RESUMEN

AIMS: Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1-SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD). METHODS: Rats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1-SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT-PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology. RESULTS: In neonatal-CRD-induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL-6 levels elevated in PVN. However, infusion of Epac agonist 8-pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV-SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL-6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI-09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL-6 into PVN simulated the visceral hypersensitivity. CONCLUSIONS: Inactivation of Epac1-SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.

Asunto(s)

Factores de Intercambio de Guanina Nucleótido , Hiperalgesia , Enfermedades Intestinales , Proteína 3 Supresora de la Señalización de Citocinas , Dolor Visceral , Animales , Enfermedades del Colon/genética , Enfermedades del Colon/metabolismo , Enfermedades del Colon/patología , Hormona Liberadora de Corticotropina/metabolismo , Dilatación Patológica/complicaciones , Dilatación Patológica/genética , Dilatación Patológica/metabolismo , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Hiperalgesia/etiología , Hiperalgesia/genética , Hiperalgesia/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Recién Nacido , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/metabolismo , Interleucina-6/metabolismo , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/genética , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/metabolismo , Dolor , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Sprague-Dawley , Enfermedades del Recto/genética , Enfermedades del Recto/metabolismo , Enfermedades del Recto/patología , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Dolor Visceral/etiología , Dolor Visceral/genética , Dolor Visceral/metabolismo

Asunto(s)

Enfermedades del Colon/diagnóstico , Histiocitosis de Células de Langerhans/diagnóstico , Úlcera/diagnóstico , Anciano , Biopsia , Enfermedades del Colon/tratamiento farmacológico , Enfermedades del Colon/genética , Colonoscopía , Femenino , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/genética , Humanos , Inmunohistoquímica , Mutación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas de Dominio T Box/genética , Úlcera/tratamiento farmacológico , Úlcera/genética

RESUMEN

The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator ß-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/ß-catenin pathway has been implicated in carcinogenesis. Aberrant Wnt signaling has been reported in a variety of malignancies, and its role in both hereditary and sporadic colorectal cancer (CRC), has been the subject of intensive study. Interestingly, the vast majority of colorectal tumors harbor mutations in the tumor suppressor gene adenomatous polyposis coli (APC). The Wnt pathway is complex, and despite decades of research, the mechanisms that underlie its functions are not completely known. Thus, although the Wnt cascade is an attractive target for therapeutic intervention against CRC, one of the malignancies with the highest morbidity and mortality rates, achieving efficacy and safety is yet extremely challenging. Here, we review the current knowledge of the Wnt different epistatic signaling components and the mechanism/s by which the signal is transduced in both health and disease, focusing on CRC. We address some of the important questions in the field and describe various therapeutic strategies designed to combat unregulated Wnt signaling, the development of targeted therapy approaches and the emerging challenges that are associated with these advanced methods.

Asunto(s)

Enfermedades del Colon/metabolismo , Neoplasias/metabolismo , Vía de Señalización Wnt , Animales , Enfermedades del Colon/tratamiento farmacológico , Enfermedades del Colon/genética , Enfermedades del Colon/microbiología , Progresión de la Enfermedad , Humanos , Microbiota , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/microbiología

RESUMEN

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4-/-) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-ß was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.

Asunto(s)

Enfermedades del Colon/patología , Citocinas/metabolismo , Sulfato de Dextran/efectos adversos , Receptor Toll-Like 4/genética , Animales , Línea Celular , Colágeno , Enfermedades del Colon/inducido químicamente , Enfermedades del Colon/genética , Enfermedades del Colon/inmunología , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Subunidad p40 de la Interleucina-12/metabolismo , Macrófagos Peritoneales/metabolismo , Ratones , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

It is known and accepted that the gut microbiota composition of an organism has an impact on its health. Many studies deal with this topic, the majority discussing gastrointestinal health. Adenomatous colon polyps have a high prevalence as colon cancer precursors, but in many cases, they are hard to diagnose in their early stages. Gut microbiota composition correlated with the presence of adenomatous colon polyps may be a noninvasive and efficient tool for diagnosis with a high impact on human wellbeing and favorable health care costs. This review is meant to analyze the gut microbiota correlated with the presence of adenomatous colon polyps as the first step for early diagnosis, prophylaxis, and treatment.

