Background & Aims Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a ...family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives. Methods Twenty-one families with pediatric IBD were recruited, comprising 26 Crohn’s disease patients in clinical remission, 10 ulcerative colitis patients in clinical remission, and 54 healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing, untargeted liquid chromatography–mass spectrometry metabolomics, and calprotectin measurement. Individuals were grouped into microbial and metabolomics states using Dirichlet multinomial models. Multivariate models were used to identify microbes and metabolites associated with these states. Results Individuals were classified into 2 microbial community types. One was associated with IBD but irrespective of disease status, had lower microbial diversity, and characteristic shifts in microbial composition including increased Enterobacteriaceae, consistent with dysbiosis. This microbial community type was associated similarly with IBD and reduced microbial diversity in an independent pediatric cohort. Individuals also clustered bioinformatically into 2 subsets with shared fecal metabolomics signatures. One metabotype was associated with IBD and was characterized by increased bile acids, taurine, and tryptophan. The IBD-associated microbial and metabolomics states were highly correlated, suggesting that they represented an integrated ecosystem. Healthy relatives with the IBD-associated microbial community type had an increased incidence of elevated fecal calprotectin. Conclusions Healthy first-degree relatives can have dysbiosis associated with an altered intestinal metabolome that may signify a predisease microbial susceptibility state or subclinical inflammation. Longitudinal prospective studies are required to determine whether these individuals have a clinically significant increased risk for developing IBD.
Intestinal Paneth cells modulate innate immunity and infection. In Crohn’s disease, genetic mutations together with environmental triggers can disable Paneth cell function. Here, we find that a ...western diet (WD) similarly leads to Paneth cell dysfunction through mechanisms dependent on the microbiome and farnesoid X receptor (FXR) and type I interferon (IFN) signaling. Analysis of multiple human cohorts suggests that obesity is associated with Paneth cell dysfunction. In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction. WD consumption in conjunction with Clostridium spp. increased the secondary bile acid deoxycholic acid levels in the ileum, which in turn inhibited Paneth cell function. The process required excess signaling of both FXR and IFN within intestinal epithelial cells. Our findings provide a mechanistic link between poor diet and inhibition of gut innate immunity and uncover an effect of FXR activation in gut inflammation.
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•Diet-induced obesity results in Paneth cell dysfunction in humans and mice•Consumption of western diet leads to Clostridium-mediated deoxycholic acid conversion•Deoxycholic acid activates both FXR and type I IFN pathways•Both FXR and type I IFN pathways are essential in triggering Paneth cell defects
Small intestinal Paneth cells are gatekeepers of gut innate immunity. Liu et al. identified a link between consumption of high fat, high sugar diet (western diet; WD) and Paneth cell dysfunction. The mechanisms involve WD-associated microbiota conversion of bile acids, which activate both FXR and type I interferon pathways.
Background
The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn’s disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for ...tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR).
Methods
We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert’s score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics.
Results
The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) 0.13–0.53). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI 0.32–1.36). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results.
Conclusion
In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.
Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage ...analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.
Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we ...performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the
gene that conferred risk for CD (N2081D variant,
= 9.5 × 10
) or protection from CD (N551K variant, tagging R1398H-associated haplotype,
= 3.3 × 10
). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated
in CD pathogenesis. Analysis of the extended
locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The
N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared
alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
There have been many reports on serologic autoantibodies in inflammatory bowel diseases (IBD),
consisting of ulcerative colitis (UC) and Crohn's disease (CD), and recently Kuwada et al
reported a new ...autoantibody against integrin αvβ6 with high sensitivity and specificity for UC. Concurrently, we had discovered autoantibodies against endothelial protein C receptor (EPCR) in Takayasu arteritis (TAK), which is sometimes complicated by UC.
Interestingly, this autoantibody was found in most patients with TAK associated with UC, and we found that the positivity rate in patients with UC without TAK was also high, suggesting that anti-EPCR antibody is a candidate autoantibody useful for the diagnosis of UC.
To clarify the diagnostic usefulness of anti-EPCR antibodies in patients with IBD and their relationship to several disease subphenotypes and their disease activities, we analyzed the serum samples from patients with IBD and non-IBD control subjects in Japan and the United States.
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants ...underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
The role of glycosylation in IBD Theodoratou, Evropi; Campbell, Harry; Ventham, Nicholas T ...
Nature reviews. Gastroenterology & hepatology,
10/2014, Letnik:
11, Številka:
10
Journal Article
Recenzirano
A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in ...intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
Towards personalized care in IBD Gerich, Mark E; McGovern, Dermot P B
Nature reviews. Gastroenterology & hepatology,
05/2014, Letnik:
11, Številka:
5
Journal Article
Recenzirano
The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust ...molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection.
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