RESUMEN
An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
Asunto(s)
Colectomía/estadística & datos numéricos , Colitis Ulcerosa/cirugía , Enfermedad de Crohn/cirugía , Sitios de Carácter Cuantitativo , Transcriptoma , Bancos de Muestras Biológicas , Estudios de Cohortes , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/genética , Colon/metabolismo , Colon/patología , Colon/cirugía , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/genética , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial , Pronóstico , Medición de Riesgo , Reino UnidoRESUMEN
Researchers are increasingly using web-based technologies to deliver family-based, prevention programming. Few studies have examined the success of such approaches for families with low incomes. The purpose of this study was to describe the level of in-class and online engagement in a childhood obesity prevention program for parents with low incomes, to examine the demographic correlates of parent engagement, and to examine dosage effects on parental feeding outcomes as a function of online exposure. All participants attended in-class nutrition education classes (Eating Smart · Being Active) as part of the Expanded Food and Nutrition Education Program (EFNEP) in Colorado and Washington State (classes were offered in English and Spanish). Participants in this analysis were 168 parents from a larger cluster randomized controlled trial who had been randomly assigned to also receive a newly developed, mobile-based version of an efficacious, feeding-focused, childhood obesity prevention program. Results showed that despite high levels of in-person attendance (70%), participants only accessed 47% of the videos (online content). Older parents and parents of girls showed higher levels of in-person attendance; currently employed parents showed lower levels. Online engagement varied as a function of ethnicity and acculturation: non-Hispanic parents accessed the most videos, low-acculturated Hispanic parents accessed the second most, and highly acculturated Hispanic parents accessed the least. In contrast, low-acculturated Hispanic parents showed the highest in-person attendance. For all but one outcome, significant online program effects were found only for parents who accessed at least half of the videos. Implications for mobile-based, family-based prevention programs for parents with low incomes are considered.ClinicalTrials.gov Identifier: NCT03170700; Registration Date: March 08, 2017.
Asunto(s)
Obesidad Infantil , Niño , Femenino , Humanos , Educación en Salud , Responsabilidad Parental , Padres/educación , Obesidad Infantil/prevención & control , Pobreza , Washingtón , Hispánicos o LatinosRESUMEN
ABSTRACT: Recently the National Academies of Sciences, Engineering, and Medicine reported a summary of recommendations from high-income countries on what and how to feed infants and children from birth to 2 years of age. The report notes generally consistent recommendations against providing sugar-sweetened beverages (SSB), juice, and beverages that contain nonnutritive sweeteners to infants and children younger than 2 years. When counselling parents and other caregivers, pediatricians should feel empowered to advise against offering these beverages.
Asunto(s)
Bebidas , Edulcorantes no Nutritivos , Niño , Dieta , Humanos , LactanteRESUMEN
BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.
Asunto(s)
Corticoesteroides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/uso terapéutico , Adolescente , Biomarcadores/metabolismo , Niño , Preescolar , Estudios de Cohortes , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
Asunto(s)
Enfermedad de Crohn/genética , Metilación de ADN/genética , Regulación de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana/métodos , Adolescente , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Enfermedad de Crohn/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Lactante , Inflamación/genética , Masculino , América del Norte , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
The current gold standard for diagnosis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is through a liver biopsy, and there is an urgent need to develop non-invasive methods for early detection. We previously demonstrated metabolic remodeling in the mouse fatty liver, which is marked by increased hepatic expression and activities of phosphoglucose isomerase (PGI) and several other glycolytic enzymes. Since PGI is actively transported out of the cell, acting as a multifunctional cytokine referred to as autocrine motility factor (AMF), we explored the possibility that PGI secreted from the fatty liver may be targeted for early detection of the silent disease. We report here that mice with NASH exhibited significantly elevated serum PGI enzyme activities compared to normal control (P < 0.005). We further confirmed the finding using serum/plasma samples (n = 73) collected from a cohort of NASH patients who were diagnosed according to Kleiner's criteria, showing a normal mean PGI of 19.5 ± 8.8 IU/L and patient mean PGI of 105.6 ± 79.9 IU/L (P < 0.005). In addition, elevated blood PGI in NASH patients coincided with increased blood L-lactate. Cell culture experiments were then conducted to delineate the PGI-lactate axis, which revealed that treatment of HepG2 cells with recombinant PGI protein stimulated glycolysis and lactate output, suggesting that the disease-induced PGI likely contributed to the increased lactate in NASH patients. Taken together, the preclinical and clinical data validate secreted PGI as a useful biomarker of the fatty liver that can be easily screened at the point of care.