Asunto(s)

Pólipos Adenomatosos/microbiología , Neoplasias del Colon/diagnóstico , Pólipos del Colon/microbiología , Microbioma Gastrointestinal/genética , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Colon/microbiología , Colon/patología , Enfermedades del Colon/diagnóstico , Enfermedades del Colon/genética , Enfermedades del Colon/microbiología , Neoplasias del Colon/genética , Neoplasias del Colon/microbiología , Pólipos del Colon/diagnóstico , Pólipos del Colon/genética , Colonoscopía , Humanos

RESUMEN

Given the role of Cav3.2 isoform among T-type Ca2+ channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Cav3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Cav3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Cav3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Cav3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Cav3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic Na2S, known to enhance Cav3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Cav3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Cav3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.

Asunto(s)

Canales de Calcio Tipo T/metabolismo , Enfermedades del Colon/inducido químicamente , Nociceptores/efectos de los fármacos , Dolor Visceral/inducido químicamente , Animales , Butiratos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/genética , Enfermedades del Colon/genética , Sulfuro de Hidrógeno/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/efectos de los fármacos , Dolor Visceral/genética

RESUMEN

The solute carrier family 6 member 14 (SLC6A14) protein imports and concentrates all neutral amino acids as well as the two cationic acids lysine and arginine into the cytoplasm of different cell types. Primarily described as involved in several cancer and colonic diseases physiopathological mechanisms, the SLC6A14 gene has been more recently identified as a genetic modifier of cystic fibrosis (CF) disease severity. It was indeed shown to have a pleiotropic effect, modulating meconium ileus occurrence, lung disease severity, and precocity of P. aeruginosa airway infection. The biological mechanisms explaining the impact of SLC6A14 on intestinal and lung phenotypes of CF patients are starting to be elucidated. This review focuses on SLC6A14 in lung and gastrointestinal physiology and physiopathology, especially its involvement in the pathophysiology of CF disease.

Asunto(s)

Sistemas de Transporte de Aminoácidos/metabolismo , Fibrosis Quística/patología , Tracto Gastrointestinal/metabolismo , Pulmón/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Enfermedades del Colon/genética , Enfermedades del Colon/metabolismo , Enfermedades del Colon/patología , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Variación Genética , Humanos , Desequilibrio de Ligamiento , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Índice de Severidad de la Enfermedad

RESUMEN

Restitution of wounds in colonic epithelium is essential in the maintenance of health. Microbial products, such as the short-chain fatty acid butyrate, can have positive effects on wound healing. We used an in vitro model of T84 colonic epithelial cells to determine if the Snail genes Slug (SNAI2) and Snail (SNAI1), implemented in keratinocyte monolayer healing, are involved in butyrate-enhanced colonic epithelial wound healing. Using shRNA-mediated Slug/Snail knockdown, we found that knockdown of Slug (Slug-KD), but not Snail (Snail-KD), impairs wound healing in scratch assays with and without butyrate. Slug and Snail had differential effects on T84 monolayer barrier integrity, measured by transepithelial resistance, as Snail-KD impaired the barrier (with or without butyrate), whereas Slug-KD enhanced the barrier, again with or without butyrate. Targeted transcriptional analysis demonstrated differential expression of several tight junction genes, as well as focal adhesion genes. This included altered regulation of Annexin A2 and ITGB1 in Slug-KD, which was reflected in confocal microscopy, showing increased accumulation of B1-integrin protein in Slug-KD cells, which was previously shown to impair wound healing. Transcriptional analysis also indicated altered expression of genes associated with epithelial terminal differentiation, such that Slug-KD cells skewed toward overexpression of secretory cell pathway-associated genes. This included trefoil factors TFF1 and TFF3, which were expressed at lower than control levels in Snail-KD cells. Since TFFs can enhance the barrier in epithelial cells, this points to a potential mechanism of differential modulation by Snail genes. Although Snail genes are crucial in epithelial wound restitution, butyrate responses are mediated by other pathways as well.NEW & NOTEWORTHY Although butyrate can promote colonic mucosal healing, not all of its downstream pathways are understood. We show that the Snail genes Snail and Slug are mediators of butyrate responses. Furthermore, these genes, and Slug in particular, are necessary for efficient restitution of wounds and barriers in T84 epithelial cells even in the absence of butyrate. These effects are achieved in part through effects on regulation of ß1 integrin and cellular differentiation state.

