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1.
Safety and efficacy of hydrothermal duodenal mucosal resurfacing in patients with type 2 diabetes: the randomised, double-blind, sham-controlled, multicentre REVITA-2 feasibility trial.
Mingrone, G, van Baar, AC, Devière, J, Hopkins, D, Moura, E, Cercato, C, Rajagopalan, H, Lopez-Talavera, JC, White, K, Bhambhani, V, et al
Gut. 2022;(2):254-264
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Abstract
OBJECTIVE Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D). DESIGN Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m2, fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks. RESULTS Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient. CONCLUSIONS DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG. TRIAL REGISTRATION NUMBER NCT02879383.
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Bifidobacterium breve BBG-001 and intestinal barrier function in preterm babies: Exploratory Studies from the PiPS Trial.
Fleming, P, Wilks, M, Eaton, S, Panton, N, Hutchinson, R, Akyempon, A, Hardy, P, Millar, MR, Costeloe, K
Pediatric research. 2021;(7):1818-1824
Abstract
BACKGROUND Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. METHODS Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. RESULTS Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. CONCLUSIONS That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. IMPACT Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.
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The role of mucosal barriers in human gut health.
Seo, K, Seo, J, Yeun, J, Choi, H, Kim, YI, Chang, SY
Archives of pharmacal research. 2021;(4):325-341
Abstract
The intestinal mucosa is continuously exposed to a large number of commensal or pathogenic microbiota and foreign food antigens. The intestinal epithelium forms a dynamic physicochemical barrier to maintain immune homeostasis. To efficiently absorb nutrients from food, the epithelium in the small intestine has thin, permeable layers spread over a vast surface area. Epithelial cells are renewed from the crypt toward the villi, accompanying epithelial cell death and shedding, to control bacterial colonization. Tight junction and adherens junction proteins provide epithelial cell-cell integrity. Microbial signals are recognized by epithelial cells via toll-like receptors. Environmental signals from short-chain fatty acids derived from commensal microbiota metabolites, aryl hydrocarbon receptors, and hypoxia-induced factors fortify gut barrier function. Here we summarize recent findings regarding various environmental factors for gut barrier function. Further, we discuss the role of gut barriers in the pathogenesis of human intestinal disease and the challenges of therapeutic strategies targeting gut barrier restoration.
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Visualising and quantifying intestinal permeability -where do we stand.
Rusticeanu, M, Zimmer, V, Lammert, F
Annals of hepatology. 2021;:100266
Abstract
Intestinal permeability is getting more and more attention in gastrointestinal research. Although well recognized, its exact role in health and disease is yet to be defined. There are many methods of quantifying intestinal permeability, but most of them fail to deliver tangible information about the morphological integrity of the intestinal barrier. In this review we aim to describe imaging options for the assessment of intestinal barrier integrity and their potential relevance for clinical practice. Our focus is on confocal laser endomicroscopy, which is at this time the only method for visualizing not only functional but also morphological aspects of the gut barrier in vivo.
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The role of histopathology in the diagnosis and management of coeliac disease and other malabsorptive conditions.
Brown, I, Bettington, M, Rosty, C
Histopathology. 2021;(1):88-105
Abstract
Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well-known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten-free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.
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Development and Validation of Test for "Leaky Gut" Small Intestinal and Colonic Permeability Using Sugars in Healthy Adults.
Khoshbin, K, Khanna, L, Maselli, D, Atieh, J, Breen-Lyles, M, Arndt, K, Rhoten, D, Dyer, RB, Singh, RJ, Nayar, S, et al
Gastroenterology. 2021;(2):463-475.e13
Abstract
BACKGROUND Oral monosaccharides and disaccharides are used to measure in vivo human gut permeability through urinary excretion. AIMS The aims were as follows: (1) to obtain normative data on small intestinal and colonic permeability; (2) to assess variance on standard 16 g fiber diet performed twice; (3) to determine whether dietary fiber influences gut permeability measurements; and (4) to present pilot data using 2 selected probes in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS Sixty healthy female and male adults, age 18-70 years, participated in 3 randomized studies (2 studies on 16.25 g and 1 study on 32.5 g fiber) in otherwise standardized diets. At each test, the following sugars were ingested: 12C-mannitol, 13C-mannitol, rhamnose (monosaccharides), sucralose, and lactulose (disaccharides). Standardized meals were administered from 24 hours before and during 24 hours post-sugars with 3 urine collections: 0-2, 2-8, and 8-24 hours. Sugars were measured using high-performance liquid chromatography-tandem mass spectrometry. Eighteen patients with IBS-D underwent 24-hour excretion studies after oral 13C-mannitol and lactulose. RESULTS Baseline sugars (>3-fold above lower limits of quantitation) were identified in the 3 studies: 12C-mannitol in all participants; sucralose in 4-8, and rhamnose in 1-3. Median excretions/24 h (percentage of administered dose) for 13C-mannitol, rhamnose, lactulose, and sucralose were ∼30%, ∼15%, 0.32%, and 2.3%, respectively. 13C-mannitol and rhamnose reflected mainly small intestinal permeability. Intraindividual saccharide excretions were consistent, with minor differences with 16.25 g vs 32.5 g fiber diets. Median interindividual coefficient of variation was 76.5% (10-90 percentile: 34.6-111.0). There were no significant effects of sex, age, or body mass index on permeability measurements in health. 13C-mannitol measurements are feasible in IBS-D. CONCLUSIONS Baseline 12C-mannitol excretion precludes its use; 13C-mannitol is the preferred probe for small intestinal permeability.