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Glucosa-6-Fosfato Isomerasa/metabolismo , Enfermedad del Hígado Graso no Alcohólico/enzimología , Adolescente , Animales , Biomarcadores/metabolismo , Niño , Preescolar , Glucosa-6-Fosfato Isomerasa/sangre , Células Hep G2 , Humanos , Ácido Láctico/metabolismo , Modelos Lineales , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangreRESUMEN
Up to 40% of individuals with cystic fibrosis have cystic fibrosis-related liver disease (CFLD); however, only 5% to 10% will have clinically evident disease. With the introduction of powerful cystic fibrosis transmembrane conductance regulator (CFTR) enhancers, effective treatment for cystic fibrosis is available. The role of CFTR enhancers in liver disease is unknown at this time. The traditionally accepted theory of the pathogenesis of CFLD is being questioned. A different pathogenesis may lead to new ways to treat CFLD. The way that CFLD is diagnosed and monitored is evolving as new imaging technology become available.
Asunto(s)
Fibrosis Quística , Hepatopatías , Fibrosis Quística/complicaciones , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Hepatopatías/etiologíaRESUMEN
OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). RESULTS: Mean age was 12.7 years; 49.6% (nâ=â212) were girls, and 83% (nâ=â351) were Caucasian. Severe total Mayo score was present in 28% (nâ=â120), mean PUCAI score was 49.8â±â20.1, and 33% (nâ=â142) had severe mucosal disease with extensive involvement in 82% (nâ=â353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. CONCLUSIONS: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
Asunto(s)
Colitis Ulcerosa , Sedimentación Sanguínea , Niño , Colitis Ulcerosa/diagnóstico , Colonoscopía , Femenino , Humanos , Recuento de Leucocitos , Masculino , Índice de Severidad de la EnfermedadRESUMEN
Chronic liver injury mainly comprises viral hepatitis, fatty liver disease, autoimmune hepatitis, cirrhosis and liver cancer. It is well established that gut microbiota serves as the key upstream modulator for chronic liver injury progression. Indeed, the term "gut-liver axis" was mostly applied for chronic liver injury. In the current chapter, we will summarize the relationship between gut microbiota and chronic liver injury, including the interaction between them based on latest clinic and basic research.
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Microbioma Gastrointestinal , Hepatopatías/etiología , Hígado/lesiones , Hígado/patología , Enfermedad Crónica , Humanos , Cirrosis Hepática/etiología , Hepatopatías/patología , Neoplasias Hepáticas/etiología , Enfermedad del Hígado Graso no Alcohólico/etiologíaRESUMEN
OBJECTIVE: Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. DESIGN: Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. RESULTS: Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. CONCLUSIONS: The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.
Asunto(s)
Ácidos y Sales Biliares , Colesterol 7-alfa-Hidroxilasa/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Microbioma Gastrointestinal/fisiología , Enfermedad del Hígado Graso no Alcohólico , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Dieta Alta en Grasa , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/microbiología , Ratas , Transducción de Señal/fisiologíaRESUMEN
A number of studies have associated obesity with altered gut microbiota, although results are discordant regarding compositional changes in the gut microbiota of obese animals. Herein we used a meta-analysis to obtain an unbiased evaluation of structural and functional changes of the gut microbiota in diet-induced obese rodents. The raw sequencing data of nine studies generated from high-fat diet (HFD)-induced obese rodent models were processed with QIIME to obtain gut microbiota compositions. Biological functions were predicted and annotated with KEGG pathways with PICRUSt. No significant difference was observed for alpha diversity and Bacteroidetes-to-Firmicutes ratio between obese and lean rodents. Bacteroidia, Clostridia, Bacilli, and Erysipelotrichi were dominant classes, but gut microbiota compositions varied among studies. Meta-analysis of the nine microbiome data sets identified 15 differential taxa and 57 differential pathways between obese and lean rodents. In obese rodents, increased abundance was observed for Dorea, Oscillospira, and Ruminococcus, known for fermenting polysaccharide into short chain fatty acids (SCFAs). Decreased Turicibacter and increased Lactococcus are consistent with elevated inflammation in the obese status. Differential functional pathways of the gut microbiome in obese rodents included enriched pyruvate metabolism, butanoate metabolism, propanoate metabolism, pentose phosphate pathway, fatty acid biosynthesis, and glycerolipid metabolism pathways. These pathways converge in the function of carbohydrate metabolism, SCFA metabolism, and biosynthesis of lipid. HFD-induced obesity results in structural and functional dysbiosis of gut microbiota. The altered gut microbiome may contribute to obesity development by promoting insulin resistance and systemic inflammation.
