A Multidisciplinary Approach to the Classification and Management of Intestinal Failure: Knowledge in Progress.

Intestinal failure (IF) is a debilitating condition characterized by the insufficient function of the gastrointestinal tract to absorb nutrients and fluids essential for life. This review consolidates recent advancements and challenges in managing IF among adult and pediatric populations, highlighting differences in etiology, management, and outcomes. Over the recent years, significant strides have been made in the nutritional and medical management of IF, significantly reducing mortality rates and improving the quality of life for patients. Key advancements include the development and availability of glucagon-like peptide-2 (GLP-2) analogs, improved formulations of parenteral nutrition, and the establishment of specialized interdisciplinary centers. Short bowel syndrome (SBS) remains the predominant cause of IF globally. The pediatric segment is increasingly surviving into adulthood, presenting unique long-term management challenges that differ from adult-onset IF. These include the need for tailored nutritional support, management of IF-associated liver disease, and addressing growth and neurodevelopmental outcomes. The therapeutic landscape for IF continues to evolve with the development of new treatment modalities and better understanding of the condition's pathophysiology. However, disparities in treatment outcomes between children and adults suggest the need for age-specific management strategies. This review underscores the importance of a nuanced approach to IF, incorporating advancements in medical science with a deep understanding of the distinct needs.

Baseline Characteristics of Adult Patients Treated and Never Treated with Teduglutide in a Multinational Short Bowel Syndrome and Intestinal Failure Registry.

The Short Bowel Syndrome (SBS) Registry (NCT01990040) is a multinational real-world study evaluating the long-term safety of teduglutide in patients with SBS and intestinal failure (SBS-IF) in routine clinical practice. This paper describes the study methodology and baseline characteristics of adult patients who have (ever-treated) or have never (never-treated) received teduglutide. A total of 1411 adult patients (679 ever-treated; 732 never-treated) were enrolled at 124 sites across 17 countries. The mean (standard deviation [SD]) age at enrollment was 55.4 (15.46) years, and 60.2% of patients were women. Crohn's disease was the most common cause of major intestinal resection in both ever-treated (34.1%) and never-treated patients (20.4%). A similar proportion of ever-treated and never-treated patients had a prior history of colorectal polyps (2.7% vs. 3.6%), whereas proportionally fewer ever-treated patients reported a history of colorectal cancer (1.8% vs. 6.2%) or any malignancy (17.7% vs. 30.0%) than never-treated patients. Never-treated patients received a numerically greater mean (SD) volume of parenteral nutrition and/or intravenous fluids than ever-treated patients (12.4 [8.02] vs. 10.1 [6.64] L/week). Ever-treated patients received a mean teduglutide dosage of 0.05 mg/kg/day. This is the first report of patient baseline characteristics from the SBS Registry, and the largest cohort of patients with SBS-IF to date. Overall, ever-treated and never-treated patients had similar baseline characteristics. Differences between treatment groups may reflect variations in patient selection and degree of monitoring.

Postsurgical Intestinal Rehabilitation Using Semisynthetic Glucagon-Like Peptide-2 Analogue (sGLP-2) at a Referral Center: Can Patients Achieve Parenteral Nutrition and sGLP-2 Independency?

