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Expression of TOB/BTG family members in patients with inflammatory bowel disease.
Fonseca-Camarillo, G, Furuzawa-Carballeda, J, Priego-Ranero, ÁA, Martínez-Benítez, B, Barreto-Zúñiga, R, Yamamoto-Furusho, JK
Scandinavian journal of immunology. 2021;(4):e13004
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Abstract
In recent years, the role of anti-proliferative TOB proteins in the regulation of immune response by inhibiting T cell activation has been demonstrated. Nevertheless, no previous studies have explored their expression in patients with IBD. The aim of the study was to characterize the gene and protein expression of the TOB/BTG family in intestinal tissue of patients with IBD. This is an observational and cross-sectional study that included 63 IBD patients. Gene expression of TOB/BTG family was measured by RT-PCR. Protein expression of TOB/CD16 and BTG/Ki-67 was evaluated by immunohistochemistry. TOB/BTG family mRNAs were detected and quantitated by RT-qPCR in rectal and ileum biopsies from UC patients and CD patients, respectively, and non-inflammatory control tissues. Results showed that TOB1 and BTG1 gene expression was decreased in the colonic mucosa from patients with UC compared with the control group. The TOB2 and BTG2 genes were over-expressed in the colonic mucosa of patients with UC in remission compared with the active UC and control group. The high TOB2 gene expression was associated with histological remission (P = .01). TOB1/CD16, TOB2/CD16, BTG1/Ki-67, BTG2/Ki-67 and BTG4/Ki-67 single and double positive cells were mostly NK, macrophages, epithelial cells, connective tissue cells and perivascular inflammatory infiltrates in tissues from patients with UC and CD. This is the first depiction of the TOB/BTG family gene and protein expression in rectal and ileum tissues by a CD16+ subpopulation in IBD.
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Therapeutic Implications of Diet in Inflammatory Bowel Disease and Related Immune-Mediated Inflammatory Diseases.
Jiang, Y, Jarr, K, Layton, C, Gardner, CD, Ashouri, JF, Abreu, MT, Sinha, SR
Nutrients. 2021;(3)
Abstract
Despite being a focal issue to patients, the effect of diet on adult inflammatory bowel disease (IBD) remains underexplored with limited guidance. While promising clinical trials are currently underway, there is a need for further evidence-based recommendations. As such, we summarize the current evidence on various diets used in the treatment of IBD and also explore the potential applications of dietary data from related immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and psoriasis, to provide additional information to inform IBD providers. To date, there have been multiple diets investigated as adjunctive therapy in IBD, but many associated studies are small, non-randomized, and not controlled. Mediterranean, vegetarian/vegan, and reduced-calorie/fasting diets have been studied and have shown some positive results in other IMIDs, which may suggest potential applicability to those with IBD, but larger, well-designed clinical trials are needed for further guidance. Gluten-free and low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP)diets do not appear to have an impact on IBD disease activity, but low FODMAP may potentially be helpful for those with concurrent functional gastrointestinal symptoms. Specific carbohydrate diets have been mainly assessed in children but show some potential in small adult studies.
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Gut Microbial Metabolite-Mediated Regulation of the Intestinal Barrier in the Pathogenesis of Inflammatory Bowel Disease.
Iyer, N, Corr, SC
Nutrients. 2021;(12)
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease. The disease has a multifactorial aetiology, involving genetic, microbial as well as environmental factors. The disease pathogenesis operates at the host-microbe interface in the gut. The intestinal epithelium plays a central role in IBD disease pathogenesis. Apart from being a physical barrier, the epithelium acts as a node that integrates environmental, dietary, and microbial cues to calibrate host immune response and maintain homeostasis in the gut. IBD patients display microbial dysbiosis in the gut, combined with an increased barrier permeability that contributes to disease pathogenesis. Metabolites produced by microbes in the gut are dynamic indicators of diet, host, and microbial interplay in the gut. Microbial metabolites are actively absorbed or diffused across the intestinal lining to affect the host response in the intestine as well as at systemic sites via the engagement of cognate receptors. In this review, we summarize insights from metabolomics studies, uncovering the dynamic changes in gut metabolite profiles in IBD and their importance as potential diagnostic and prognostic biomarkers of disease. We focus on gut microbial metabolites as key regulators of the intestinal barrier and their role in the pathogenesis of IBD.
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IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.
Cananzi, M, Wohler, E, Marzollo, A, Colavito, D, You, J, Jing, H, Bresolin, S, Gaio, P, Martin, R, Mescoli, C, et al
Human genetics. 2021;(9):1299-1312
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Abstract
Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
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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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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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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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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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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.