Immunological networks defining the heterogeneity of inflammatory bowel diseases.
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ABSTRACT:
SUBMITTER: Selin KA
PROVIDER: S-EPMC8575046 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVES:In patients with inflammatory bowel disease (IBD) using biological therapy, non-adherence leads to anti-drug antibody formation and reduced effectiveness. Little is known about the optimal level of adherence in IBD patients on biologic therapy. We aimed to identify the association between adherence and disease flare and determine an optimal level of adherence. METHODS:We analyzed claims data for IBD patients prescribed adalimumab (ADA) and certolizumab (CZP) from the Truven Health MarketScan Commercial Claims and Encounters database from 2009 to 2013. Adherence was calculated using the medication possession ratio (MPR) from initiation until flare occurrence. A disease flare was defined as any hospitalization or new steroid prescription>90-days after drug initiation. The optimal MPR was determined using log-rank testing. The association between the optimal MPR and flare was assessed using multivariable Cox-Proportional hazards ratio. RESULTS:There were 6,048 patients who were prescribed ADA (n=5,325) or CZP (n=723) for IBD. The average age was 41 years (±15) and 54% were female. The optimal MPR identified was 0.86 for ADA and 0.87 for CZP; 24% of the patients were below this level. Adjusting for age, gender, and concomitant medications at initiation, patients who were adherent above these levels had a 25% lower risk of flare for ADA (HR: 0.75, 95%CI: 0.67-0.83, P<0.01) and 41% lower risk for CZP (HR: 0.59, 95%CI: 0.46-0.76, P<0.01). CONCLUSIONS:Patients who delay refills >2 days on average every 2 weeks of their subcutaneous biologics have significantly increased risk of flare. Further studies to improve adherence among those patients who consistently delay medication use are necessary.
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Project description:Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is associated with a loss or an imbalance of host-microbe interactions. Depletion-assisted deep metaproteomics was employed to reveal disease-specific networks of host-microbial protein associations in IBD.
2023-06-28 | PXD043380 |
Project description:Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy.
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Project description:In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.
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Project description:The epithelium of the gastrointestinal tract is one of the most versatile tissues in the organism, responsible for providing a tight barrier between dietary and bacterial antigens and the mucosal and systemic immune system while maintaining efficient digestive and absorptive processes to ensure adequate nutrient and energy supply. Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are associated with a breakdown of both functions, which in some cases are clearly interrelated. In this updated literature review, we focus on the effects of intestinal inflammation and the associated immune mediators on selected aspects of the transepithelial transport of macronutrients and micronutrients. The mechanisms responsible for nutritional deficiencies are not always clear and could be related to decreased intake, malabsorption, and excess losses. We summarize the known causes of nutrient deficiencies and the mechanism of inflammatory bowel disease-associated diarrhea. We also overview the consequences of impaired epithelial transport, which infrequently transcend its primary purpose to affect the gut microbial ecology and epithelial integrity. Although some of those regulatory mechanisms are relatively well established, more work needs to be done to determine how inflammatory cytokines can alter the transport process of nutrients across the gastrointestinal and renal epithelia.
| S-EPMC4103619 | biostudies-literature
Project description:Inflammatory bowel diseases (IBD) are chronic intestinal disorders characterized by dysregulated immune responses to resident microbiota in genetically susceptible hosts. The activation of the cholinergic system has been proposed for the treatment of IBD patients according to its potential anti-inflammatory effect in vivo. The α-7-nicotinic-acetylcholine receptor (α7nAChR) is involved in the inhibition of inflammatory processes, modulating the production of cytokines, suppressing dendritic cells and macrophage activity, leading to the suppression of T cells. In this review, we address the most recent studies and clinical trials concerning cholinergic signaling and its therapeutic potential for inflammatory bowel diseases.
| S-EPMC8683952 | biostudies-literature
Project description:A growing body of evidence has demonstrated an intricate association between inflammatory bowel disease (IBD) and neurodegenerative conditions, expanding beyond previous foci of comorbidities between IBD and mood disorders. These new discoveries stem from an improved understanding of the gut-microbiome-brain axis: specifically, the ability of the intestinal microbiota to modulate inflammation and regulate neuromodulatory compounds. Clinical retrospective studies incorporating large sample sizes and population-based cohorts have demonstrated and confirmed the relevance of IBD and chronic neurodegeneration in clinical medicine. In this review, we expound upon the current knowledge on the gut-microbiome-brain axis, highlighting several plausible mechanisms linking IBD with neurodegeneration. We also summarize the known associations between IBD with Parkinson disease, Alzheimer disease, vascular dementia and ischemic stroke, and multiple sclerosis in a clinical context. Finally, we discuss the implications of an improved understanding of the gut-microbiome-brain axis in preventing, diagnosing, and managing neurodegeneration among IBD and non-IBD patients.
