Interleukin-6 promotes skeletal muscle catabolism by activating tryptophan-indoleamine 2,3-dioxygenase 1-kynurenine pathway during intra-abdominal sepsis.

BACKGROUND: Inflammatory cytokine interleukin-6 (IL-6) plays a pivotal role in skeletal muscle degradation after intra-abdominal sepsis (IAS), with mechanism remained to be elucidated. Indoleamine 2,3-dioxygenase 1 (IDO-1), a key enzyme in converting tryptophan into kynurenine, could be activated by IL-6, and kynurenine has been shown to be involved in muscle degradation. We hypothesized that IL-6 could promote muscle degradation via tryptophan-IDO-1-kynurenine pathway in IAS patients. METHODS: Serum and rectus abdominis (RA) were obtained from IAS or non-IAS patients. Mouse model of IAS-induced muscle wasting was generated by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection. IL-6 signalling was blocked by anti-mouse IL-6 antibody (IL-6-AB), and the IDO-1 pathway was blocked by navoximod. To elucidate the role of kynurenine in muscle mass and physiology, kynurenine was administered to IAS mice treated with IL-6-AB. RESULTS: Compared to non-IAS patients, kynurenine levels in serum (+2.30-fold vs. non-IAS, P < 0.001) and RA (+3.11-fold vs. non-IAS, P < 0.001) were elevated, whereas tryptophan levels in serum (-53.65% vs. non-IAS, P < 0.01) and RA (-61.39% vs. non-IAS, P < 0.01) were decreased. Serum IL-6 level of the IAS group was significantly higher compared to non-IAS patients (+5.82-fold vs. non-IAS, P = 0.01), and muscle cross-sectional area (MCSA) was markedly reduced compared to non-IAS patients (-27.73% vs. non-IAS, P < 0.01). In animal experiments, IDO-1 expression was up-regulated in the small intestine, colon and blood for CLP or LPS-treated mice, and there was correlation (R2  = 0.66, P < 0.01) between serum and muscle kynurenine concentrations. Navoximod significantly mitigated IAS-induced skeletal muscle loss according to MCSA analysis (+22.94% vs. CLP, P < 0.05; +23.71% vs. LPS, P < 0.01) and increased the phosphorylated AKT (+2.15-fold vs. CLP, P < 0.01; +3.44-fold vs. LPS, P < 0.01) and myosin heavy chain (+3.64-fold vs. CLP, P < 0.01; +2.13-fold vs. LPS, P < 0.01) protein expression in myocytes. In the presence of anti-IL-6 antibody, a significantly decreased IDO-1 expression was observed in the small intestine, colon and blood in CLP or LPS mice (all P < 0.01), whereas the decrease of MCSA was alleviated (+37.43% vs. CLP + IgG, P < 0.001; +30.72% vs. LPS + IgG, P < 0.001). In contrast, additional supplementation of kynurenine decreased the MCSA in septic mice treated with IL-6-AB (both P < 0.01). CONCLUSIONS: This study provided novel insights into the tryptophan-IDO-1-kynurenine-dependent mechanisms that underlie inflammatory cytokine-induced skeletal muscle catabolism during intra-abdominal sepsis.

Use of the Water-Soluble Contrast Medium Gastrografin in Treatment of Adhesive Small Bowel Obstruction in Patients with and Without Chronic Radiation Enteropathy: A Single-Center Retrospective Study.

BACKGROUND This retrospective cohort study from a single center aimed to compare patient outcomes following the use of the water-soluble contrast medium Gastrografin in the treatment of adhesive small bowel obstruction (ASBO) in patients with and without a history of chronic radiation enteropathy (CRE). MATERIAL AND METHODS Fifty-nine patients with CRE-induced small bowel obstruction (SBO) and 53 patients with ASBO at Jinling Hospital between April 2014 and February 2018 were enrolled. The patients were given 100 ml Gastrografin through a naso-jejunal tube, and erect abdominal X-rays were taken. Risk factors were found to be correlated with successful non-operative management (SNM) through statistical analyses. RESULTS The success rate of conservative treatment was higher in the Gastrografin group than in the control group (P<0.05). The Gastrografin challenge test is predictive of need for surgery in CRE-induced SBO and ASBO (AUC=0.860 and 0.749, respectively). The predictors associated with SNM in the CRE-induced SBO group were the total dose of radiotherapy, the Gastrografin challenge test, and previous operations for SBO. In the ASBO group, the predictors were the Gastrografin challenge test and previous operations for SBO. The operation rate of SBO patients with Gastrografin treatment was significantly lower than that in the control group (P<0.05). CONCLUSIONS The findings from this study showed that the use of Gastrografin effectively resolved ASBO in patients with and without a history of CRE, but a long-term requirement for surgery could not be avoided. The Gastrografin challenge may be a useful test to predict surgical outcomes.