BACKGROUND: Teduglutide, a semisynthetic analogue of glucagon-like peptide-2 (sGLP-2), increases intestinal absorption of fluids and nutrients, reducing the need for parenteral nutrition (PN). This report aims to describe our experience with sGLP-2 in a cohort of adult patients with short-bowel syndrome. METHODS: This is a prospective observational study on adult patients initially evaluated in our specialized intestinal rehabilitation program that received sGLP-2 from June 2014 to March 2020. RESULTS: Autologous gastrointestinal reconstruction surgery (AGIRS) was performed in 108 patients; 68.5% (74 of 108) achieved intestinal sufficiency with standard medical therapy. Seventeen patients were treated with sGLP-2; 66.5% (8 of 12) received treatment for a mean time of 25.8 weeks (3.4-54.0) and could suspend PN. One patient reinitiated treatment due to renal lithiasis and acute renal failure. Currently, 7 of 12 patients (53.8%) continue without PN for a mean time of 165.6 weeks. Volume, energy, and days of PN were reduced in all patients. No serious adverse events were registered. Four of 7 patients (57.1%) who discontinued PN could also discontinue sGLP-2. Therefore, the use of sGLP-2 increased the overall success rate of PN independency after AGIRS to 76% (82 of 108). CONCLUSION: This study confirmed that sGLP-2 should be considered as part of the standard therapy for postsurgical medical rehabilitation treatment in patients with chronic intestinal failure. We add to the current knowledge that some patients can discontinue both PN and sGLP-2 in the long term, achieving complete recovery of their quality of life.

Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon-like peptide-2-mediated mechanism.

AIM: MRP2 is an intestinal ABC transporter that prevents the absorption of dietary xenobiotics. The aims of this work were: (1) to evaluate whether a short-term regulation of intestinal MRP2 barrier function takes place in vivo after luminal incorporation of nutrients and (2) to explore the underlying mechanism. METHODS: MRP2 activity and localization were assessed in an in vivo rat model with preserved irrigation and innervation. Nutrients were administered into distal jejunum. After 30-minutes treatments, MRP2 activity was assessed in proximal jejunum by quantifying the transport of the model substrate 2,4-dinitrophenyl-S-glutathione. MRP2 localization was determined by quantitative confocal microscopy. Participation of extracellular mediators was evaluated using selective inhibitors and by immunoneutralization. Intracellular pathways were explored in differentiated Caco-2 cells. RESULTS: Oleic acid, administered intraluminally at dietary levels, acutely stimulated MRP2 insertion into brush border membrane. This was associated with increased efflux activity and, consequently, enhanced barrier function. Immunoneutralization of the gut hormone glucagon-like peptide-2 (GLP-2) prevented oleic acid effect on MRP2, demonstrating the participation of this trophic factor as a main mediator. Further experiments using selective inhibitors demonstrated that extracellular adenosine synthesis and its subsequent binding to enterocytic A2B adenosine receptor (A2BAR) take place downstream GLP-2. Finally, studies in intestinal Caco-2 cells revealed the participation of A2BAR/cAMP/PKA intracellular pathway, ultimately leading to increased MRP2 localization in apical domains. CONCLUSION: These findings reveal an on-demand, acute regulation of MRP2-associated barrier function, constituting a novel physiological mechanism of protection against the absorption of dietary xenobiotics in response to food intake.

Treating short bowel syndrome with pharmacotherapy.

INTRODUCTION: Short bowel syndrome (SBS) has traditionally been regarded as a rapidly fatal medical catastrophe. The advent of pharmacological options directly targeting disease pathophysiology justified this review. AREAS COVERED: Since the 1970s, home parenteral nutrition has reduced mortality, converting SBS into a chronic and disabling compensated and occasionally curable illness. Off-label antidiarrheal drugs and related products, though having minimal scientific evidence of efficacy, represent the standard-of-care and are here reviewed. Trophic intestinal hormones, including GLP-2 and its analogs, have great promise for alleviating malabsorption, the most important symptom within a nonsurgical, routine outpatient framework. Current indications involve adults with massive intestinal losses (fecal wet weight >1500 g/day). Surgical options such as intestinal lengthening or transplantation are also addressed although these options are considerably more aggressive and have stricter indications. EXPERT OPINION: GLP-2 analogs are the first candidates from a pioneering pharmacotherapic family within the SBS framework, namely disease-modifying, absorption-restoring agents. This family of drugs, potentially applicable in all contexts of severe intestinal loss, could become the therapeutic benchmark of the near future.

Glucagon-like peptide 2 prevents down-regulation of intestinal multidrug resistance-associated protein 2 and P-glycoprotein in endotoxemic rats.

