Emerging drugs for the treatment of short bowel syndrome.

INTRODUCTION: SBS is a rare and disabling condition. The standard management is based on diet optimization with parenteral supplementation. In addition, glucagon-like peptide-2 (GLP-2)analogs, have shown promising results as disease-modifying therapies for SBS. AREAS COVERED: Short bowel syndrome (SBS) is defined as a reduction in functional intestinal length to less than 200 cm, leading to intestinal failure (IF) leading to malnutrition and parenteral support dependency. This review discusses the current management of SBS-CIFpatients, the place of GLP-2 analog treatment in terms of efficacy, safety and availability, and the new perspectives opened by the use of enterohormones. EXPERT OPINION: Clinical trials and real-world experience demonstrated that Teduglutide   reduces dependence on parenteral support and has a place in the management of patients with SBS-CIF.  The use of Teduglutide should be discussed in patients stabilized after resection and its introduction requires the advice of an expert center capable of assessing the benefit-risk ratio. The complex, individualized management of SBS-C IF requires theexpertise of a specialized IF center which a multidisciplinary approach. The arrival of new treatments will call for new therapeutic strategies, and the question of how to introduce and monitor them will represent a new therapeutic challenge.

Pancytopenia related to acquired sea-blue histiocytosis during chronic parenteral nutrition.

Bone marrow smear showing histiocytes (black arrow) containing sea blue granules stained with May-Grünwald Giemsa.

Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options.

PURPOSE: Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune-mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. METHODS: Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn's disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. RESULTS: Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56bright:CD16lo:CD16hi NK subtype ratios were not modified by ruxolitinib. CONCLUSION: SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases.

The indications and results of the use of teduglutide in patients with short bowel.

Short bowel syndrome (SBS) is a rare condition defined as a reduced residual functional small intestinal length to less than 200 cm often resulting from extensive intestinal resection, and can lead to chronic intestinal failure (CIF). Patients with SBS-CIF are unable to absorb sufficient nutrients or fluids to maintain metabolic homeostasis through oral or enteral intake and require long-term parenteral nutrition and/or fluids and electrolytes. However, complications may arise from both SBS-IF and life-sustaining intravenous support, such as intestinal failure-associated liver disease (IFALD), chronic renal failure, metabolic bone disease and catheter-related complications. An interdisciplinary approach is required to optimize intestinal adaptation and decrease complications. In the last two decades, glucagon-like peptide 2 (GLP-2) analogs have sparked pharmacological interest as a potential disease-modifying therapy for SBS-IF. Teduglutide (TED) is the first developed and marketed GLP-2 analog for SBS-IF. It is approved in the United States, Europe, and Japan for use in adults and children with SBS-IF who are intravenous supplementation dependent. This article discusses the indications, candidacy criteria and results of the use of TED in patients with SBS.

The EFFect of dietary fat content on the recurrence of pancreaTitis (EFFORT): Protocol of a multicenter randomized controlled trial.

BACKGROUND: Around 20% of patients with acute pancreatitis (AP) will develop acute recurrent pancreatitis (ARP) and 10% will progress to chronic pancreatitis. While interventions to avoid recurrences exist for the two most common causes - abstinence for alcoholic and cholecystectomy for biliary pancreatitis - the are no known preventive measures in idiopathic ARP. Though it is not included in any of the guidelines, a low-fat diet is often recommended. Our aim is to test dietary fat reduction's effect on AP recurrence in a randomized controlled setting, in order to provide high-quality evidence for the validity of such an intervention. METHODS, DESIGN: Participants with at least 2 episodes of AP in the preceding 2 years of which the last episode was idiopathic will be randomized to one of two diets with different fat contents: a 'reduced fat diet' (15% fat, 65% carbohydrate, 20% protein) and a 'standard healthy diet' (30% fat, 50% carbohydrate, 20% protein; based on WHO recommendations). Participants will be followed-up for 2 years (visits will be scheduled for months 3, 6, 12, 18 and 24) during which they will receive a repeated session of nutritional guidance, complete food frequency questionnaires and data on relapse, mortality, BMI, cardiovascular parameters and serum lipid values will be collected. DISCUSSION: This study will determine the effect of modifying the dietary fat content on AP recurrence, mortality, serum lipids and weight loss in idiopathic cases.