Asunto(s)

Butiratos/uso terapéutico , Enfermedades del Colon/tratamiento farmacológico , Enfermedades del Colon/genética , Factores de Transcripción de la Familia Snail/genética , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular , Técnicas de Silenciamiento del Gen , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas de Uniones Estrechas/efectos de los fármacos , Proteínas de Uniones Estrechas/genética , Factor Trefoil-1/biosíntesis , Factor Trefoil-1/genética , Factor Trefoil-3/biosíntesis , Factor Trefoil-3/genética

RESUMEN

Intestinal fibrosis is a serious complication in inflammatory bowel disease (IBD). Despite the remarkable success of recent anti-inflammatory therapies for IBD, incidence of intestinal fibrosis and need for bowel resection have not significantly changed. To clarify the contribution of haematopoietic-derived cells in intestinal fibrosis, we prepared bone marrow (BM) chimeric mice (chimeras), which were reconstituted with BM cells derived from enhanced green fluorescent protein (EGFP)-transgenic mice or CC chemokine receptor 2 (CCR2)-deficient mice. After 2 months of transplantation, BM chimeras were treated with azoxymethane/dextran sodium sulphate. During chronic inflammation, CCR2+ BM-derived monocyte and fibrocyte infiltration into the colon and CC chemokine ligand 2 production increased, leading to colon fibrosis in EGFP BM chimeras. In CCR2-deficient BM chimeras, monocyte and fibrocyte numbers in the colonic lamina propria significantly decreased, and colon fibrosis was attenuated. In colon tissue, mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 but not of collagen I, transforming growth factor-ß1 or matrix metalloproteinases was significantly different between the two chimeras. CCR2+ monocytes and fibrocytes showed high Timp1 mRNA expression. Our results suggest that infiltrating CCR2+ monocytes and their progenies, fibrocytes, promote colon fibrosis by inhibiting collagen degradation through TIMP-1 production.

Asunto(s)

Colon/metabolismo , Enfermedades del Colon/metabolismo , Monocitos/metabolismo , Receptores CCR2/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/biosíntesis , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colon/patología , Enfermedades del Colon/genética , Enfermedades del Colon/patología , Fibrosis , Ratones , Ratones Transgénicos , Monocitos/patología , Receptores CCR2/genética , Inhibidor Tisular de Metaloproteinasa-1/genética

RESUMEN

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Asunto(s)

Enfermedades del Colon/genética , Tejido Conectivo/fisiología , Enfermedades Diverticulares/genética , Epitelio/fisiología , Estudio de Asociación del Genoma Completo , Unión Neuromuscular/fisiología , Adulto , Anciano , Estudios de Casos y Controles , Enfermedades del Colon/patología , Bases de Datos Genéticas , Enfermedades Diverticulares/patología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Reino Unido

