The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids.

Physiol Behav. 2015 Oct 15;150:38-42

Authors: Gutierrez-Aguilar R, Thompson A, Marchand N, Dumont P, Woods SC, de Launoit Y, Seeley RJ, Ulrich-Lai YM

Abstract
The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.

PMID: 25813907 [PubMed - indexed for MEDLINE]

Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

PLoS One. 2015;10(6):e0128113

Authors: Andersson C, Kvist PH, McElhinney K, Baylis R, Gram LK, Pelzer H, Lauritzen B, Holm TL, Hogan S, Wu D, Turpin B, Miller W, Palumbo JS

Abstract
The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

PMID: 26098308 [PubMed - indexed for MEDLINE]

Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.

PLoS One. 2015;10(6):e0128074

Authors: Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research Group, Kugathasan S

Abstract
BACKGROUND: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
METHODS: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
CONCLUSIONS: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

PMID: 26098103 [PubMed - indexed for MEDLINE]

The Telehealth Enhancement of Adherence to Medication (TEAM) in pediatric IBD trial: Design and methodology.

Contemp Clin Trials. 2015 Jul;43:105-13

Authors: Hommel KA, Gray WN, Hente E, Loreaux K, Ittenbach RF, Maddux M, Baldassano R, Sylvester F, Crandall W, Doarn C, Heyman MB, Keljo D, Denson LA

Abstract
Medication nonadherence is a significant health care issue requiring regular behavioral treatment. Lack of sufficient health care resources and patient/family time commitment for weekly treatment are primary barriers to receiving appropriate self-management support. We describe the methodology of the Telehealth Enhancement of Adherence to Medication (TEAM) trial for medication nonadherence in pediatric inflammatory bowel disease (IBD). For this trial, participants 11-18 years of age will be recruited from seven pediatric hospitals and will complete an initial 4-week run in to assess adherence to a daily medication. Those who take less than 90% of their prescribed medication will be randomized. A total of 194 patients with IBD will be randomized to either a telehealth behavioral treatment (TBT) arm or education only (EO) arm. All treatments will be delivered via telehealth video conferencing. The patients will be assessed at baseline, post-treatment, 3, 6, and 12 months. We anticipate that participants in the TBT arm will demonstrate a statistically significant improvement at post-treatment and 3-, 6-, and 12-month follow-up compared to participants in the EO arm for both medication adherence and secondary outcomes (i.e., disease severity, patient quality of life, and health care utilization). If efficacious, the TEAM intervention could be disseminated broadly and reduce health care access barriers so that the patients could receive much needed self-management intervention.

PMID: 26003436 [PubMed - indexed for MEDLINE]