Multidrug resistance-associated protein 2 (Mrp2, ABCC2) and P-glycoprotein (P-gp, ABCB1) constitute essential components of the intestinal biochemical barrier that prevent incorporation of food contaminants, drugs or toxic metabolites into the blood stream. Endotoxemia induced in rats by administration of bacterial lipopolysaccharide (LPS) results in elevated intestinal permeability and toxicity of xenobiotics in part associated with down-regulation of expression and activity of Mrp2 and P-gp. We evaluated the protective effect of glucagon-like peptide 2 (GLP-2), a peptide hormone with enterotrophic properties, on Mrp2 and P-gp alterations induced by single i.p. injection of LPS (5mg/kg b.wt.) to rats. Two different protocols of GLP-2 administration, namely prevention and reversion, were examined. The prevention protocol consisted of 7s.c. injections of GLP-2 (125µg/kg b.wt.) administered every 12h, starting 60h before LPS administration. The reversion protocol consisted of 2 doses of GLP-2, starting 3h after LPS injection. Intestinal samples were collected 24h after LPS administration and expression (protein and mRNA) and activity of Mrp2 were evaluated in proximal jejunum whereas those of P-gp were studied in ileum. GLP-2 completely neutralized down-regulation of expression of Mrp2 and P-gp and loss of their respective activities induced by LPS under prevention protocol. GLP-2 was also able to prevent internalization of both transporters from the apical membrane of the enterocyte to intracellular compartments, as detected by confocal microscopy. LPS induced an increase in IL-1ß and oxidized glutathione tissue levels, which were also counterbalanced by GLP-2 administration. In contrast, the reversion protocol failed to attenuate Mrp2 and P-gp down-regulation induced by LPS. We conclude that GLP-2 can prevent down-regulation of intestinal expression and activity of Mrp2 and P-gp in endotoxemic rats and that IL-1ß and oxidative stress constitute potential targets of GLP-2 protective effects.

c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines.

It is widely accepted that the c-Fos gene has a role in proliferation and differentiation of bone cells. ATP-induced c-Fos activation is relevant to bone homeostasis, because nucleotides that are present in the environment of bone cells can contribute to autocrine/paracrine signalling. Gut hormones have previously been shown to have an effect on bone metabolism. In this study, we used the osteoblastic Saos-2 cell line transfected with a c-Fos-driven reporter stimulated with five gut hormones: glucose inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), ghrelin and obestatin, in the presence or absence of ATP. In addition, TE-85 cells were used to determine the time course of c-Fos transcript induction following stimulation with GLP-1, and GLP-2 with or without ATP, using reverse transcription qPCR. The significant results from the experiments are as follows: higher level of c-Fos induction in presence of GIP, obestatin (p = 0.019 and p = 0.011 respectively), and GIP combined with ATP (p < 0.001) using the luciferase assay; GLP-1 and GLP-2 combined with ATP (p = 0.034 and p = 0.002, respectively) and GLP-2 alone (p < 0.001) using qPCR. In conclusion, three of the gut peptides induced c-Fos, providing a potential mechanism underlying the actions of these hormones in bone which can be directed or enhanced by the presence of ATP.