Isolated colonic Crohn's disease is associated with a reduced response to exclusive enteral nutrition compared to ileal or ileocolonic disease.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) as a primary therapy is safe and effective for inducing the clinical remission of active luminal Crohn's disease (CD). Whether isolated colonic involvement affects the efficacy of EEN is controversial. We aimed to identify the influence of isolated colonic CD on the efficacy of EEN and to determine other potential predictors of the response to induction therapy with EEN in adult patients with CD. METHODS: Data for adult CD patients treated with EEN as an induction therapy at our centre from January 1, 2014, to May 31, 2017, were reviewed. Eligible patients were divided into an isolated colonic Crohn's disease (cCD) group and a non-isolated colonic Crohn's disease (non-cCD) group according to the disease location. The rates of clinical remission and inflammatory and nutritional serum markers were compared between the groups. Possible relationships between isolated colonic involvement or other potential factors and the efficacy of EEN were assessed by univariate and multivariate analyses. The propensity score matching method was used to confirm the results. RESULTS: Overall, 241 patients were included in the analysis: 52 patients in the cCD group and 189 patients in the non-cCD group. The rates of clinical remission differed between the two groups (cCD group: 51.9% versus non-cCD group: 68.3%, P = 0.029). Multivariate analyses indicated that isolated colonic involvement was associated with a reduced response to EEN (OR = 2.74; [CI] 95% = [1.2-6.23], P = 0.016). Additionally, the lean body mass index (LBMI) before treatment was associated with the efficacy of EEN (OR = 0.636; [CI] 95% = [0.444-0.912], P = 0.014). These associations were confirmed using the propensity score model. For patients with isolated colonic CD, multivariate analysis showed that pancolitis (OR = 16.7; [CI] 95% = [1.074-260.5], P = 0.044) was another independent factor for the efficacy of EEN. Further analysis showed that even in patients who achieved clinical remission after EEN, inflammatory serum markers declined more slowly in the cCD group than in the non-cCD group, and the time to remission was longer in the cCD group. CONCLUSIONS: Isolated colonic CD showed a reduced response to induction therapy with EEN compared with ileal or ileocolonic disease in adult patients. Patients with isolated colonic CD required more time to benefit from EEN therapy compared with patients with non-colonic CD. Additionally, LBMI before treatment was associated with the efficacy of EEN.

Postoperative Interleukin-6 Predicts Intra-abdominal Septic Complications at an Early Stage After Elective Intestinal Operation for Crohn's Disease Patients.

BACKGROUND: The role of interleukin-6 (IL-6) in the prediction of intra-abdominal septic complications (IASCs) in patients with Crohn's disease (CD) remains unclear. We assessed the serum IL-6 time course and its association with postoperative IASCs in patients undergoing elective intestinal operations for CD. METHODS: In total, 118 patients who underwent intestinal operations for CD were prospectively evaluated. They were divided into an IASC group and non-IASC group. Multivariate analyses were used to identify risk factors, and receiver operating characteristic curve analysis was performed. RESULTS: Multivariate analysis showed that a high IL-6 concentration of >137.25 pg/mL on postoperative day (POD) 1 was independently associated with IASCs (odds ratio, 5.74; 95% confidence interval [CI], 1.46-22.67; P = 0.012) and a longer postoperative length of hospitalization (6 vs 9 days, P < 0.001). The median interval between surgery and IASCs (interquartile range) was 6 (4-22) days, and the IL-6 concentration was significantly different between patients with and without IASCs on PODs 1, 3, and 5. The ideal IL-6 cutoff value on POD 1 for the prediction of postoperative IASCs was 137.25 pg/mL, yielding a sensitivity of 81%, specificity of 58%, and area under the curve of 0.71 (95% CI, 0.59-0.83), with a negative predictive value of 0.93. CONCLUSIONS: A high IL-6 concentration on POD 1 is independently associated with the occurrence of postoperative IASCs in patients undergoing elective surgery for CD and could allow for earlier diagnosis and earlier intervention for IASCs compared with C-reactive protein.

Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Score (MES) in guiding the need for colectomy in patients with acute severe colitis.

