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BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) develops from a combination of genetic and environmental factors. The aim of this study was to determine the contribution of established environmental risk factors and genetic risk on age of IBD diagnosis in a diverse cohort. METHODS: IBD patients in clinic completed detailed questionnaires. Blood was drawn for genetic analysis. Environmental risk factors and age of diagnosis were analyzed by ethnicity (Hispanic/Latinx or non-Hispanic White [NHW] individuals) and IBD subtype (ulcerative colitis or Crohn's disease [CD]). Weighted genetic risk scores and environmental risk scores were developed. We examined the relationship between environmental risk scores, genetic risk scores, and age of diagnosis. RESULTS: A total of 2952 patients were included: 58.9% had CD. A total of 46.83% were of Hispanic background. Early life exposures like cesarean delivery and being born in a developed country were associated with a younger age of IBD diagnosis. Childhood exposures such as frequent plastic water bottle use and having more than 1 bathroom at home were associated with a younger age of IBD. Hispanic and NHW individuals shared similar susceptibilities to environmental exposures. Environmental factors explained 21% of the variance in age of CD diagnosis and 39% in ulcerative colitis. In models incorporating genetic risk score and environmental risk score, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups. CONCLUSIONS: Early life and childhood exposures impact IBD diagnosis and influence Hispanic and NHW individuals similarly. A cumulative environmental risk score contributes more to age of IBD diagnosis than genetic risk.
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Exposición a Riesgos Ambientales , Enfermedades Inflamatorias del Intestino , Humanos , Femenino , Masculino , Adulto , Exposición a Riesgos Ambientales/efectos adversos , Adulto Joven , Persona de Mediana Edad , Enfermedades Inflamatorias del Intestino/genética , Adolescente , Encuestas y Cuestionarios , Factores de Riesgo , Anciano , Estudios de Cohortes , Niño , Predisposición Genética a la Enfermedad , Factores de Edad , PreescolarRESUMEN
BACKGROUND & AIMS: A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC. METHODS: We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet. RESULTS: Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02). CONCLUSIONS: In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.
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Colitis Ulcerosa , Calidad de Vida , Estudios Cruzados , Dieta , Disbiosis , Heces , Femenino , Humanos , Inflamación , MasculinoRESUMEN
BACKGROUND: A significant number of patients receiving therapy with antitumor necrosis factor (TNF) agents for Crohn's disease experience primary or secondary nonresponse. The aim of this study was to assess whether patients with nonresponse to anti-TNF agents have increased expression of alternative cytokine pathways. METHODS: We designed a prospective, cross-sectional study that included patients with Crohn's disease receiving anti-TNF undergoing colonoscopy with adequate serum trough drug levels (≥8 µg/mL) and without anti-drug antibodies. Inflammatory cytokines and cell adhesions markers measured included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, interleukin (IL)-8, IL-1ß, and IL-6. The primary outcome was the presence of active endoscopic inflammation defined as the presence of at least 1 ulceration ≥5 mm. RESULTS: In total, 47 patients were included. Patients with active inflammation had significantly higher levels of ICAM-1 and IL-1ß when compared with those without intestinal inflammation (45.9 vs. 35.8 ng/mL, P<0.0001 and 3.2 vs. 1.5 pg/mL, P=0.002, respectively). There were no significant differences in the other study variables. Using receiving operating curves, ICAM and IL-1ß had a good correlation (receiver operating characteristic ≥0.8) with inflammation in this cohort of patients with "anti-TNF resistance." The results were similar in the group of patients with previous anti-TNF exposure. CONCLUSION: Our study suggests that patients who have active inflammation with seemingly adequate serum anti-TNF levels have increased levels of specific inflammatory pathways that may serve as biomarkers of nonresponse as well as potential targets of therapy in anti-TNF nonresponders.