Diagnosing undernutrition children and adults: new French criteria. Why, for what and for whom? A joint statement of the French National Authority for Health and French Federation of Nutrition.

The objective was to establish new diagnostic criteria for undernutrition for the French population, concordant for children aged <18 years and adults aged <70 years, easy to use by health professionals and applicable whatever the situation (in and outpatients). A multi-disciplinary working and a reading group were involved. The procedure was divided into four phases: (1) systematic review and synthesis of the literature; (2) writing of the initial version of the guidelines; (3) reading and (4) finalisation. The literature search included international guidelines, meta-analyses, systematic reviews and randomised control trials from January 2007 to 31 July 2018. A two-step approach was selected: diagnosing undernutrition and then grading its severity. For diagnosis at least one phenotypic criterion associated with at least one aetiologic criterion were required for both children and adults. Phenotypic criteria for children were weight loss, Body Mass Index (BMI) < International Obesity Task Force curve 18·5, weight stagnation, reduction of muscle mass/function; for adults: weight loss, BMI < 18·5 and reduction of muscle mass/function. Aetiological criteria for children and adults were reduction in dietary intake, reduced absorption and hypercatabolism. Phenotypic metrics were used in both children and adults for grading severity (moderate or severe). These new French recommendations integrate the proposals of recent international recommendations combining aetiologic with phenotypic criteria, but for the first time, they are concordant for children and adults. The WHO threshold of 18·5 for BMI was kept as phenotypic criteria because epidemiological data show an increased mortality for that threshold.

Short Bowel Syndrome: A Paradigm for Intestinal Adaptation to Nutrition?

Short bowel syndrome (SBS) is a rare disease that results from extensive resection of the intestine. When the remaining absorption surface of the intestine cannot absorb enough macronutrients, micronutrients, and water, SBS results in intestinal failure (IF). Patients with SBS who suffer from IF require parenteral nutrition for survival, but long-term parenteral nutrition may lead to complications such as catheter sepsis and metabolic diseases. Spontaneous intestinal adaptation occurs weeks to months after resection, resulting in hyperplasia of the remnant gut, modification of gut hormone levels, dysbiosis, and hyperphagia. Oral nutrition and presence of the colon are two major positive drivers for this adaptation. This review aims to summarize the current knowledge of the mechanisms underlying spontaneous intestinal adaptation, particularly in response to modifications of luminal content, including nutrients. In the future, dietary manipulations could be used to treat SBS.

State-of-the-art colorectal disease: conservative surgical management of intestinal failure in adults.

PURPOSE: Intestinal failure (IF) is defined by the reduction of gut function under the minimum necessary for adequate absorption of macronutrients and/or electrolytes, requiring home parenteral nutrition (HPN) to maintain health and/or growth. Among the different causes of IF, short bowel syndrome (SBS) is one of the main causes of IF in adults. Management of IF and SBS is complex and requires a multidisciplinary approach. The aim of this study was to review the place and the modalities of conservative surgical procedures performed for IF in adults. RESULTS-CONCLUSION: HPN has drastically modified the poor prognosis of these patients, leading to an overall survival around 70-75% at 5 years in patients without cancer. However, HPN is associated with life-threatening long-term complications, including liver failure and catheter-related complications, main causes of deaths for these patients. Surgery can be proposed, in order to try to reduce SBS consequences with either conservative or non-conservative procedures. Simple bowel continuity restoration should be performed as often as possible in order to wean or at least to reduce HPN. Lengthening procedures are proposed to increase the absorption surface of the remnant bowel. These procedures can be only performed on a dilated small bowel. The slowing transit time procedure is represented by segmental reversal of the small bowel. Intestinal transplantation is the last surgical option for patients with IF but is still today associated with high mortality and failure rates. Thus, conservative procedures have a major role in the surgical armentarium for patients with IF.

Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure.

BACKGROUND AND AIM: No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. METHODS: At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1-2, 2-3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). RESULTS: Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients' death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2-3 and PN >3 L/day). CONCLUSIONS: The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

Beyond 10 years, with or without an intestinal graft: Present and future?

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n = 26) and without (group 2, n = 9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87 mL/min/1.73 m2 . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10 years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.

Normal Lactate and Unenhanced CT-Scan Result in Delayed Diagnosis of Acute Mesenteric Ischemia.

INTRODUCTION: To investigate the factors associated with a delayed diagnosis (DD) of acute mesenteric ischemia (AMI). METHODS: An observational cohort study from an intestinal failure center. The primary outcome was DD >24 hours. RESULTS: Between 2006 and 2015, 74 patients with AMI were included and 39 (53%) had a DD. Plasma lactate <2 mmol/L (odd ratio: 3.2; 95% confidence interval: 1.1-9.1; P = 0.03) and unenhanced computed tomography scan (odds ratio: 5.9; 95% confidence interval: 1.4-25.8; P = 0.01) were independently associated with DD. DISCUSSION: Suspicion of AMI should no longer be affected by normal plasma lactate levels and should prompt evaluation by a contrast-enhanced computed tomography-scan.

The new place of enterohormones in intestinal failure.

PURPOSE OF REVIEW: Since the approval of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, for the treatment of patients with short bowel syndrome (SBS) associated with intestinal failure, enterohormone therapy has received significant interest and is becoming the first choice of treatment in selected patients. As such, it is paramount to assess and understand the new place of hormonal therapy in the algorithm of treatments in SBS-intestinal failure. RECENT FINDINGS: Specialized intestinal failure units have recently reported their outcomes with teduglutide to evaluate if they are consistent with the phase III trials results. SBS-intestinal failure patients are very heterogenous including their response to this treatment, hence the importance of real-life studies beyond the context of clinical trials. Moreover, it is essential to find a consensus on criteria identifying candidate patients for teduglutide. In addition, the impact of teduglutide on quality of life and its cost-effectiveness are emerging as well as new enterohormone treatments are being studied whether it is long action GLP-2 analog or other ileocolonic break hormones like glucagon-like peptide-1 analog. SUMMARY: Hormonotherapy is currently modifying the natural history of patients with SBS-intestinal failure by decreasing their need for parenteral support and possibly even complications associated with long-term parenteral support. Enterohormone treatment is now the cornerstone in SBS-intestinal failure and should be offered as a first-line therapy to selected patients.

[Clinicopathologic features and postoperative outcome of the radiation-induced enteritis: a retrospective study of 41 patients]. / Caractéristiques clinicopathologiques et résultats postopératoires de l'entérite radio-induite : une étude rétrospective de 41 patients.

INTRODUCTION: Surgery is required in patients with symptoms of chronic radiation-induced enteritis (CRE) resistant to medical therapy. The study aimed to correlate histopathologic features of CRE to the clinical presentation and the postoperative recurrence. MATERIAL AND METHOD: All patients with small bowel resection performed for CRE between 2006 and 2017 were studied. Histological data were retrospectively correlated to initial clinical data and to postoperative recurrence of CRE (occlusion, need for parenteral nutrition) observed during a median follow-up of 32 months. RESULTS: Forty-one patients were studied (39 women and 2 men, median age 62 yo at time of radiation for pelvic cancer, 80% gynecologic). Median time to surgery after radiation was 3 years. Ileocaecal resections (80% of patients) removed 60cm (median length). Histologically, a diffuse obliterative arteriopathy was present in 24 (59%) patients, highly associated to amyotrophy, villous atrophy and ulceration observed in 66, 63 and 34% of patients respectively (P<.05). Diffuse arteriopathy was uncorrelated with patient's age and vascular risk factor (tobacco, diabetes, hypertension, dyslipidemia). Median time to surgery after radiation was longer in patients presenting with obliterative arteriopathy (13 years vs. 2.6 years, P=0.0002). During follow-up, half of the patients had a recurrence of CRE, uncorrelated to the arteriopathy. CONCLUSION: Radiation-induced enteritis requiring late surgery after radiation presented histologically with a diffuse obliterative arteriopathy and ischemic features. In our center, half of the patients were cured by surgery. The arterial injury was not a risk factor for postoperative recurrence.