BACKGROUND: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo Endoscopic Score (MES) were developed as an objective method of the endoscopic severity in ulcerative colitis (UC); however, it was still unclear whether UCEIS vs MES could guide the need for colectomy in acute severe colitis (ASC). METHODS: Consecutive ASC patients between January 2012 and May 2016 were retrospectively evaluated. Demographic data, previous therapy, clinical observations, laboratory parameters, medical therapy and endoscopic assessments were documented. The primary outcome was the need for colectomy during admission and follow-up. RESULTS: Ninety-two patients were enrolled. 37 (40.2%) needed colectomy. UCEIS score is a predictor of requirement for colectomy in multivariate analysis (OR, 3.25; 95% CI, 1.77-5.97; P < 0.001). Receiver-operator characteristic (ROC) area of UCEIS is 0.85, with a sensitivity of 60.3% and specificity of 85.5% using cut-off value of 7, which outperforms MES with the ROC area of 0.65; When UCEIS score ≥7, 80% of patients eventually need colectomy. CONCLUSION: UCEIS outperformed MES as a predictor for need for colectomy in ASC patients. The high probability of medical treatment failure and benefits of early colectomy should be discussed in patients with baseline UCEIS ≥ 7.Acute severe colitis; colectomy; Ulcerative Colitis Endoscopic Index of Severity; Mayo Endoscopic Score.

Validation and optimization of the Systemic Inflammation-Based modified Glasgow Prognostic Score in predicting postoperative outcome of inflammatory bowel disease: preliminary data.

Systemic Inflammation-Based modified Glasgow Prognostic Score (mGPS) was developed as an objective tool to grade state of inflammation. However, the association between mGPS and postoperative complications for inflammatory bowel disease (IBD) patients was still unknown. In our study, 270 IBD patients [Crohn's disease (CD), n = 186; Ulcerative colitis (UC), n = 84] from January 2013 and January 2016 who underwent elective bowel resection were retrospectively analyzed, and, the levels of preoperative C-reactive protein (CRP) and albumin were included as parameters of mGPS. The incidence of overall postoperative complications was 44.81% (121/270), including 46.77% (87/186) of CD and 40.48% (34/84) of UC. According to multivariate analysis, mGPS (CD: OR = 3.47, p = 0.003; UC: OR = 3.28, p = 0.019) was independently associated with an increased risk of postoperative complications. Patients with a higher mGPS also suffered longer postoperative stay and increased SSIs (both p < 0.05). Combining mGPS with neutrophil ratio improved its prognostic value with a better area under the curve (AUC), using receiver operating characteristic (ROC) method. Then we confirmed that mGPS was associated with postoperative complications in IBD patients undergoing elective bowel resection and the addition of neutrophil ratio enhanced its prognostic value.

Increased incidence of prolonged ileus after colectomy for inflammatory bowel diseases under ERAS protocol: a cohort analysis.

BACKGROUND: Postoperative ileus is a common problem after colorectal surgery. The aim of the study was to investigate the incidence and risk factors for prolonged postoperative ileus (POI) after colectomy for inflammatory bowel diseases (IBDs). METHODS: Consecutive patients who underwent colorectal resection for IBD versus colorectal cancer (CRC) patients under enhanced recovery after surgery protocol were retrospectively analyzed. Primary assessment end point is the incidence of prolonged POI (>4 days); secondary end points were GI-2 recovery (time to first toleration of solid food and first bowel movement), nasogastric tube reinsertion, and postoperative length of stay. Risk factors for prolonged POI in IBD patients were assessed by multiple logistic regression analysis with P score matching. RESULTS: The incidence of prolonged POI was higher in IBD versus CRC group (28.8% versus 14.8%, P < 0.001). Patients with IBD had a longer time to GI-2 recovery (4.8 ± 2.1 versus 3.7 ± 1.4 d, P < 0.001), postoperative length of stay (10.7 ± 6.2 versus 7.9 ± 5.3 d, P < 0.001), higher incidence of nasogastric tube reinsertion (9.8% versus 4.0%, P = 0.02). After propensity-score matching analysis, the differences were still significant. Preoperative steroid use >20 mg/d (odds ratio, [OR] = 2.19, P = 0.048), hypoalbuminemia (<35 g/L; OR 2.72, P = 0.03), systemic inflammatory response syndrome status (OR 4.91, P = 0.03), and postoperative intraabdominal sepsis (OR 9.31, P = 0.001) were independent risk factors for prolonged POI in IBD patients. CONCLUSIONS: In the setting of enhanced recovery after surgery, colectomy for IBD is associated with delayed gastrointestinal function recovery and higher incidence of prolonged POI compared to CRC patients. Normalizing preoperative albumin level, weaning off steroids, reducing preoperative systemic inflammatory response syndrome, and early management of postoperative intraabdominal sepsis may reduce POI in IBD population.

Fecal calprotectin as an alternative to ulcerative colitis endoscopic index of severity to predict the response to corticosteroids of acute severe ulcerative colitis: A prospective observational study.