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Enfermedad de Crohn/tratamiento farmacológico , Citocinas/metabolismo , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Enfermedad de Crohn/fisiopatología , Estudios Transversales , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/farmacocinética , Adulto JovenRESUMEN
INTRODUCTION: Recent studies have identified a critical role of stromal-immune cell interactions in immunity and immune tolerance. Transcriptomic profiling has implicated stromal cells in immune-mediated disorders including the 2 common forms of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). Stromal-immune interactions may edify inflammatory state and the development of IBD-related complications such as fibrosis, yet the lack of protein markers has hampered studying stromal-immune perturbation. METHODS: In this study, we designed a 40-color spectral flow cytometry assay to characterize hematopoietic and nonhematopoietic cells in intestinal biopsies and matched blood samples from patients with CD or UC. RESULTS: We identified circulating stromal-like cells that are significantly more abundant in IBD blood samples than in healthy controls. Those cells expressed podoplanin (PDPN), a commonly used marker for fibroblasts, and they were associated with activated and memory T and B cells and altered natural killer cell, monocyte, and macrophage populations. PDPN + cells in the blood correlated with PDPN + cells in the colon. Principal component analysis distinctly separated healthy blood samples from IBD blood samples, with stromal-like cells and B-cell subtypes dominating the IBD signature; Pearson correlation detected an association between PDPN + stromal-like cells and B-cell populations in IBD blood and gut biopsies. DISCUSSION: These observations suggest that PDPN + cells in the blood may serve as a biomarker of IBD. Understanding the relationship between stromal cells and immune cells in the intestine and the blood may provide a window into disease pathogenesis and insight into therapeutic targets for IBD.
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Background: The impact of social determinants of health in inflammatory bowel disease (IBD) remains understudied. We evaluated the impact of social barriers on IBD outcomes within a diverse cohort of patients. Methods: We performed a cross-sectional study on adult IBD patients and assessed known social determinants of health. We calculated the total prevalence of these barriers in the sample as a whole and within each ethnic group. We summed the number of barriers present for each individual to create a cumulative social barrier score (SBS), and we evaluated the relationship of each barrier and of the cumulative SBS with IBD outcomes, including disease activity and depressive symptoms. Results: A total of 316 patients were included in the study. Disparities in the prevalence of social barriers emerged by ethnicity: non-Hispanic Blacks reported the greatest number of social barriers, followed by Hispanic patients. Prevalent social barriers included financial strains (38.4%), such as food insecurity, medical care delays (~30%), and low educational attainment (26.8%). Social barriers associated with poor IBD outcomes included low educational attainment, poor health literacy, and financial insecurity. High SBS was associated with greater depressive symptoms [odds ratio (OR) 1.94, 95% confidence interval (CI) 1.21-2.9, p = 0.001] and lower reported use of medications. Greater ulcerative colitis (UC) disease activity was observed in patients with greater SBS. No associations were identified between SBS and IBD surgeries, hospitalizations, or disease location. Conclusion: Our study identifies social barriers that may impact IBD care and are disproportionately higher in non-Hispanic Blacks and Hispanics in the United States. Future studies should focus on implementing interventions to reduce these barriers and improve delivery of care.
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BACKGROUND AND AIMS: Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, inflammation state, and medication use in patients with IBD. METHODS: Phagocytic immune cells in the lamina propria, as defined by the marker CD11b, were isolated from 54 unique patients (n = 111 gut mucosal biopsies). We performed flow cytometry for cell phenotyping (n = 30) and RNA sequencing with differential gene expression analysis (n = 58). We further cultured these cells in vitro and exposed them to janus kinase inhibitors to measure cytokine output (n = 27). Finally, we matched patient genomic data to our RNA sequencing data to perform candidate gene expression quantitative trait locus analysis (n = 34). RESULTS: We found distinct differences in gene expression between CD11b+ cells from the colon vs ileum, as well as in different inflammatory states and, to a lesser degree, IBD types (Crohn's disease or ulcerative colitis). These genes mapped to targetable immune pathways and metabolic and cancer pathways. We further explored the janus kinase-signal transducer and activator of transcription pathway, which was upregulated across many comparisons including in biopsies from anti-tumor necrosis factor refractory patients. We found that isolated CD11b+ cells treated with janus kinase inhibitors had decreased secretion of cytokines tumor necrosis factora and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b+ data set. CONCLUSIONS: Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy.