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Microbioma Gastrointestinal/fisiología , Inflamación/inmunología , Inflamación/microbiología , Resistencia a la Insulina/fisiología , Obesidad/inmunología , Obesidad/microbiología , Animales , Dieta Alta en Grasa/efectos adversos , RoedoresRESUMEN
BACKGROUND: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.
Asunto(s)
Enfermedad de Crohn/complicaciones , Adalimumab/uso terapéutico , Adolescente , Antiinflamatorios no Esteroideos/uso terapéutico , Niño , Estudios de Cohortes , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/microbiología , Progresión de la Enfermedad , Femenino , Microbioma Gastrointestinal , Humanos , Infliximab/uso terapéutico , Obstrucción Intestinal/etiología , Masculino , Pronóstico , Puntaje de Propensión , Estudios Prospectivos , Medición de Riesgo/métodos , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND & AIMS: There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. METHODS: We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12). CONCLUSIONS: In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
Asunto(s)
Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Inmunidad Mucosa/genética , Interleucinas/genética , Mucosa Intestinal/inmunología , Adolescente , Área Bajo la Curva , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colon/patología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Expresión Génica , Humanos , Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/genética , Interleucina-17/genética , Interleucina-23/genética , Interleucina-5/genética , Mucosa Intestinal/metabolismo , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , ARN Mensajero/análisis , Curva ROC , Recto , Transcriptoma , Regulación hacia ArribaRESUMEN
OBJECTIVES: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype. METHODS: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates. RESULTS: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03). CONCLUSIONS: Early life environmental factors influence the eventual phenotypes and disease course in CD.
Asunto(s)
Lactancia Materna/estadística & datos numéricos , Enfermedad de Crohn/diagnóstico , Exposición a Riesgos Ambientales/efectos adversos , Efectos Tardíos de la Exposición Prenatal/epidemiología , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Adolescente , Niño , Colon/patología , Constricción Patológica/epidemiología , Constricción Patológica/etiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/etiología , Enfermedad de Crohn/terapia , Progresión de la Enfermedad , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hospitalización/estadística & datos numéricos , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , América del Norte/epidemiología , Fenotipo , Embarazo , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Fumar/epidemiología , Factores de Tiempo , Contaminación por Humo de Tabaco/estadística & datos numéricosRESUMEN
The mucosal maltase enzymes are characterized by an activity that produces glucose from linear glucose polymers, assayed with the disaccharide maltose. The related enzyme isomaltase produces glucose from branched glucose polymers, assayed with palatinose. Maltase and isomaltase activities are part of the 4 disaccharidases assayed from clinical duodenal biopsy homogenates. The reported maltase activities are more difficult to interpret than lactase or sucrase activities because both the sucrase-isomaltase and maltase-glucoamylase proteins have overlapping maltase activities. The early work of Dahlqvist identified 4 maltase activities from human small intestinal mucosa. On one peptide, sucrase (maltase Ib) and isomaltase (maltase Ia) activities shared maltase activities but identified the enzymes as sucrase-isomaltase. On the other peptide, no distinguishing characteristics of the 2 maltase activities (maltases II and III) were detected and the activities identified as maltase-glucoamylase. The nutritional/clinical importance of small intestinal maltase and isomaltase activities are due to their crucial role in the digestion of food starches to absorbable free glucose. This review focuses on the interpretation of biopsy maltase activities in the context of reported lactase, sucrase, maltase, and palatinase biopsy assay activity patterns. We present a classification of mucosal maltase deficiencies and novel primary maltase deficiency (Ib, II, III) and provide a clarification of the role of maltase activity assayed from clinically obtained duodenal biopsies, as a path toward future clinical and molecular genomic investigations.