RESUMEN

Purpose: Melanosis coli (MC) is a disorder of pigmentation of the wall of the colon, often identified at the time of colonoscopy. The aim of the present study is to identify candidate biomarkers for MC. Methods: The transcriptome data for MC (GSE78933) with five MC tissues and five corresponding normal tissues is obtained from the NCBI Gene Expression Omnibus (GEO) database. R/Bioconductor package limma was used to screen differently expressed genes (DEGs). ClueGO of cytoscape was applied for Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Based on STRING V10 database, protein-protein interaction (PPI) network was constructed. The pathological tissue and normal tissue from 23 MC patients and 23 controls were collected, respectively. The relative expression of hub nodes was detected by qRT-PCR and Western blot. For regulating the expression of these genes, overexpression vector was constructed or siRNA transfection was used. Finally, apoptosis was detected by flow cytometry. Results: Total 1342 DEGs were screened, including 786 up-regulated and 556 down-regulated genes. These genes were mainly enriched in stimulatory C-type lectin receptor signaling pathway, polysaccharide biosynthetic process, intracellular, and oxidative phosphorylation. PPI network was then constructed with 426 DEGs and 895 interactions. Thereinto, G-protein subunit γ 5 (GNG5), lysophosphatidic acid receptor 3 (LPAR3), mitogen-activated protein kinase 8 (MAPK8), NHP2L1, proteasome 26S subunit, ATPase 6 (PSMC6), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit ß (PIK3CB) were hub nodes with higher degree. RT-PCR and Western blot results showed that GNG5, LPAR3, MAPK8, and PSMC6 were differently expressed with significance. The expression of these screened genes is also related with cell apoptosis. Conclusion: GNG5, LPAR3, MAPK8, and PSMC6 might be candidate biomarkers associated with apoptosis in MC.

Asunto(s)

ATPasas Asociadas con Actividades Celulares Diversas/genética , Enfermedades del Colon/genética , Subunidades gamma de la Proteína de Unión al GTP/genética , Melanosis/genética , Proteína Quinasa 8 Activada por Mitógenos/genética , Complejo de la Endopetidasa Proteasomal/genética , Receptores del Ácido Lisofosfatídico/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Apoptosis/fisiología , Biomarcadores , Estudios de Casos y Controles , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Humanos , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Mapas de Interacción de Proteínas , Receptores del Ácido Lisofosfatídico/metabolismo , Transcriptoma

RESUMEN

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.

Asunto(s)

Trasplante de Médula Ósea , Colon/inmunología , Enfermedades del Colon/inmunología , Enfermedad Injerto contra Huésped/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Células Th17/inmunología , Aloinjertos , Animales , Colon/patología , Enfermedades del Colon/genética , Enfermedades del Colon/patología , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células T Invariantes Asociadas a Mucosa/patología , Células Th17/patología

RESUMEN

We demonstrate the application of whole exome sequencing to discover the rare variants for congenital pouch colon, acronymed CPC. For 18 affected individuals in a total of 64 samples, we sequenced coding regions to a mean coverage of 100×. A sufficient depth of ca. 94% of targeted exomes was achieved. Filtering against the public SNP/variant repositories, we identified a host of candidate genes, EPB41L4A and CTC1 associated with colon, neural/brain muscles and Dyskeratosis Congenita maladies. Furthermore, the stop gain mutations in the form of JAG1,OR5AR1,SLC22A24,PEX16,TSPAN32,TAF1B,MAP2K3 and SLC25A19 appears to be localized to Chromosomes 2, 11, 17 and 20 in addition to the three stop lost mutants across three genes, viz. OAS2, GBA3 and PKD1L2 affecting the colon tissue. While our results have paved way for transcendence of monogenic traits in identifying the genes underlying rare genetic disorders, it will provide helpful clues for further investigating genetic factors associated with anorectal anomalies, particularly CPC.

Asunto(s)

Colon/anomalías , Enfermedades del Colon/congénito , Enfermedades del Colon/genética , Predisposición Genética a la Enfermedad , Exoma , Femenino , Humanos , Recién Nacido , Masculino , Secuenciación del Exoma

RESUMEN

RNA sequencing is the use of high throughput next generation sequencing technology to survey, characterize, and quantify the transcriptome of a genome. RNA sequencing has been used to analyze the pathogenesis of several malignancies such melanoma, lung cancer, and colorectal cancer. RNA sequencing can identify differential expression of genes (DEG's), mutated genes, fusion genes, and gene isoforms in disease states. RNA sequencing has been used in the investigation of several colorectal diseases such as colorectal cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and irritable bowel syndrome.