The role of enteric hormone GLP-2 in the response of bone markers to a mixed meal in postmenopausal women with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) is a complex disease associated with several chronic complications, including bone fragility and high fracture risk due to mechanisms not yet fully understood. The influence of the gastrointestinal tract and its hormones on bone remodeling has been demonstrated in healthy individuals. Glucagon-like peptide 2 (GLP-2), an enteric hormone secreted in response to nutrient intake, has been implicated as a mediator of nutrient effects on bone remodeling. This study aimed to analyze the dynamics of bone resorption marker C-terminal telopeptide of type I collagen (CTX), bone formation marker osteocalcin, and GLP-2 in response to a mixed meal in diabetic postmenopausal women. METHODS: Forty-three postmenopausal women with osteopenia or osteoporosis (20 controls - group CO - and 23 diabetic - group T2D) were subjected to a standard mixed meal tolerance test, with determination of serum CTX, plasma osteocalcin and serum GLP-2 concentrations at baseline and 30, 60, 120 and 180 minutes after the meal. RESULTS: T2D women had higher body mass index as well as higher femoral neck and total hip bone mineral density. At baseline, luteinizing hormone, follicle-stimulating hormone, osteocalcin and CTX levels were lower in group T2D. In response to the mixed meal, CTX and osteocalcin levels decreased and GLP-2 levels increased in both groups. The expected CTX suppression in response to the mixed meal was lower in group T2D. CONCLUSIONS: Bone turnover markers were significantly reduced in T2D women at baseline. Confirming the role of nutrient intake as a stimulating factor, GLP-2 increased in response to the mixed meal in both groups. Importantly, CTX variation in response to the mixed meal was reduced in T2D women, suggesting abnormal response of bone remodeling to nutrient intake in T2D.

Association of insulin resistance and GLP-2 secretion in obesity: a pilot study / Associação entre resistência insulínica e secreção de GLP-2 em obesos: um estudo piloto

OBJECTIVE: The objective of this pilot study was to determine whether glugagon-like peptide 2 (GLP-2) secretion relates to insulin sensitivity (IS) in obese subjects. SUBJECTS AND METHODS: Twenty four obese subjects [body mass index (BMI) 40.0 ± 3.0 kg/m² (mean ± standard deviation)] were included, nine of which were male, age 43 ± 8 years. Twelve subjects had type 2 diabetes, all treated with oral anti-diabetic agents only. The subjects were submitted to standard meal tolerance test (MTT) for dosage of the curves: glucose, insulin, and GLP-2. Insulin sensitivity was measured by HOMA-IR, and OGIS was derived from the MTT. Spearman linear correlations and partial correlations were obtained. RESULTS: There was an inverse relationship between the GLP-2 secretion and IS: HOMA-IR correlated with GLP-2 AUC (R = 0.504; p = 0.012), and OGIS correlated with GLP-2 incremental AUC (R = -0.54; p = 0.054). The correlation persisted after controlling for BMI. CONCLUSION: We found an association of GLP-2 secretion and insulin resistance (IR). The understanding of the underlying mechanisms may provide future directions in the pharmacological manipulation of incretins, and in the treatment of obesity and related metabolic disorders.

OBJETIVO: O objetivo deste estudo piloto foi determinar a relação entre a secreção de glugagon like peptide 2 (GLP-2) e a sensibilidade insulínica (SI) em indivíduos obesos. SUJEITOS E MÉTODOS: Vinte e quatro indivíduos obesos [IMC 40.0 ± 3.0 kg/m² (média ± desvio-padrão)] foram incluídos no estudo, sendo 9 homens, com idade de 43 ± 8 anos. Do total, 12 indivíduos tinham diabetes tipo 2, todos tratados somente com antidiabéticos orais. Os sujeitos foram submetidos ao teste de refeição padrão (MTT) para dosagens das curvas: glicose, insulina e GLP-2. A sensibilidade insulínica foi mensurada pelos HOMA-IR e OGIS, obtidos pelos valores do MTT. As correlações lineares e correlações parciais foram obtidas. RESULTADOS: Observou-se uma relação inversa entre a secreção de GLP-2 e SI: HOMA-IR correlacionou-se com GLP-2 AUC (R = 0,504; p = 0,012) e OGIS correlacionou-se com GLP-2 incremental AUC (R = -0,54; p = 0,054). A correlação persistiu controlando o IMC. CONCLUSÃO: Encontramos uma associação entre a secreção de GLP-2 e a resistência insulínica. A compreensão desses mecanismos poderá direcionar o futuro farmacológico da manipulação de incretinas no tratamento da obesidade e das desordens metabólicas.