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Mucosa Intestinal/enzimología , alfa-Glucosidasas/deficiencia , Animales , Digestión/fisiología , Humanos , Mucosa Intestinal/metabolismo , Mutación , alfa-Glucosidasas/análisis , alfa-Glucosidasas/metabolismoRESUMEN
Semisynthetic bile acid (BA) obeticholic acid, a potent farnesoid X receptor (FXR) agonist, exhibited beneficial effects on nonalcoholic fatty liver disease (NAFLD). Obeticholic acid, however, did not cause a resolution of nonalcoholic steatohepatitis. Here we discuss several prominent knowledge gaps in BA/FXR biology. Firstly, although many groups reported elevated serum BA levels, there are reports of decreased or normal serum BA levels in NAFLD, underlining the complexity of BA regulation by environmental and genetic factors. Secondly, conflicting data exist in animal studies regarding the effects of FXR signaling on obesity and associated metabolic abnormalities. Thirdly, it remains obscure how the gut microbiome and the BA pool interact and influence the pathogenesis of NAFLD. Lastly, it is not known how FXR-mediated signaling interact with G protein-coupled BA receptor 1-mediated signaling. Answering these questions may lead to an improved pharmaceutical intervention for NAFLD targeting the FXR signaling pathway.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/uso terapéutico , Animales , Ácidos y Sales Biliares/sangre , Biomarcadores/sangre , Humanos , Enfermedad del Hígado Graso no Alcohólico/sangre , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES: Anemia is the most frequent extra-intestinal finding in inflammatory bowel disease (IBD). The aim of this study is to determine the prevalence and types of anemia in pediatric patients with IBD at diagnosis and at approximately 1 year follow-up. METHODS: This is a retrospective chart review of patients diagnosed with IBD from 2005 to 2012, ages 1 to 18 years. Patients who had hemoglobin, hematocrit, mean corpuscular volume, and iron indices obtained at the time of diagnosis and at approximately 1 year follow-up were included in the study. The prevalence of anemia at the beginning and the end of the study was recorded. Using the soluble transferrin receptor index the type of anemia was determined. RESULTS: At diagnosis, 67.31% of patients were anemic. Overall, 28.85% of patients had either iron deficiency anemia (IDA) or a combination of IDA and anemia of chronic disease (ACD), whereas 38.46% had ACD alone. At follow-up, 20.51% were anemic. 15.38% had either IDA or a combination of IDA and ACD; 5.13% had ACD alone. The pattern of anemia and response to therapy differed among the IBD phenotypes CONCLUSIONS:: Anemia is frequent in inflammatory bowel disease. The prevalence was higher in Crohn disease (CD). At 1 year, the prevalence of anemia decreased significantly, but persisted. Anemia of chronic disease predominated in CD. Iron deficiency anemia continued to be present in CD and ulcerative colitis.
Asunto(s)
Anemia/epidemiología , Enfermedades Inflamatorias del Intestino/epidemiología , Adolescente , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Lactante , Masculino , New York/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Computed tomography scans (CTs), more recently magnetic resonance imaging, are often used to assess the gastrointestinal tract in patients complaining of abdominal pain. We aim to determine the strength of agreement among abdominal imaging, endoscopic, and histologic findings. METHODS: Retrospective chart review of pediatric patients who underwent colonoscopy between January 1, 2012, and December 31, 2014, at Women and Children's Hospital of Buffalo. Patients who had abdominal and pelvic CTs or magnetic resonance imaging within 30 days before or after a colonoscopy were included. RESULTS: One hundred two patients were included: mean age 12.7â±â3.8 years, 66% girls. A total of 109 imaging studies were performed. Overall 61% of imaging studies were abnormal. The most frequent intestinal radiological findings were colonic wall thickening (CWT) (55%) and colonic wall enhancement (CWH) (24%). Free fluid (20%) and fat stranding (18%) were the most common extra-intestinal findings. Imaging studies agreed with histology in 81% and with colonoscopy in 75% with a moderate strength of agreement (k: 0.59 and 0.466, respectively). CWT agreed with histology in 74% with a moderate strength of agreement (k: 0.47). History of weight loss (OR 5.35, Pâ=â0.041), chronic diarrhea (OR 4.22, Pâ=â0.014), a positive lactoferrin (OR 7.00, Pâ=â0.011), and presence of CWT on imaging study (OR 5.20, Pâ=â0.001) were predictive of having abnormal histology. CONCLUSIONS: The strength of agreement among imaging, endoscopic, and histologic findings was suboptimal. Colonoscopy and imaging are both likely to be necessary in patients with suspected inflammatory bowel disease. Although colonoscopy may be superior in diagnosis of colitis, imaging may provide more information regarding small bowel disease.