Asunto(s)

Enfermedades del Colon/diagnóstico , Enfermedades del Colon/genética , Secuenciación de Nucleótidos de Alto Rendimiento , ARN/genética , Análisis de Secuencia de ARN/métodos , Biomarcadores de Tumor/genética , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/genética , Enfermedades del Colon/terapia , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/genética , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , ARN Neoplásico/genética , Factores de Riesgo

RESUMEN

No disponible

Asunto(s)

Humanos , Masculino , Adulto , Enfermedades del Colon/genética , Enfermedades del Colon , Fístula Intestinal , Enfermedades Duodenales , Enfermedades en Gemelos , Enfermedad de Crohn/complicaciones , Gemelos Monocigóticos/genética , Fístula Cutánea/complicaciones , Enfermedades Duodenales/complicaciones , Fístula Cutánea , Tránsito Gastrointestinal/efectos de la radiación

RESUMEN

A 13-year-old boy was admitted to our hospital because of persistent diarrhea, abdominal pain, and bloody stools. The patient had experienced repeated hospitalizations for the treatment of respiratory infections since early childhood. Colonoscopic and pathological studies led to a diagnosis of gut-associated T-cell lymphoproliferative disease (T-cell LPD). Laboratory data showed T-lymphocytopenia (492/µl), increased serum IgG levels (1,984 mg/dl), and low serum antibody titers for specific pathogens. Combined immunodeficiency accompanied by T-LPD suggested the diagnosis of activated PI3Kδ syndrome (APDS). Genetic analyses identified a heterozygous mutation of the PIK3CD gene (c.1573 G to A p.Glu525Lys). Although prednisolone and cyclosporine therapy has controlled the T-cell LPD, this patient awaits allogeneic hematopoietic cell transplantation to achieve a complete cure of his APDS.

Asunto(s)

Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Enfermedades del Colon/diagnóstico por imagen , Trastornos Linfoproliferativos/diagnóstico por imagen , Linfocitos T , Adolescente , Fosfatidilinositol 3-Quinasa Clase I/genética , Enfermedades del Colon/genética , Activación Enzimática , Humanos , Trastornos Linfoproliferativos/genética , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones

RESUMEN

We report a 54-year-old female patient with myelodysplastic syndrome (MDS) associated with trisomy 8, who had multiple colonic ulcers. The patient had been diagnosed as having MDS of refractory cytopenia with trisomy 8 10 years previously. She underwent colonoscopy for abdominal pain, which revealed severe circumferential stenosis with multiple ulcers in the ileocecal region and a discrete excavating ulcer in the transverse colon. The patient had been free from any dermatological, oral, genital or ocular symptoms suggestive of Behçet's disease (BD). A diagnosis of multiple colonic ulcers associated with MDS with trisomy 8 was thus suggested. Follow-up colonoscopies 5 and 6 years later revealed progression of the ileocecal stenosis to a circumferential ulcer, while the ulcer in the transverse colon had not changed. Because our patient lacked extraintestinal symptoms of BD, trisomy 8 was presumed to be responsible for her colonic ulcers.

Asunto(s)

Enfermedades del Colon/genética , Síndromes Mielodisplásicos/genética , Trisomía , Úlcera/genética , Enfermedades del Ciego/genética , Cromosomas Humanos Par 8 , Enfermedades del Colon/diagnóstico , Colonoscopía , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Enfermedades del Íleon/genética , Obstrucción Intestinal/genética , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Úlcera/diagnóstico

RESUMEN

This project was focused on the study of the effect of the different acupoints on visceral hypersensitivity and the correlation with the brain-gut axis. By using a mouse model of zymosan-induced colorectal hypersensitivity, and observing the response of hypersensitivity model to colorectal distension stimulation in acupuncture at different acupoints, we selected the specific acupoints. With immunohistochemical staining method, we observed c-fos expression, distribution and changes after acupuncture on sensory pathway, including colorectum, spinal dorsal horn and different regions of brain center in the model with colorectal distension stimulation, and evaluated the acupuncture effect on brain-gut axis. The results revealed that the effectiveness of acupuncture for alleviating visceral hypersensitivity was different at individual acupoint, meaning Tianshu (ST25), Zusanli (ST36) and Shangjuxu (ST37) > Quchi (LI11) and Dachangshu (BL25) > Ciliao (BL32). C-fos expression was concentrated in anterior cingulate cortex, hypothalamus, spinal dorsal horn and colorectum in model of zymosan-induced colorectal hypersensitivity and it was down-regulated after acupuncture. The results demonstrates that the acupoint specificity presents in acupuncture for relieving visceral hypersensitivity and the effects are more predominated at the acupoints on stomach meridian innervated by the same or adjacent spinal ganglion segments. The model of zymosan-induced colorectal hypersensitivity can be the animal model simulating brain-gut interaction.

