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Probiotics as a Coadjuvant Factor in Active or Quiescent Inflammatory Bowel Disease of Adults-A Meta-Analytical Study.
Pabón-Carrasco, M, Ramirez-Baena, L, Vilar-Palomo, S, Castro-Méndez, A, Martos-García, R, Rodríguez-Gallego, I
Nutrients. 2020;(9)
Abstract
(1) Background: Inflammatory bowel diseases are pathologies of unknown etiology and auto-immune pathogenia. The use of probiotics is studied in order to increase the arsenal of treatments. The aim was to assess the efficacy of the probiotics in these diseases in the active or quiescent phases; (2) Methods: A systematic review with meta-analysis was performed by an exhaustive bibliographic search in Medline, Cinahl, Embase, Scopus, Web of Science, and Cochrane Library. The inclusion criteria were studies of more than 10 years, English/Spanish, clinical trials, and involving human beings. Relative risk was used to compare efficacy, which was meta-analyzed using a fixed effects model. Heterogeneity was evaluated with the Higgins I2 test; (3) Results: Nineteen studies were included in the systematic review and 17 in the meta-analysis, with a total of 1537 patients (nexperimental group = 762; nplacebo group = 775). There are significant remission differences in ulcerative colitis (relative risk (RR) = 0.81; 95% CI = 0.72-0.91; I2 = 32%; p = 0.16). However, no significant differences were found in the use of probiotics for the prevention of ulcerative colitis, and for the remission of Crohn's disease; (4) Conclusions: There are data showing an additional beneficial effect of probiotics on active ulcerative colitis. More and better studies are needed which assess its possible therapeutic efficacy for quiescent ulcerative colitis and for Crohn's disease.
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Synergic interactions between polyphenols and gut microbiota in mitigating inflammatory bowel diseases.
Li, H, Christman, LM, Li, R, Gu, L
Food & function. 2020;(6):4878-4891
Abstract
Inflammatory bowel diseases (IBD) are a group of chronic and recurring inflammatory conditions in the colon and intestine. Their etiology is not fully understood but involves the combination of gut dysbiosis, genetics, immune functions, and environmental factors including diet. Polyphenols from plant-based food synergistically interact with gut microbiota to suppress inflammation and alleviate symptoms of IBD. Polyphenols increase the diversity of gut microbiota, improve the relative abundance of beneficial bacteria, and inhibit the pathogenic species. Polyphenols not absorbed in the small intestine are catabolized in the colon by microbiota into microbial metabolites, many of which have higher anti-inflammatory activity and bioavailability than their precursors. The polyphenols and their microbial metabolites alleviate IBD through reduction of oxidative stress, inhibition of inflammatory cytokines secretion (TNF-α, IL-6, IL-8, and IL-1β), suppression of NF-κB, upregulation of Nrf2, gut barrier protection, and modulation of immune function. Future studies are needed to discover unknown microbial metabolites of polyphenols and correlate specific gut microbes with microbial metabolites and IBD mitigating activity. A better knowledge of the synergistic interactions between polyphenols and gut microbiota will help to devise more effective prevention strategies for IBD. This review focuses on the role of polyphenols, gut microbiota and their synergistic interactions on the alleviation of IBD as well as current trends and future directions of IBD management.
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Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD.
Werner, L, Lee, YN, Rechavi, E, Lev, A, Yerushalmi, B, Ling, G, Shah, N, Uhlig, HH, Weiss, B, Somech, R, et al
Frontiers in immunology. 2020;:109
Abstract
Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that likely have a role in mediating tissue damage. Nevertheless, the lack of shared clones between patients provides another piece of evidence that the adaptive immune response in IBD is not triggered against common antigens. Additional studies are required to define the specific antigens that interact with the expanded IL10/IL10R-deficient clones.
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Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease.
Pugliese, D, Privitera, G, Pizzolante, F, Gasbarrini, A, Guidi, L, Armuzzi, A
Minerva gastroenterologica e dietologica. 2019;(4):280-290
Abstract
Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations <20 µg/mL at week 6 and >12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.
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5.
Enteral Nutrition in Patients with Inflammatory Bowel Disease. Systematic Review, Meta-Analysis, and Meta-Regression.