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BACKGROUND: Inflammatory bowel disease (IBD) involves chronic T cell-mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4ß7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn's disease (CD). AIM: We sought to identify immune cell phenotypic and gene expression signatures that related to response to VDZ. METHODS: Peripheral blood (PBMC) and lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry and Cytofkit. Sorted CD4â +â memory (Tmem) or regulatory T (Treg) cells from PBMC and LPMC were analyzed by RNA sequencing (RNA-seq). Clinical response (≥2-point drop in partial Mayo scores [UC] or Harvey-Bradshaw index [CD]) was assessed 14 to 22 weeks after VDZ initiation. Machine-learning models were used to infer combinatorial traits that predicted response to VDZ. RESULTS: Seventy-one patients were enrolled: 37 received VDZ and 21 patients remained on VDZâ >2 years. Fourteen of 37 patients (38%; 8 UC, 6 CD) responded to VDZ. Immune cell phenotypes and CD4â +â Tmem and Treg transcriptional behaviors were most divergent between the ileum and colon, irrespective of IBD subtype or inflammation status. Vedolizumab treatment had the greatest impact on Treg metabolic pathways, and response was associated with increased expression of genes involved in oxidative phosphorylation. The strongest clinical predictor of VDZ efficacy was concurrent use of thiopurines. Mucosal tissues offered the greatest number of response-predictive biomarkers, whereas PBMC Treg-expressed genes were the best predictors in combinatorial models of response. CONCLUSIONS: Mucosal and peripheral blood immune cell phenotypes and transcriptional profiles can inform VDZ efficacy and inform new opportunities for combination therapies.
Vedolizumab (VDZ) is effective in the treatment of IBD. Immunophenotyping and RNAseq of T cells were used to inform its mechanism of action. Changes in T regulatory cells in the periphery and mucosa have the greatest relationship to VDZ response.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Fármacos Gastrointestinales/uso terapéutico , Linfocitos T Reguladores/metabolismo , Leucocitos Mononucleares/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. METHODS: Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. RESULTS: Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. CONCLUSIONS: VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.
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Enfermedad de Crohn , Pentoxifilina , Adulto , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inducido químicamente , Fármacos Gastrointestinales , Pentoxifilina/efectos adversos , Proyectos Piloto , Inducción de Remisión , Proteína C-Reactiva , Resultado del TratamientoRESUMEN
Background: Limited data exist on adherence to fecal calprotectin (FCP) testing in patients with inflammatory bowel disease. Methods: Completion rates for patients who had at least one FCP test ordered (n = 3082) and a subgroup with C-reactive protein, complete blood count, and Clostridium difficile tests also ordered (n = 1563) were analyzed. Results: More patients completed blood than stool tests, with FCP having the poorest adherence of all tests analyzed. Older patients had higher FCP completion rates. No differences were noted in completion rates across age, gender, or ethnicity for blood tests. Conclusions: Further studies are needed to develop strategies that improve the uptake of FCP.
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Background: Interruptions in infliximab therapy are associated with the development of antibodies to infliximab (ATI), infusion reactions (IRs), and loss of response. Despite these challenges, recent observational studies suggest that reinitiating infliximab after a drug holiday can be safe and effective. We assessed the utility of our protocol for restarting infliximab using early serum infliximab and ATI measurements. Methods: A retrospective cohort study of patients restarted on infliximab after at least a 6-month drug holiday. The cohort was divided into 2 groups: a "therapeutic drug monitoring (TDM) group," those who had serum infliximab and ATI measured 1-3 weeks after first reinduction dose, and a "non-TDM group." Outcomes included results of TDM, occurrence of immediate IR (IIR) and delayed hypersensitivity reactions, and medication persistence at 14 weeks and 1 year. Results: About 76 patients were included: 49 in the TDM group and 27 in the non-TDM group. Of 76, 67 (88%) patients tolerated the first reinduction dose without IR. Formation of ATI was seen in 17 of 49 (35%) patients and was associated with longer drug holidays. Most did not experience IR during the entire therapy course-in 26 of 32 (81%) without ATI and 20 of 27 (74%) in the non-TDM group. Infliximab persistence at 14 weeks and 1 year was 76% and 57% for the cohort, respectively. Conclusion: Infliximab can be safely and effectively restarted after a drug holiday. We suggest performing TDM with a drug-tolerant assay 1-3 weeks after the first reinduction infusion as a means to identify patients at risk for severe IIR at the second dose.
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BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.