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Project description:Alexithymia is usually described by three main dimensions difficulty identifying feelings (DIF), difficulty describing feelings (DDF), and externally oriented thinking (EOT). The most commonly used questionnaire investigating alexithymia, the Toronto Alexithymia Scale (TAS-20), supports this three-factor structure. One important assumption is that alexithymia severity is associated to vulnerability to somatic diseases, among them gastrointestinal disorders. However, the association between alexithymia and gastrointestinal disorders is not systematic, thus questioning the role of alexithymia as a vulnerability factor for those illnesses. A recent factor analysis suggested another four-factor structure for the TAS-20: difficulties in awareness of feelings (DAF), difficulties in interoceptive abilities (DIA), externally oriented thinking (EOT), and poor affective sharing (PAS). We assume that DIA and DAF might be more relevant to investigate the association between alexithymia and gastrointestinal disorders. The rationale is that DIA and DAF reflect impairments in emotion regulation that could contribute to an inappropriate autonomic and HPA axis homeostasis in irritable bowel syndrome (IBS), ulcerative colitis (UC), or Crohn's disease (CD). The aim of this study was to investigate whether DIA and DAF are associated with the presence of IBS, UC or CD, while checking for anxiety, depression, parasympathetic (vagus nerve) activity and cortisol levels. We recruited control participants (n=26), and patients in remission who were diagnosed with IBS (n=24), UC (n=18), or CD (n=21). Participants completed questionnaires to assess anxiety, depression, and alexithymia. A blood sample and an electrocardiogram were used to measure the level of cortisol and parasympathetic activity, respectively. Logistic regressions with the four-factor structure of the TAS-20 revealed that DIA was a significant predictor of IBS (W(1)=6.27, p=.01). Conversely, DIA and DAF were not significant predictors in CD and UC patients. However, low cortisol level was a significant predictor of UC (W(1)=4.67, p=.035). Additional logistic regressions based on the original 3-factor structure of TAS-20 (DIF, DDF, and EOT) showed that only DDF was a significant predictor of CD [W(1)=6.16, p < .001]. The present study suggests that DIA is an important dimension for assessing potential risk for gastrointestinal diseases, in particular for IBS.
| S-EPMC7142209 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is the common name for chronic disorders associated with the inflammation of the gastrointestinal tract. IBD is triggered by environmental factors in genetically susceptible individuals and has a significant number of incidences worldwide. Crohn's disease (CD) and ulcerative colitis (UC) are the two distinct types of IBD. While involvement in ulcerative colitis is limited to the colon, Crohn's disease may involve the whole gastrointestinal tract. Although these two disorders differ in macroscopic inflammation patterns, they share various molecular pathogenesis, yet the diagnosis can remain unclear, and it is important to reveal their molecular signatures in the network level. Improved molecular understanding may reveal disease type-specific and even individual-specific targets. To this aim, we determine the subnetworks specific to UC and CD by mapping transcriptome data to protein-protein interaction (PPI) networks using two different approaches [KeyPathwayMiner (KPM) and stringApp] and perform the functional enrichment analysis of the resulting disease type-specific subnetworks. TP63 was identified as the hub gene in the UC-specific subnet and p63 tumor protein, being in the same family as p53 and p73, has been studied in literature for the risk associated with colorectal cancer and IBD. APP was identified as the hub gene in the CD-specific subnet, and it has an important role in the pathogenesis of Alzheimer's disease (AD). This relation suggests that some similar genetic factors may be effective in both AD and CD. Last, in order to understand the biological meaning of these disease-specific subnets, they were functionally enriched. It is important to note that chemokines-special types of cytokines-and antibacterial response are important in UC-specific subnets, whereas cytokines and antimicrobial responses as well as cancer-related pathways are important in CD-specific subnets. Overall, these findings reveal the differences between IBD subtypes at the molecular level and can facilitate diagnosis for UC and CD as well as provide potential molecular targets that are specific to disease subtypes.
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Project description:Methotrexate (MTX) is an established therapy for patients with steroid-dependent Crohn's disease (CD). MTX is also frequently used in combination with anti-TNF agents to suppress anti-drug antibody formation. It has been suggested in the past that MTX lacks any clinical effectiveness in patients with ulcerative colitis (UC); however, newer data at least partially contradict this assumption. The following review will discuss recent data for the use of MTX in CD, UC and in combination with anti-TNF agents.
| S-EPMC4820247 | biostudies-literature