RESUMO
BACKGROUND AND AIMS: Individuals with familial adenomatous polyposis (FAP) may undergo a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) to surgically treat their disease. Inflammation of the ileal pouch, termed pouchitis, is uncommon in FAP patients but prevalent in patients who received IPAA for ulcerative colitis, a type of inflammatory bowel disease (IBD). METHODS AND RESULTS: We report on two FAP siblings, living in the same household, who underwent IPAA surgery within one week of each other. Their mother also had an IPAA for FAP. One sibling developed pouchitis while his brother and mother have remained pouchitis-free. We investigated the genetic and microbial factors that might explain the development of pouchitis in the one sibling. We surveyed DNA isolated from the two brothers and their parents for NOD2 IBD risk variants by Sanger sequencing. The composition of mucosa-associated bacteria was analyzed by 16S rRNA gene sequencing on terminal ileum and rectal tissue collected at the time of surgical resection from the two brothers. The sibling with pouchitis inherited the IBD-associated risk alleles for NOD2 (rs17221417 and rs2076756) from his healthy father. Both the mother and unaffected brother lacked these variants. Microbiome sequencing of the terminal ileum and rectum found reduced levels of potentially 'beneficial' bacteria (Faecalibacterium prausnitzii, Bacteroides, and Ruminococcaceae) in the sibling with pouchitis relative to his brother. CONCLUSION: These findings suggest that the NOD2 signaling pathway may contribute to intrinsic bacterial dysbiosis which is pre-existing and which may then predispose individuals to pouchitis after IPAA surgery.
Assuntos
Polipose Adenomatosa do Colo/genética , Microbioma Gastrointestinal , Predisposição Genética para Doença/genética , Proteína Adaptadora de Sinalização NOD2/genética , Pouchite/genética , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Disbiose/genética , Disbiose/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proctocolectomia Restauradora/efeitos adversos , Proctocolectomia Restauradora/métodos , IrmãosRESUMO
BACKGROUND: Septic perianal Crohn's disease (SPCD) is a treatment challenge in spite of tumor necrosis factor antagonists (anti-TNF). Our aim was to define the success of SPCD management with a combined medical and surgical approach and to identify clinical and genetic factors predictive of healing. STUDY DESIGN: A retrospective chart review of patients with SPCD treated at the Penn State Milton S Hershey Medical Center was done. Primary end point was complete healing (ie normal clinical exam and no pain for at least 6 months). Genetic analysis of 185 single nucleotide polymorphisms associated with Crohn's disease was performed in 78 patients. RESULTS: One hundred and thirty-five episodes of SPCD were identified in 114 patients with a mean follow-up of 77 ± 7.4 months. Overall, 80 of 135 episodes healed (59.3%) and did not differ between those receiving anti-TNF and not (60.4% vs 56.8%). There appeared to be a consistent improved heal rate in each subcategory of surgically managed patients that received anti-TNF. Female sex was significantly predictive of healing in only those receiving anti-TNF agents (63.6% vs 25.0%; p = 0.0005). Twenty-two (19.3%) patients ultimately received a permanent diversion with either a total proctocolectomy or completion proctectomy. Multivariate analysis suggested several single nucleotide polymorphisms in Crohn's disease-associated genes to be possibly associated with healing, but lost significance after Bonferroni correction. CONCLUSIONS: Overall, there is an approximate 60% rate of healing SPCD using a combined medical and surgical approach. About 20% of SPCD patients will require a permanent stoma. There were no clear genetic predictors of healing SPCD.
Assuntos
Doenças do Ânus/terapia , Doença de Crohn/terapia , Sepse/terapia , Adulto , Doenças do Ânus/etiologia , Doenças do Ânus/patologia , Terapia Combinada , Doença de Crohn/etiologia , Doença de Crohn/patologia , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Sepse/etiologia , Sepse/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , CicatrizaçãoRESUMO
BACKGROUND: Proton pump inhibitors seem to promote Clostridium difficile infection (CDI). Although the current literature suggests that this association is mediated through gastric acid suppression, there has been little investigation into whether a direct effect on expression of colonocyte genes may also have a role. The aim of this study was to investigate the effect of omeprazole on genome-wide gene expression in a human colonic cell line. METHODS: T84 cell monolayers were treated with acid-activated omeprazole at 0, 1, 10, or 100 µmol/L for 48 hours. Cells were lysed and total RNA samples were reverse transcribed and used to generate biotinylated cRNA. Whole-genome transcript expression levels were then quantified using an Illumina HT-12 BeadChip microarray targeting 25,440 genes. Transcripts with a stringent minimum absolute fold change of 1.5 and an adjusted nominal P value <.05 (false discovery) were identified as being differentially expressed. RESULTS: Significant changes in expression were observed for 322 colonocyte transcripts, including genes with potential implications for susceptibility to CDI. These genes include roles in cell junctions, toxin susceptibility, and bile acid metabolism and transport. CONCLUSION: Omeprazole treatment decreases the expression of genes that have important functions in colonocyte integrity. Such impairment in colonocyte function may promote CDI.
Assuntos
Clostridioides difficile , Infecções por Clostridium/etiologia , Colo/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Linhagem Celular , Marcadores Genéticos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Neoplasia complicating ulcerative colitis (UC-neoplasia) is a problem that is poorly addressed by present surveillance techniques. The association of greater than 300 single nucleotide polymorphisms (SNPs) with inflammatory bowel disease (IBD) suggests the possibility that certain genetic polymorphisms might identify patients with UC destined for malignant degeneration. This present study tested the hypothesis that presently known IBD-associated SNPs may correlate with UC-neoplasia. MATERIALS AND METHODS: A total of 41 patients with UC-neoplasia (mean age 56 ± 2.1 years) were identified from our divisional IBD Biobank (low-grade dysplasia n = 13, high-grade dysplasia n = 8, colorectal cancer [CRC] n = 20). These patients were individually age, sex, and disease duration matched with UC patients without neoplasia. Primary sclerosing cholangitis and family history of CRC were recorded. Patients were genotyped for 314 of the most commonly IBD-associated SNPs by a custom SNP microarray. Logistic regression and Fischer exact test were used for statistical analysis. RESULTS: After Bonferroni correction, none of the 314 IBD-associated SNPs correlated with UC-neoplasia when compared with matched UC controls. The incidence of primary sclerosing cholangitis was greater in the UC-neoplasia group (10/41, 24% vs 3/41, 7%; P = .03) compared with UC controls. The severity of neoplasia (low grade dysplasia versus high grade dysplasia versus CRC) correlated with disease duration (7.9 vs 13.4 vs 20.7 years, respectively). CONCLUSION: The lack of correlation between well-known IBD-associated SNPs and UC-neoplasia demonstrated in this study suggests that the development of neoplasia in patients with UC is associated with genetic determinants other than those that predispose to inflammation or results from posttranslational modifications or epigenetic factors rather than germline polymorphisms.