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Drivers of transcriptional variance in human intestinal epithelial organoids.
Criss, ZK, Bhasin, N, Di Rienzi, SC, Rajan, A, Deans-Fielder, K, Swaminathan, G, Kamyabi, N, Zeng, XL, Doddapaneni, H, Menon, VK, et al
Physiological genomics. 2021;(11):486-508
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Abstract
Human intestinal epithelial organoids (enteroids and colonoids) are tissue cultures used for understanding the physiology of the human intestinal epithelium. Here, we explored the effect on the transcriptome of common variations in culture methods, including extracellular matrix substrate, format, tissue segment, differentiation status, and patient heterogeneity. RNA-sequencing datasets from 276 experiments performed on 37 human enteroid and colonoid lines from 29 patients were aggregated from several groups in the Texas Medical Center. DESeq2 and gene set enrichment analysis (GSEA) were used to identify differentially expressed genes and enriched pathways. PERMANOVA, Pearson's correlation, and dendrogram analysis of the data originally indicated three tiers of influence of culture methods on transcriptomic variation: substrate (collagen vs. Matrigel) and format (3-D, transwell, and monolayer) had the largest effect; segment of origin (duodenum, jejunum, ileum, colon) and differentiation status had a moderate effect; and patient heterogeneity and specific experimental manipulations (e.g., pathogen infection) had the smallest effect. GSEA identified hundreds of pathways that varied between culture methods, such as IL1 cytokine signaling enriched in transwell versus monolayer cultures and E2F target genes enriched in collagen versus Matrigel cultures. The transcriptional influence of the format was furthermore validated in a synchronized experiment performed with various format-substrate combinations. Surprisingly, large differences in organoid transcriptome were driven by variations in culture methods such as format, whereas experimental manipulations such as infection had modest effects. These results show that common variations in culture conditions can have large effects on intestinal organoids and should be accounted for when designing experiments and comparing results between laboratories. Our data constitute the largest RNA-seq dataset interrogating human intestinal epithelial organoids.
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Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?
Dening, TJ, Douglas, JT, Hageman, MJ
Molecular pharmaceutics. 2021;(8):3086-3098
Abstract
Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.
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A novel technique capable of taking 'protected' biopsies for reliable assessment of the distribution of microbiota along the colonic mucosa.
Strobbe, F, Bénard, MV, Rossen, NG, de Vos, WM, Kumar, N, Lawley, TD, Zoetendal, EG, Hugenholtz, F, Ponsioen, CY
Journal of microbiological methods. 2021;:106204
Abstract
We evaluated a novel 'protected' biopsy method to reliably ascertain the spatial distribution of the mucosa-adherent colonic microbiota. Apart from minor differences at genus level, overall similarities along the colon were high between the various areas, irrespective of protected or unprotected sampling.
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Intestinal permeation enhancers: Lessons learned from studies using an organ culture model.
Danielsen, EM
Biochimica et biophysica acta. Biomembranes. 2021;(1):183474
Abstract
Permeation enhancers (PEs) are compounds aimed to increase intestinal uptake of oral drugs with poor bioavailability. This mini-review focuses on results recently obtained with PEs using an intestinal organ culture model. The model predicts which paracellular/transcellular pathways across the epithelium are susceptible to different classes of PEs (mainly surfactants and cell penetrating peptides). PEs: 1) generate a transmembrane transcellular pathway, 2) block apical endocytosis (first step in apical-to-basolateral transcytosis), and 3) perturb normal cell membrane integrity. The results argue that surfactants and cell penetrating peptides are not suitable for use in formulations aimed to exploit transcytosis in oral drug delivery.