Asunto(s)
Colon/patología , Enfermedades del Colon/diagnóstico , Colonoscopía/métodos , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Dolor Abdominal/diagnóstico , Adolescente , Niño , Colon/diagnóstico por imagen , Femenino , Humanos , Masculino , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: A subset of children with functional gastrointestinal disorders (FGIDs), which includes functional dyspepsia, may have duodenal disaccharidase deficiencies. OBJECTIVES: To determine the frequency, demographics, and clinical characteristics associated with duodenal disaccharidase deficiencies in children with functional dyspepsia. METHODS: Children ages 4 to 18 years undergoing esophagogastroduodenoscopy (EGD) evaluation for dyspepsia were enrolled in either a retrospective (study 1) or prospective (study 2) evaluation. Those with histologic abnormalities were excluded. Duodenal biopsies were obtained for disaccharidase enzyme analysis. In the retrospective study, both demographic and clinical characteristics were obtained via chart review. In the prospective study, parents completed the Rome II Questionnaire on Gastrointestinal Symptoms before the EGD. RESULTS: One hundred and twenty-nine children (nâ=â101, study 1; nâ=â28, study 2) were included. Mean age was 11.2â±â3.8 (SD) years in study 1 and 10.6â±â3.2 years in study 2. Forty-eight (47.5%) of subjects in study 1 and 13 (46.4%) of subjects in study 2 had at least 1 disaccharidase deficiency identified. All of those with a disaccharidase deficiency in both studies had lactase deficiency with 8 (7.9%) and 5 (17.9%) of those in studies 1 and 2, respectively, having an additional disaccharidase deficiency. The second most common disaccharidase deficiency pattern was that of pan-disaccharidase deficiency (PDD) in both studies. In study 1 (where both race and ethnicity were captured), self-identified Hispanic (vs non-Hispanic, Pâ<â0.05) and non-white (vs white, Pâ<â0.01) children were more likely to have lactase deficiency. Age, sex, and type of gastrointestinal symptom were not associated with presence or absence of a disaccharidase deficiency. CONCLUSIONS: Approximately half of children with functional dyspepsia undergoing EGD were identified as having a disaccharidase deficiency (predominantly lactase deficiency). Race/ethnicity may be associated with the likelihood of identifying a disaccharidase deficiency. Other clinical characteristics were not able to distinguish those with versus without a disaccharidase deficiency.
Asunto(s)
Disacaridasas/deficiencia , Duodeno/enzimología , Dispepsia/etiología , Mucosa Intestinal/enzimología , Síndromes de Malabsorción/epidemiología , Adolescente , Niño , Preescolar , Duodeno/patología , Endoscopía del Sistema Digestivo , Femenino , Humanos , Mucosa Intestinal/patología , Síndromes de Malabsorción/complicaciones , Síndromes de Malabsorción/diagnóstico , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND AND HYPOTHESES: Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic α-amylase; sucrase and isomaltase (from sucrose-isomaltase [SI]), and maltase and glucoamylase (from maltase-glucoamylase [MGAM]). Together these enzymes cleave starch to smaller molecules ultimately resulting in the absorbable monosaccharide glucose. Approximately 80% of all mucosal maltase activity is accounted for by SI and the reminder by MGAM. Clinical studies suggest that starch may be poorly digested in those with congenital sucrase-isomaltase deficiency (CSID). Poor starch digestion occurs in individuals with CSID and can be documented using a noninvasive C-breath test (BT). METHODS: C-Labled starch was used as a test BT substrate in children with CSID. Sucrase deficiency was previously documented in study subjects by both duodenal biopsy enzyme assays and C-sucrose BT. Breath CO2 was quantitated at intervals before and after serial C-substrate loads (glucose followed 75âminutes later by starch). Variations in metabolism were normalized against C-glucose BT (coefficient of glucose absorption). Control subjects consisted of healthy family members and a group of children with functional abdominal pain with biopsy-proven sucrase sufficiency. RESULTS: Children with CSID had a significant reduction of C-starch digestion mirroring that of their duodenal sucrase and maltase activity and C-sucrase BT. CONCLUSIONS: In children with CSID, starch digestion may be impaired. In children with CSID, starch digestion correlates well with measures of sucrase activity.