Comeche, JM, Caballero, P, Gutierrez-Hervas, A, García-Sanjuan, S, Comino, I, Altavilla, C, Tuells, J
Nutrients. 2019;(11)
Abstract
Inflammatory bowel disease (IBD) is a chronic disease mediated by the immune system and is characterized by inflammation of the gastrointestinal tract. One of the possible treatments for this pathology is a change in the type of diet, of which enteral nutrition (EN) is one. This study is to understand how the use of EN can affect the adult population diagnosed with IBD. We conducted a systematic review, meta-analysis, and a meta-regression. On the different databases (MEDLINE, Scopus, Cochrane, LILACS, CINAHL, WOS), we found 363 registers with an accuracy of 12% (44 registers). After a full-text review, only 30 research studies were selected for qualitative synthesis and 11 for meta-analysis and meta-regression. The variables used were Crohn's disease activity index (CDAI), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). EN has been shown to have efficacy for the treatment of Crohn's disease and is compatible with other medicines. As for the CDAI or rates of remission, there were no differences between enteral and parenteral nutrition. Polymeric formulas have shown better results with respect to the CRP. The long-term treatment could dilute the good CDAI results that are obtained at the start of the EN treatment.
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Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders.
Hirten, RP, Iacucci, M, Shah, S, Ghosh, S, Colombel, JF
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(9):1374-1384
Abstract
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
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Inflammatory bowel disease and immunonutrition: novel therapeutic approaches through modulation of diet and the gut microbiome.
Celiberto, LS, Graef, FA, Healey, GR, Bosman, ES, Jacobson, K, Sly, LM, Vallance, BA
Immunology. 2018;(1):36-52
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Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, thought to at least in part reflect an aberrant immune response to gut bacteria. IBD is increasing in incidence, particularly in populations that have recently immigrated to western countries. This suggests that environmental factors are involved in its pathogenesis. We hypothesize that the increase in IBD rates might reflect the consumption of an unhealthy Western diet, containing excess calories and lacking in key nutritional factors, such as fibre and vitamin D. Several recent studies have determined that dietary factors can dramatically influence the activation of immune cells and the mediators they release through a process called immunonutrition. Moreover, dietary changes can profoundly affect the balance of beneficial versus pathogenic bacteria in the gut. This microbial imbalance can alter levels of microbiota-derived metabolites that in turn can influence innate and adaptive intestinal immune responses. If the diet-gut microbiome disease axis does indeed underpin much of the 'western' influence on the onset and progression of IBD, then tremendous opportunity exists for therapeutic changes in lifestyle, to modulate the gut microbiome and to correct immune imbalances in individuals with IBD. This review highlights four such therapeutic strategies - probiotics, prebiotics, vitamin D and caloric restriction - that have the potential to improve and add to current IBD treatment regimens.
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Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease.
Lahat, A, Shitrit, AB, Naftali, T, Milgrom, Y, Elyakim, R, Goldin, E, Levhar, N, Selinger, L, Zuker, T, Fudim, E, et al
Journal of Crohn's & colitis. 2018;(1):120-123
Abstract
INTRODUCTION There are no data on the transfer of vedolizumab in breast milk of nursing mothers. We aimed to assess the presence of vedolizumab in breast milk of nursing inflammatory bowel disease [IBD] patients. METHODS This was a prospective observational study of vedolizumab-treated breastfeeding patients with IBD. Serum and breast milk samples were obtained at pre-defined tim -points. The in-house developed enzyme-linked immunosorbent assay [ELISA] for measuring vedolizumab in blood was adapted and validated for measurement of the drug in breast milk. The level of vedolizumab was also measured in breast milk of a control group of nursing healthy mothers. RESULTS Vedolizumab was undetectable in breast milk in IBD patients before the first infusion of vedolizumab [n = 3] and in all of the healthy controls [n = 5]. Vedolizumab was measurable in all lactating women who received vedolizumab [n = 5]. However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels. CONCLUSIONS Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant.
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Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.
de Lange, KM, Moutsianas, L, Lee, JC, Lamb, CA, Luo, Y, Kennedy, NA, Jostins, L, Rice, DL, Gutierrez-Achury, J, Ji, SG, et al
Nature genetics. 2017;(2):256-261
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Abstract
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
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Fine-mapping inflammatory bowel disease loci to single-variant resolution.
Huang, H, Fang, M, Jostins, L, Umićević Mirkov, M, Boucher, G, Anderson, CA, Andersen, V, Cleynen, I, Cortes, A, Crins, F, et al
Nature. 2017;(7662):173-178
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Abstract
Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.