Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine.
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ABSTRACT:
SUBMITTER: Gao H
PROVIDER: S-EPMC10474308 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
Publications
Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine.
Gao Han H Liu Ruize R Huang Hailiang H Liu Zhanju Z
Clinical and translational medicine 20230901 9
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Project description:Ulcerative colitis and Crohn's disease are traditionally defined as the two main subtypes of inflammatory bowel disease. However, a more recent view considers IBD as a spectrum of heterogeneous phenotypes with consistent differences in clinical presentation and behaviors, likely explained by differences in underlying pathogenetic mechanisms. The etiology is still elusive, and the suggested pathogenesis is a complex interplay among genetic predisposition and abnormal immune response at the mucosal intestinal level, activated by only partially identified environmental triggers leading to altered intestinal permeability and impaired handling of gut microbiota. The undeniable continuous progress of medical therapy with more frequent shifts from traditional to more advanced modalities also underlines the actual unmet needs. We are using medications with completely different mechanisms of action, with a lack of predictive factors of outcomes and response and still an unsatisfactory rate of success. In addition, we are missing still valuable and accurate markers to predict disease progression and severity in order to avoid under- or over-treatment. In such a complex scenario, it is undoubtful that the application of artificial intelligence and machine learning algorithms may improve the management and pave the way for precision and eventually personalized medicine in these patients; however, there are still several challenges that will be the focus of this review.
| S-EPMC10487169 | biostudies-literature
Project description:Background and aimsInflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity.MethodsDNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls.ResultsA total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients.ConclusionsOur data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.
| S-EPMC5013897 | biostudies-literature
Project description:Combining explainable machine learning, demographic and multi-omic data to identify precision medicine strategies for inflammatory bowel disease
| PRJEB43220 | ENA
Project description:Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
| S-EPMC10184262 | biostudies-literature
Project description:IntroductionInflammatory Bowel Disease (IBD), encompassing Crohn's disease and ulcerative colitis, presents significant clinical challenges due to its heterogeneous nature and complex etiology. Recent advancements in biomedical research have enhanced our understanding of IBD's genetic, microbial, and biochemical aspects. However, persistent issues in clinical management, including treatment non-response, surgical interventions, and diagnostic uncertainties, underscore the need for more targeted approaches. This review examines the convergence of artificial intelligence (AI) and precision medicine (PM) in IBD management. By leveraging AI's capacity to analyze complex, multi-dimensional datasets, this emerging field offers promising applications in improving diagnostic accuracy, predicting treatment responses, and forecasting disease progression, potentially transforming IBD patient care.MethodThe systematic review (SR) was conducted by searching the following databases: PubMed, PubMed PMC, BVS, Scopus, Web of Science, Embase, Cochrane, and ProQuest up to February 2024. Studies that employed AI in IBD applied to precision medicine were included.Results139 studies on applying AI in precision medicine for IBD were identified. Most studies (>70%) were published after 2020, indicating a recent surge in interest. The AI applications primarily focused on diagnosis, treatment response prediction, and prognosis. Machine learning algorithms were predominantly used, particularly random forest, logistic regression, and support vector machines. Omics data were frequently employed as predictors, especially transcriptomics and microbiome analyses. Studies demonstrated good predictive performance across all three areas, with median AUC values ranging from 0.85 to 0.90.ConclusionAI applications in IBD show promising potential to enhance clinical practice, particularly in disease prognosis and predicting treatment response. However, clinical implementation requires further validation through prospective studies. Future research should focus on standardizing protocols, defining clinically significant outcomes, and evaluating the efficacy of these tools.
| S-EPMC11826164 | biostudies-literature
Project description:The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.
| S-EPMC10037250 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
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Project description:Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Genetic markers are associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. IBD has a clear immunological background and interleukins play key role in the process. Almost 130 original papers were revised including meta-analysis. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but text often do not available for the doctors use these in the clinical practice nowadays. We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD, performing an electronic search of PubMed Database from publications of the last 10 years, and used the following medical subject heading terms and/or text words: IBD, CD, UC, interleukins and polymorphisms.
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