MicroRNAs Classify Different Disease Behavior Phenotypes of Crohnʼs Disease and May Have Prognostic Utility

Peck, Bailey C. E.; Weiser, Matthew; Lee, Saangyoung E.; Gipson, Gregory R.; Iyer, Vishal B.; Sartor, Ryan B.; Herfarth, Hans H; Long, Millie D.; Hansen, Jonathan J.; Isaacs, Kim L.; Trembath, Dimitri G.; Rahbar, Reza; Sadiq, Timothy S.; Furey, Terrence S.; Sethupathy, Praveen; Sheikh, Shehzad Z.

doi:10.1097/mib.0000000000000478

Cited by 74 publications

(76 citation statements)

References 42 publications

(53 reference statements)

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“…The mechanisms through which these miRNAs modulate the stability and translation of target mRNAs are still being unraveled, but they have future potential to be used as fecal biomarkers of intestinal function and diseases such as IBD and cancer (125, 195). …”

Section: Biomarkers Of Intestinal Epithelial Permeability and Integrimentioning

confidence: 99%

Homeostasis of the gut barrier and potential biomarkers

Wells

Brummer

Derrien

et al. 2017

American Journal of Physiology-Gastrointestinal and Liver Physi

475

377

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The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts.

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Section: Biomarkers Of Intestinal Epithelial Permeability and Integrimentioning

confidence: 99%

Homeostasis of the gut barrier and potential biomarkers

Wells

Brummer

Derrien

et al. 2017

American Journal of Physiology-Gastrointestinal and Liver Physi

475

377

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“…Eight out of 13 DE miRNAs were significantly upregulated ( red ) and the remaining five were downregulated ( green ) ( p < 0.05). Red arrows indicate miRNAs previously reported and linked to inflammatory disorders [55,56,57,58,59,60,61]. …”

Section: Figurementioning

confidence: 99%

Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease

et al. 2016

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The composition of the gut microbiome reflects the overall health status of the host. In this study, stool samples representing the gut microbiomes from 6 gluten-sensitive (GS) captive juvenile rhesus macaques were compared with those from 6 healthy, age- and diet-matched peers. A total of 48 samples representing both groups were studied using V4 16S rRNA gene DNA analysis. Samples from GS macaques were further characterized based on type of diet administered: conventional monkey chow, i.e., wheat gluten-containing diet (GD), gluten-free diet (GFD), barley gluten-derived diet (BOMI) and reduced gluten barley-derived diet (RGB). It was hypothesized that the GD diet would lower the gut microbial diversity in GS macaques. This is the first report illustrating the reduction of gut microbial alpha-diversity (p < 0.05) following the consumption of dietary gluten in GS macaques. Selected bacterial families (e.g., Streptococcaceae and Lactobacillaceae) were enriched in GS macaques while Coriobacteriaceae was enriched in healthy animals. Within several weeks after the replacement of the GD by the GFD diet, the composition (beta-diversity) of gut microbiome in GS macaques started to change (p = 0.011) towards that of a normal macaque. Significance for alpha-diversity however, was not reached by the day 70 when the feeding experiment ended. Several inflammation-associated microRNAs (miR-203, -204, -23a, -23b and -29b) were upregulated (p < 0.05) in jejunum of 4 biopsied GS macaques fed GD with predicted binding sites on 16S ribosomal RNA of Lactobacillus reuteri (accession number: NR_025911), Prevotella stercorea (NR_041364) and Streptococcus luteciae (AJ297218) that were overrepresented in feces. Additionally, claudin-1, a validated tight junction protein target of miR-29b was significantly downregulated in jejunal epithelium of GS macaques. Taken together, we predict that with the introduction of effective treatments in future studies the diversity of gut microbiomes in GS macaques will approach those of healthy individuals. Further studies are needed to elucidate the regulatory pathways of inflammatory miRNAs in intestinal mucosa of GS macaques and to correlate their expression with gut dysbiosis.

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“…The expression levels of miRNAs are altered in many diseases, including neurodegenerative, oncogenic, cardiovascular, metabolic, and auto-inflammatory diseases (Wang and Sen, 2011; Rottiers and Naar, 2012; Satoh, 2012; Wang et al , 2012; Papaconstantinou et al , 2013; Dong et al , 2014). Additionally, expression levels of miRNAs in tissues and in circulation can be diagnostic, as well as prognostic, and predictive of patient therapeutic response (Slaby et al , 2010; Preis et al , 2011; Peck et al , 2015). …”

Section: Introductionmentioning

confidence: 99%

Environmental contaminants and microRNA regulation: Transcription factors as regulators of toxicant-altered microRNA expression

Sollome

Martin

Sethupathy

et al. 2016

Toxicology and Applied Pharmacology

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MicroRNAs (miRNAs) regulate gene expression by binding mRNA transcripts and inhibiting translation and/or inducing degradation of the associated transcripts. Expression levels of miRNAs have been shown to be altered in response to environmental toxicants, thus impacting cellular function and influencing disease risk. Transcription factors (TFs) are known to be altered in response to environmental toxicants and play a critical role in the regulation of miRNA expression. To date, environmentally-responsive TFs that are important for regulating miRNAs remain understudied. In a state-of-the-art analysis, we utilized in silico bioinformatic analysis to characterize potential transcriptional regulators of environmentally-responsive miRNAs. Using the miRStart database, genomic sequences of promoter regions for all available human miRNAs (n=847) were identified and promoter regions were defined as −1000/+500 base pairs from the transcription start site. Subsequently, the promoter region sequences of environmentally-responsive miRNAs (n=128) were analyzed using enrichment analysis to determine overrepresented TF binding sites (TFBS). While most (56/73) TFs differed across environmental contaminants, a set of 17 TFs was enriched for promoter binding among miRNAs responsive to numerous environmental contaminants. Of these, one TF was common to miRNAs altered by the majority of environmental contaminants, namely SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 3 (SMARCA3). These identified TFs represent candidate common transcriptional regulators of miRNAs perturbed by environmental toxicants.

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MicroRNAs Classify Different Disease Behavior Phenotypes of Crohnʼs Disease and May Have Prognostic Utility

Abstract: Article first published online 6 July 2015.Supplemental Digital Content is Available in the Text.

Cited by 74 publications

References 42 publications

Homeostasis of the gut barrier and potential biomarkers

Homeostasis of the gut barrier and potential biomarkers

Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease

Environmental contaminants and microRNA regulation: Transcription factors as regulators of toxicant-altered microRNA expression

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