BACKGROUND: Fecal calprotectin (FC) might be an alternative to ulcerative colitis endoscopic index of severity (UCEIS) to predict the response to corticosteroids (CS) in acute severe colitis (ASC). METHODS: One hundred and seventeen ASC patients were prospectively enrolled. Demographic, clinical, laboratory and sigmoidoscopic data were documented. Multivariate and ROC analyses were performed to identify risk factors for non-response to CS, and the predictive accuracy of possible predictors was assessed. RESULTS: Totally, 39 (33.33%) patients failed intravenous CS therapy. CS responders among mild (UCEIS 3-4), moderate (UCEIS 5-6) and severe (UCEIS 7-8) groups were 40/44 (90.91%) vs. 36/55 (65.45%) vs. 2/18 (11.11%) (p<0.001). UCEIS (OR=5.08; 95% CI, 1.93-8.66; p<0.001) and FC (OR=2.56; 95% CI, 1.17-3.55; p=0.022) were found to be independent risk factors for CS non-responders. Compared with C-reactive protein, platelet, hemoglobin and albumin, baseline FC had the strongest correlation with UCEIS (r=0.701, p<0.001). ROC analysis of UCEIS and baseline FC in predicting CS non-response showed an AUC of 0.85 and 0.76 respectively. CONCLUSIONS: Baseline FC levels correlated significantly with UCEIS in ASC, and both were useful in predicting short-term outcome of CS treatment. Baseline FC levels could be used as an alternative of UCEIS to guide the decision of early salvage therapy or colectomy and reduce the adverse effects of long-term futile CS usage.

Acute Colonic Pseudo-Obstruction with Feeding Intolerance in Critically Ill Patients: A Study according to Gut Wall Analysis.

Objective. To compare the differences between acute colonic pseudo-obstruction (ACPO) with and without acute gut wall thickening. Methods. ACPO patients with feeding tolerance were divided into ACPO with no obvious gut wall thickening (ACPO-NT) group and ACPO with obvious acute gut wall thickening (ACPO-T) group according to computed tomography and abdominal radiographs. Patients' condition, responses to supportive measures, pharmacologic therapy, endoscopic decompression, and surgeries and outcomes were compared. Results. Patients in ACPO-T group had a significantly higher APACHE II (11.82 versus 8.25, p = 0.008) and SOFA scores (6.47 versus 3.54, p < 0.001) and a significantly higher 28-day mortality (17.78% versus 4.16%, p = 0.032) and longer intensive care unit stage (4 versus 16 d, p < 0.001). Patients in ACPO-NT group were more likely to be responsive to supportive treatment (62.50% versus 24.44%, p < 0.001), neostigmine (77.78% versus 17.64%, p < 0.001), and colonoscopic decompression (75% versus 42.86%, p = 0.318) than those in ACPO-T group. Of the patients who underwent ileostomy, 81.25% gained benefits. Conclusions. ACPO patients with gut wall thickening are more severe and are less likely to be responsive to nonsurgical treatment. Ileostomy may be a good option for ACPO patients with gut wall thickening who are irresponsive to nonsurgical treatment.

Skeletal muscle depletion correlates with disease activity in ulcerative colitis and is reversed after colectomy.

BACKGROUND & AIMS: The body composition of patients with ulcerative colitis (UC) remains unclear. This study evaluated body composition in adult patients with UC and the associations of body composition with disease activity and surgical intervention. METHODS: This study included 99 patients with UC, 105 with Crohn's disease (CD) and 60 controls. Skeletal muscle area (SMA), visceral fat area (VFA) and subcutaneous fat area (SFA) of the third lumbar vertebrae were evaluated by abdominal computed tomography. The effects of medical therapy and surgery on body composition in UC patients were determined. RESULTS: Sarcopenia was more frequent in UC patients (27.3%) than in controls (8.3%), but less frequent than in CD patients (59.0%). The prevalence of sarcopenia was significantly higher (33.8% vs. 4.5%, p < 0.001), and SMA (144.26 vs. 182.32 cm2, p < 0.001), skeletal muscle index (SMI) (52.22 vs. 65.52 cm2/m2, p < 0.001) significantly lower, in UC patients with high (≥6) than low (<6) Mayo score, but SFA and VFA were similar. The prevalence of sarcopenia and alterations in body composition were reversed, along with UC disease activity, following medical treatment or surgery. SMA and SMI correlated significantly with disease activity in UC patients. Multivariate analysis showed that sarcopenia (odds ratio, 8.49; 95% confidence interval, 1.80-40.10; p = 0.007) was a negative predictor of high Mayo score in UC patients. Sarcopenic patients with UC had high probability of need for colectomy in Kaplan-Meier survival curves. CONCLUSIONS: Sarcopenia is associated with high disease activity and poor clinical outcome in UC patients. Medical treatment and colectomy have positive effects on sarcopenia and skeletal muscle depletion.