Oral Antibiotics Reduce Intestinal Necrosis in Acute Mesenteric Ischemia: A Prospective Cohort Study.

OBJECTIVES: To identify treatments likely to prevent progression towards irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI). METHODS: Prospective observational cohort study from a French intestinal stroke center. Multivariate analysis using a time-dependent Cox regression model. RESULTS: Between 2009 and 2015, 67 patients with AMI were included. ITIN occurred in 34% of patients and mortality was 13%. Oral antibiotics was independently associated with a decreased risk of ITIN (HR: 0.16 (95% CI = 0.03-0.62); p = 0.01). CONCLUSIONS: By decreasing luminal bacterial load and translocation, oral antibiotics in addition to early revascularization might reduce progression of AMI to ITIN.

Life of patients 10 years after a successful pediatric intestinal transplantation in Europe.

A multicenter Europe-wide single-point study in intestinal transplantation (ITx) centers was conducted to identify and describe patients surviving for more than 10 years after ITx in childhood. The health and nutritional status, care requirements and psychosocial status were recorded. Among 120 transplanted before 2005, 38 patients with a functioning graft were included. Thirty (79%) had an exclusive oral diet, seven (18%) complimentary enteral nutrition for eating disorders, and one a combination of parenteral and enteral nutrition. They received a median of five drugs daily and five had a stoma. We did not observe any catch-up growth during the 10 years of follow-up. In the previous five years, 22 patients needed unplanned hospitalization with a median in-patient stay of six days. Eleven needed ongoing psychiatric follow-ups, and nine needed other specialist follow-ups. An increasing independency from parents was seen after the age of 18, with three having a stable employment and 31 pursuing education. Despite a good graft function, growth may not catch up. The burden of medical care remains high in the long term. This has to be closely followed in a multidisciplinary setting to improve long-term quality of life in these patients.

What's new in short bowel syndrome?

PURPOSE OF REVIEW: Short bowel syndrome (SBS) is a rare disease but with many complications due to intestinal failure, parenteral nutrition and underlying disease. A better prevention, comprehension and treatment could improve the outcome of these patients. RECENT FINDINGS: Recent studies have been published on acute intestinal failure, first cause of SBS, and gives us strategy to avoid extended intestinal resection and thus SBS. There has been progress in the comprehension of intestinal adaptation, characterized by improvements in intestinal absorption, changes on hormonal secretion, development of a hyperphagia and dysbiosis of the gut microbiota. Hormonal treatment focusing on intestinal rehabilitation by promoting intestinal hyperadaptation has been proposed in patients with SBS, who require parenteral nutrition and intravenous fluids, such as glucagon-like peptide-2 (GLP-2) analog which is now recommended by the latest European Society for Clinical Nutrition and Metabolism Guidelines. SUMMARY: Multimodal treatment of acute meseteric ischemia may avoid intestinal resection and is an effective prevention strategy for SBS. New understandings in intestinal adaptation can help us to optimize this adaptation, including with hormonal therapy. GLP-2 analog is now the treatment of reference in SBS patients with chronic intestinal failure.

Ultra-short bowel is an independent risk factor for liver fibrosis in adults with home parenteral nutrition.

