreover, typical cytokines of T helper type 1 (Th1) and Th17 cells and p‐STAT‐3 expression were also suppressed by SEW2871 treatment. SEW2871 treatment ameliorates established experimental colitis in IL‐10–/– mice, which may provide a new therapeutic approach for human CD therapy.

Role of Exclusive Enteral Nutrition in the Preoperative Optimization of Patients With Crohn's Disease Following Immunosuppressive Therapy

AbstractWe conducted a study to evaluate the impact of the exclusive enteral nutrition (EEN) on perioperative outcome in Crohns 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.

The role of the mesentery in Crohn's disease: The contributions of nerves, vessels, lymphatics, and fat to the pathogenesis and disease course

Abstract:Crohns disease (CD) is a complex gastrointestinal disorder involving multiple levels of cross talk between the immunological, neural, vascular, and endocrine systems. The current dominant theory in CD is based on the unidirectional axis of dysbiosis–innate immunity–adaptive immunity–mesentery-body system. Emerging clinical evidence strongly suggests that the axis be bidirectional. The morphologic and/or functional abnormalities in the mesenteric structures likely contribute to the disease progression of CD, to a less extent the disease initiation. In addition to adipocytes, mesentery contains nerves, blood vessels, lymphatics, stromal cells, and fibroblasts. By the secretion of adipokines that have endocrine functions, the mesenteric fat tissue exerts its activity in immunomodulation mainly through response to afferent signals, neuropeptides, and functional cytokines. Mesenteric nerves are involved in the pathogenesis and prognosis of CD mainly through neuropeptides. In addition to angiogenesis observed in CD, lymphatic obstruction, remodeling, and impaired contraction maybe a cause and consequence of CD. Lymphangiogenesis and angiogenesis play a concomitant role in the progress of chronic intestinal inflammation. Finally, the interaction between neuropeptides, adipokines, and vascular and lymphatic endothelia leads to adipose tissue remodeling, which makes the mesentery an active participator, not a bystander, in the disease initiation and precipitation CD. The identification of the role of mesentery, including the structure and function of mesenteric nerves, vessels, lymphatics, and fat, in the intestinal inflammation in CD has important implications in understanding its pathogenesis and clinical management.

Dietary Non-digestible Polysaccharides Ameliorate Intestinal Epithelial Barrier Dysfunction in IL-10 Knockout Mice.

BACKGROUND Enteral nutrition [EN] was reported to be as effective as steroids in achieving short-term remission in patients with Crohns disease [CD], and exclusive EN [EEN] is widely used as primary therapy in children with CD. The aim of this study was to investigate the effect of a specific multi-fibre mix [MF], designed to match the fibre content of a healthy diet, on intestinal epithelial barrier function in IL-10 knockout [IL-10(-/-)] mice with spontaneous chronic colitis. METHODS IL-10(-/-) mice aged 16 weeks, with established colitis, were used for the experiments with multi-fibre mix diet [MF] for 4 weeks. Severity of colitis, levels of short cahin fatty acids [SCFA] in caecum contents, expression of STAT 3 and STAT 4 proteins, CD4(+) CD45(+) lymphocytes, CD4(+)Foxp3(+) regulatory T cells [Tregs] and cytokines in the lamina propria [LP], epithelial expression of tight junction proteins, TNF-α/TNFR2 mRNA expression, and epithelial apoptosis in the proximal colon were measured at the end of the experiment. RESULTS MF feeding effectively attenuated disease activity index and colitis associated with decreased lamina propria CD4(+) CD45(+) lymphocytes, IFN-γ/IL-17A mRNA expression, and p-STAT 3 and p-STAT 4 expression in colonic mucosa of IL-10(-/-) mice [p < 0.05]. Furthermore, CD4(+)Foxp3(+) Tregs in the LP and concentrations of total SCFA, acetate, propionate, and butyrate in the caecum were markedly increased after MF feeding in IL-10(-/-) mice. After MF feeding, increased epithelial expression and correct localisation of tight junction proteins [occludin and zona occludens protein 1], as well as reduced TNF-α/TNFR2 mRNA expression and epithelial apoptosis, were also observed in IL-10(-/-) mice. CONCLUSIONS These results indicated that EEN supplemented with the tested fibre mix, known to modulate the intestinal microbiota composition and SCFA production, could possibly improve efficacy in inducing remission in patients with active CD.

Influence of exclusive enteral nutrition therapy on visceral fat in patients with Crohn's disease.

Background:Mesenteric fat plays an important role in the pathogenesis of Crohns disease (CD), and a higher ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) is related to complicated disease status. Exclusive enteral nutrition (EEN) is an effective treatment option for patients with CD, and the aims of this study were to assess the effects of EEN on abdominal fat in patients with CD. Methods:Patient data were obtained from a prospectively maintained database. The SFA and VFA were measured in 38 patients with CD before and after 8-week EEN therapy, and the mesenteric fat index (MFI), defined as the ratio of VFA to SFA, was calculated. The correlations between MFI and CD activity index and C-reactive protein level were also evaluated. Results:The median age of the patients in our study was 29 years, and the median duration of disease was 3.05 years. Both VFA (P = 0.029) and MFI (P = 0.021) were significantly decreased in patients after EEN, but no significant change was observed in SFA (P = 0.335). MFI was significantly correlated with CD activity index (r = 0.523, P = 0.001) and C-reactive protein (r = 0.634, P < 0.0001) in patients with active CD before EEN, although no positive correlations were observed in patients after EEN treatment. Conclusions:EEN induction therapy was associated with a significant decrease in VFA in patients with CD, and MFI was significantly correlated with CD activity index and C-reactive protein in active CD. Thus, our data reveal additional beneficial therapeutic mechanisms of enteral nutrition treatment in CD.

Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: a randomized clinical trial.

BACKGROUND Tripterygium wilfordii Hook. f. (TwHF) has been used for many years to induce the remission of Crohns disease in China. AIMS To compare TwHF versus azathioprine for the prevention of postoperative recurrence in Crohns disease. METHODS 90 Crohns disease patients who had undergone resection were treated with TwHF 1.5mg/kg/day or azathioprine 2.0 mg/kg/day. The primary endpoint was clinical recurrence, and the secondary endpoint was endoscopic recurrence. RESULTS 47 patients completed the trial. Clinical recurrence was observed in 6/45 patients in the TwHF group and 4/45 patients in the azathioprine group at week 26 (P=0.74). At week 52, 8/45 azathioprine patients and 12/45 TwHF patients had clinical recurrence (P = 0.45). During the first 26 weeks, 56.8% of the patients in the TwHF group versus 47.7% in the azathioprine group experienced endoscopic recurrence (P = 0.52). However, at week 52, 74.4% of patients in the TwHF group and 50% in the azathioprine group had endoscopic recurrence (P = 0.03). CONCLUSIONS TwHF was less effective in maintaining endoscopic remission at week 52, even though TwHF was comparable to azathioprine for preventing postoperative clinical recurrence.