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Regulación de la Expresión Génica , Inmunosupresores/farmacología , Síndrome del Colon Irritable/fisiopatología , Peptidil-Dipeptidasa A/genética , Serina Endopeptidasas/genética , Adolescente , Adulto , Anciano , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/metabolismo , Biopsia , COVID-19 , Colon/efectos de los fármacos , Colon/metabolismo , Biología Computacional , Infecciones por Coronavirus/fisiopatología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Inmunosupresores/uso terapéutico , Inflamación/fisiopatología , Mucosa Intestinal/metabolismo , Síndrome del Colon Irritable/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Pandemias , Neumonía Viral/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , SARS-CoV-2 , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND & AIMS: The interaction between intestinal microbiota and the immune system plays a vital role in inflammatory bowel disease (IBD). Although numerous deep-sequencing studies have suggested dysbiosis in IBD, identifying specific bacteria from the stool or mucosa that are responsible for disease susceptibility or severity has remained a challenge. Lamina propria phagocytes ideally are localized to interact with bacteria that are in close proximity to, or have invaded, the tissue. Thus, we examined the microbial populations associated with the lamina propria phagocytes in 20 Crohn's disease and 12 ulcerative colitis patients. Specifically, we aimed to address whether the phagocyte-associated microbiota differed from the mucosa-associated microbiota and whether this varied based on IBD type or the state of inflammation. METHODS: 16S ribosomal RNA gene sequencing and innate immune gene expression profiling was done on CD11b+ lamina propria phagocytes isolated from the biopsies obtained from IBD patients. RESULTS: Phagocyte-associated microbiota was enriched in bacterial species belonging to phylum Proteobacteria, whereas species belonging to phylum Bacteroidetes were enriched in the mucosal microbiota of IBD patients. Disease type was the most influential factor in driving differences in the microbiota of both the mucosa and the lamina propria phagocytes, irrespective of inflammation state o`r anatomic location. Crohn's disease and ulcerative colitis specimens showed similar patterns of increased inflammatory gene expression in phagocytes isolated from inflamed areas compared with those isolated from uninflamed regions. CONCLUSIONS: This pilot study shows the feasibility of using lamina propria phagocytes to characterize the microbiota in IBD patients. The approach used in this study can narrow the spectrum of potentially dysbiotic bacterial populations and clinically relevant gene expression signatures in IBD patients.
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Colitis Ulcerosa/microbiología , Enfermedad de Crohn/microbiología , Disbiosis/diagnóstico , Microbioma Gastrointestinal/inmunología , Inmunidad Innata/genética , Fagocitos/microbiología , Biopsia , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , ADN Bacteriano/aislamiento & purificación , Disbiosis/inmunología , Disbiosis/microbiología , Disbiosis/patología , Estudios de Factibilidad , Femenino , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Humanos , Separación Inmunomagnética , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Tipificación Molecular/métodos , Fagocitos/metabolismo , Proyectos Piloto , ARN Ribosómico 16S/genéticaRESUMEN
INTRODUCTION: In this study, we identify the frequency of pseudopolyps (PPs) with normal histology and their association to surrounding tissue. METHODS: Patients were enrolled in a study identifying endoscopic characteristics of PPs (n = 29) or were collected as part of our IBD biobank (n = 16). Statistical analysis included Stata v.15.0. chi-square and Student t-test. RESULTS: A total of 45 patients with 117 PP biopsies were identified. More patients with healed PP were in endoscopic remission compared with those with inflammatory PP (82.6% vs 17.4%, respectively). CONCLUSION: This is the first study to find mucosal healing of PPs and its association with deep remission.
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OBJECTIVES: Hispanics represent an understudied inflammatory bowel disease (IBD) population. Prior studies examining genetic predisposition to IBD in Hispanics are limited. In this study, we examined whether European-derived IBD variants confer risk in Hispanics and their influence on IBD phenotype in Hispanics compared to non-Hispanic whites (NHW). METHODS: Self-identified Hispanics and NHWs with IBD were included. Hispanic controls were included for our genetic analyses. We performed single-variant testing at previously identified Crohn's disease (CD) and ulcerative colitis (UC) IBD variants in Hispanic cases and controls. These risk variants were used to compute individual genetic risk scores. Genetic risk scores and phenotype associations were compared between Hispanic and NHW. RESULTS: A total of 1,115 participants were included: 698 controls and 417 IBD patients (230 Hispanics). We found evidence of association within our Hispanic cohort at 22 IBD risk loci, with ~76% of the risk loci demonstrating over-representation of the European risk allele; these included loci corresponding to IL23R and NOD2 genes. CD genetic risk score for Hispanics (199.67) was similar to the score for NHW (200.33), P=0.51; the same was true in UC. Genetic risk scores did not predict IBD phenotype or complications in Hispanics or NHW except for a younger age of CD onset in Hispanics (P=0.04). CONCLUSIONS: This study highlights the fundamental importance of these loci in IBD pathogenesis including in our diverse Hispanic population. Future studies looking at non-genetic mechanisms of disease are needed to explain differences in age of presentation and phenotype between Hispanics and NHW.