BACKGROUND & AIMS: Intestinal failure-associated liver disease is rare in adults and risk factors are unclear. The aim of this study was to determine risk factors of liver fibrosis in adults receiving home parenteral nutrition for intestinal failure and its impact on survival. METHODS: We retrospectively analysed patients with irreversible intestinal failure who underwent a liver biopsy between 2000 and 2013. Significant liver fibrosis was defined as ≥F2 according to NASH-CRN score. RESULTS: Thirty-two patients (46 years [29-60]) underwent liver biopsy 55 months (9-201) after beginning parenteral nutrition. Twenty-six patients (81%) had a short bowel (gut < 200 cm), including 12 (37%) with an ultra-short bowel (gut < 20 cm). Eighteen patients (56%) had liver fibrosis (4 F2, 10 F3, 4 F4), associated with steatohepatitis (72%) and/or cholestasis (17%). Factors associated with occurrence of liver fibrosis included ultra-short bowel (83% vs 13% at 60 months; P < .001), alcohol consumption (73% vs 33% at 60 months; P < .001) and diabetes (80% vs 34% at 60 months; P = .01). Home parenteral nutrition composition, quantity, or duration, episodes of sepsis, abandoned bowel segment were not associated with fibrosis. Ultra-short bowel [risk ratio 12.4, P < .001] and alcohol consumption [risk ratio 7.4, P = .009] independently predicted the development of liver fibrosis on multivariate analysis. After a median follow-up of 118 months (72-155), survival was poorer in patients who developed liver fibrosis than in those without (59% vs 92% at 120 months; P = .02). CONCLUSION: An ultra-short bowel and alcohol consumption are independent risk factors for liver fibrosis in adults requiring HPN.

Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.

OBJECTIVES: To identify predictive factors for irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI) and establish a risk score for ITIN. METHODS: This single-center prospective cohort study was performed between 2009 and 2015 in patients with AMI. The primary outcome was the occurrence of ITIN, confirmed by specimen analysis in patients who underwent surgery. Patients who recovered from AMI with no need for intestinal resection were considered not to have ITIN. Clinical, biological and radiological data were compared in a Cox regression model. RESULTS: A total of 67 patients were included. The origin of AMI was arterial, venous, or non-occlusive in 61%, 37%, 2% of cases, respectively. Intestinal resection and ITIN concerned 42% and 34% of patients, respectively. Factors associated with ITIN in multivariate analysis were: organ failure (hazard ratio (HR): 3.1 (95% confidence interval (CI): 1.1-8.5); P=0.03), serum lactate levels >2 mmol/l (HR: 4.1 (95% CI: 1.4-11.5); P=0.01), and bowel loop dilation on computerized tomography scan (HR: 2.6 (95% CI: 1.2-5.7); P=0.02). ITIN rate increased from 3% to 38%, 89%, and 100% in patients with 0, 1, 2, and 3 factors, respectively. Area under the receiver operating characteristics curve for the diagnosis of ITIN was 0.936 (95% CI: 0.866-0.997) depending on the number of predictive factors. CONCLUSIONS: We identified three predictive factors for irreversible intestinal ischemic injury requiring resection in the setting of AMI. Close monitoring of these factors could help avoid unnecessary laparotomy, prevent resection, as well as complications due to unresected necrosis, and possibly lower the overall mortality.

Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.

The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs). (IEC)LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (HFD). The analyses of the animals involved histology and immunohistochemistry of intestinal mucosa, indirect calorimetric measurements, whole-body composition, and expression and activities of nutrient transporters. (IEC)LEPR-B-KO mice exhibited a 2-fold increase in length of jejunal villi and have normal growth on a normal diet but were less susceptible (P<0.01) to HFD-induced obesity. No differences occurred in energy intake and expenditure between (IEC)LEPR-B-WT and -KO mice, but (IEC)LEPR-B-KO mice fed an HFD showed increased excreted fats (P<0.05). Activities of the Na(+)/glucose cotransporter SGLT-1 and GLUT2 were unaffected in LEPR-B-KO jejunum, while GLUT5-mediated fructose transport and PepT1-mediated peptide transport were substantially reduced (P<0.01). These data demonstrate that intestinal LEPR-B signaling is important for the onset of diet-induced obesity. They suggest that intestinal LEPR-B could be a potential per os target for prevention against obesity.