Asunto(s)

Puntos de Acupuntura , Terapia por Acupuntura/métodos , Encéfalo/fisiopatología , Enfermedades del Colon/terapia , Enfermedades Gastrointestinales/fisiopatología , Hiperalgesia/terapia , Enfermedades del Recto/terapia , Animales , Enfermedades del Colon/inducido químicamente , Enfermedades del Colon/genética , Electromiografía , Expresión Génica , Genes fos , Hiperalgesia/inducido químicamente , Hiperalgesia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Estimulación Física , Enfermedades del Recto/inducido químicamente , Enfermedades del Recto/genética , Zimosan

RESUMEN

OBJECTIVE: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. BACKGROUND: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. METHODS: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. RESULTS: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. CONCLUSIONS: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.

Asunto(s)

Colectomía/métodos , Enfermedades del Colon/genética , ADN/genética , Diverticulitis/genética , Polimorfismo de Nucleótido Simple , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Adulto , Anciano , Alelos , Enfermedades del Colon/cirugía , Diverticulitis/cirugía , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Estudios Retrospectivos

RESUMEN

BACKGROUND: Intestinal tuberculosis (TB) and Crohn's disease closely resemble each other clinically and morphologically. Little is known of cytokine regulation in intestinal TB. OBJECTIVE: To compare cytokine gene expression in colonic mucosa and peripheral blood mononuclear cells (PBMC) in TB with that in Crohn's disease. METHODS: Biopsies were obtained from normal and ulcerated colonic mucosa of 12 intestinal TB and 11 Crohn's disease patients, and PBMC from 15 intestinal TB and 12 Crohn's disease patients and 11 healthy volunteers. RNA was extracted, and the expression of selected cytokines, chemokines and pattern recognition receptors quantified by reverse transcriptase real-time polymerase chain reaction using SYBR green. RESULTS: The mRNA expression of interleukin-8 (IL-8), induced protein-10, tumour necrosis factor-alpha, IL-23 p19 and IL-12 p40, and Toll-like receptors (TLR) 1 and 2 in the ulcerated mucosa was increased in both intestinal TB and Crohn's disease. Expression of growth-related oncogene-alpha was increased in intestinal TB, while expression of interferon-gamma (IFN-) and TLR 4, 5 and 9 was increased in Crohn's disease. Expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) was decreased in Crohn's disease. Secretion of IFN- or IL-10 from PBMC was not significantly altered in either disease. PBMC mRNA expression of IL-1, IL-6 and IL-8 mRNA was upregulated in Crohn's disease, while that of IL-17 was upregulated in intestinal TB. CONCLUSIONS: Cytokine gene expression patterns in intestinal mucosa and PBMC of intestinal TB were remarkably similar to Crohn's disease, and demonstrated innate immune activation and T-helper 1 polarisation.

Asunto(s)

Colon/inmunología , Enfermedades del Colon/inmunología , Enfermedad de Crohn/inmunología , Citocinas/genética , Mucosa Intestinal/inmunología , Leucocitos Mononucleares/inmunología , Tuberculosis Gastrointestinal/inmunología , Adulto , Anciano , Biopsia , Estudios de Casos y Controles , Colon/microbiología , Enfermedades del Colon/genética , Enfermedades del Colon/microbiología , Colonoscopía , Enfermedad de Crohn/genética , Citocinas/sangre , Femenino , Regulación de la Expresión Génica , Humanos , Inmunidad Innata/genética , Mucosa Intestinal/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , ARN Mensajero/análisis , ARN Mensajero/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/inmunología , Tuberculosis Gastrointestinal/genética , Tuberculosis Gastrointestinal/microbiología , Adulto Joven