Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

Haberman, Yael; Tickle, Timothy L.; Dexheimer, Phillip; Kim, Miok; Tang, Dora; Karns, Rebekah; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel R.; Heyman, Melvin B.; Griffiths, Anne M.; Crandall, Wallace; Mack, David R.; Baker, Susan S.; Huttenhower, Curtis; Keljo, David J.; Hyams, Jeffrey S.; Kugathasan, Subra; Walters, Thomas D.; Aronow, Bruce J.; Xavier, Ramnik J.; Gevers, Dirk; Denson, Lee A.

doi:10.1172/jci79657

Cited by 45 publications

(64 citation statements)

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“…5B,C; Supplemental Table S7). Focusing on the iCD data set from the largest of these previous studies (Haberman et al 2014), we found that differential iCD genes associated with HNF4A sites are enriched for distinct ontologies and pathways that are dysregulated in IBD (Fig. 5H-K).…”

Section: Hnf4a Mediates Microbial Control Of Iec Genesmentioning

confidence: 89%

“…However, a mechanistic link between microbiota and HNF4A in the context of IBD pathogenesis has not been established. Previous transcriptomic studies have identified genes differentially expressed in ileal (iCD) and colonic CD (cCD) and UC (Arijs et al 2009;Haberman et al 2014) …”

Section: Hnf4a Mediates Microbial Control Of Iec Genesmentioning

confidence: 99%

“…In accord, genetic variants at human HNF4A are associated with risk for both UC and CD as well as colon cancer (Barrett et al 2009;Jostins et al 2012;Marcil et al 2012;Chellappa et al 2016). HNF4A is predicted to bind a majority of IBD-linked CRRs and to regulate IBD-linked genes (Haberman et al 2014;Meddens et al 2016). Similarly, genetic variants near human HNF4G have been associated with obesity and CD (Franke et al 2007;Berndt et al 2013).…”

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confidence: 99%

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Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

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Section: Hnf4a Mediates Microbial Control Of Iec Genesmentioning

confidence: 89%

Section: Hnf4a Mediates Microbial Control Of Iec Genesmentioning

confidence: 99%

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confidence: 99%

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Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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“…23 The Pediatric Crohn's Disease Activity Index and Pediatric Ulcerative Colitis Clinical Activity Index were used as measures of clinical severity of IBD. 22,24 We observed a significant increase in the transcript levels of iNOS in CD-and UC-affected biopsies compared with normal tissue (Figure 1). …”

Section: Results Inos Expression Is Up-regulated In Uc Patientsmentioning

confidence: 82%

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Arora

Sinha

Zhang

et al. 2015

The American Journal of Pathology

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Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC-and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembraneconductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na þ /H þ exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2 À/À mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2 þ/þ mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders. (Am J Pathol 2015 http://dx

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“…Th ese studies are still in their infancy, but data suggest that Faecalibacterium prausnitzii abundance may be associated with disease recurrence in CD ( 30 ). In addition, results from a pediatric inception cohort suggest that increased Enterobacteriaceae, Pasturellaceae, Veillonellaceae, and Fusobacteriaceae together with decreased Erysipelotrichales, Bacteroidales, and Clostridiales were not only associated with CD but also with disease severity ( 31 ). Th is gives cause for optimism that assessing microbiomal parameters may hold prognostic promise in CD.…”

Section: Th E Microbiome In CDmentioning

confidence: 99%

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

Lichtenstein¹,

McGovern²

2016

Am J Gastroenterol Suppl

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Biomarkers, radiology fi ndings, and endoscopic studies, together with clinical assessment of patients with infl ammatory bowel disease, can be used to help determine prognosis, assess disease activity, and increasingly to inform treatment decision-making. This article reviews the current "state of the science" regarding the multitude of different tests that can be performed and how these can be used in the clinic to guide management. Initially, when patients present with symptoms suggestive of infl ammatory bowel disease (IBD), standard endoscopic studies and radiographic studies should be performed and the use of combinations of serologic and fecal markers may additionally be incorporated into patient assessment. Once the patient has a formal diagnosis, prognosis should be assessed and serologic evaluation may be used, but in conjunction with endoscopic and radiographic studies. Within the context of evaluating clinical predictors of disease (e.g., disease location, nutritional status, routine blood tests), early mucosal healing has been linked to better outcomes, and failure to heal the mucosa has been associated with poorer outcomes. Evaluation of response to therapy can be approximated with the use of biomarkers (e.g., C-reactive protein, fecal calprotectin, lactoferrin), and therapeutic drug monitoring has enabled us to assess levels of drug metabolites, drug levels, and antidrug antibodies to guide the ongoing management. Although there is not yet universal adoption of biomarkers to determine treatment choices (e.g., the use of anti-tumor necrosis factor therapy), biomarkers have enabled us to "fi ne tune" treatment of some patients with IBD. Establishing mechanisms of communicating these risks/benefi ts to patients will be a considerable challenge and remains a priority area of research.

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Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

Cited by 45 publications

References 0 publications

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

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