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The intestinal microbiome plays an important role in the pathogenesis of inflammatory bowel disease (IBD). We are able to use the microbiome as a therapeutic target with use of fecal microbiota transplantation (FMT) for cure of recurrent Clostridium difficile infection. Given our ability to target the dysbiotic state with FMT, its use as therapy in IBD has tremendous potential. This overview discusses the practical considerations of FMT therapy with respect to our current understanding of safety and efficacy in IBD, screening for donors and recipients, specimen handling and storage, methods of delivery, and regulatory considerations.
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Disbiosis/cirugía , Endoscopía Gastrointestinal/métodos , Trasplante de Microbiota Fecal/métodos , Enfermedades Inflamatorias del Intestino/cirugía , Disbiosis/complicaciones , Microbioma Gastrointestinal , Humanos , Enfermedades Inflamatorias del Intestino/microbiologíaRESUMEN
Imbalances in the composition and number of bacteria in the gut microbiota have been implicated in inflammatory bowel disease (IBD), and modulation of the gut microbiota by probiotics and antibiotics in IBD has been an active area of research, with mixed results. This narrative review summarizes the findings of relevant publications identified using the PubMed database. Although antibiotics have been associated with an increased risk of IBD development and flares, several meta-analyses demonstrate that antibiotics are efficacious for the induction of remission and treatment of flares in patients with IBD. Data supporting their use include a large number of antibiotic studies in Crohn's disease and evidence suggests antibiotics are efficacious in both Crohn's disease and ulcerative colitis, although there are fewer studies of the latter. For Crohn's disease, antibiotics have been shown to be useful for the induction of remission and in the postoperative management of patients undergoing surgery. Additionally, patients with fistulizing disease, particularly perianal, can benefit from antibiotics administered short term. Both antimicrobials and probiotics have been shown to be useful for the treatment of pouchitis. Additional randomized controlled trials are needed to further elucidate the role of bacteria in IBD and to better inform clinicians about appropriate antibiotic therapies.
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Antibacterianos/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Intestinos/microbiología , Microbiota , Probióticos/uso terapéutico , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/microbiología , Humanos , Fístula Rectal/tratamiento farmacológico , Fístula Rectal/etiología , Inducción de RemisiónRESUMEN
Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients' pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.
Asunto(s)
Monitoreo de Drogas/métodos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Adalimumab , Anticuerpos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Azatioprina/administración & dosificación , Genotipo , Humanos , Factores Inmunológicos , Inflamación , Infliximab , Metiltransferasas/genética , Fenotipo , Purinas/química , Tioguanina/administración & dosificación , Tionucleósidos/química , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: The wide use of abdomino-pelvic computed tomography (APCT) in emergency departments (ED) has raised the concern for radiation exposure, costs and potential reactions to contrast agents. The aim of this study was to determine the yield and predictive factors for clinically actionable findings (CAF) in APCTs performed in patients with inflammatory bowel disease (IBD) who visit the ED. METHODS: We performed a cross-sectional study including patients with IBD who visited the ED. Variables considered were demographics, IBD phenotype, clinical symptoms, IBD medication use prior to ED visit, laboratory values, and imaging results. The primary outcome was a composite of CAF, defined as new, intra-abdominal abscess or tumor, bowel obstruction, fistulae, diverticulitis, choledocholithiasis, or appendicitis. RESULTS: 354 patients were included. One or more CAF were reported in 26.6% of the APCTs (32.1% in CD and 12.8% in UC [p<0.01]). Independent predictive variables of CAF in CD were: CRP level ≥5mg/dl (p=0.04), previous history of IBD surgery (p=0.037), Black race (p<0.01) and low body mass index (p<0.01). None of the study variables predicted CAF in UC. CONCLUSIONS: The yield for CAF with APCT in the ED was high for CD patients but minimal for those with UC and was not improved by the use of contrast. Elevated CRP, low BMI, Black race and previous history of IBD surgery predicted CAF in CD but no variables were predictive of CAF in UC.