Antibiotics in the pathogenesis of diabetes and inflammatory diseases of the gastrointestinal tract.

Antibiotic use is increasing worldwide. However, the use of antibiotics is clearly associated with changes in gut microbiome composition and function, and perturbations have been identified as potential environmental risk factors for chronic inflammatory disorders of the gastrointestinal tract. In this Review, we examine the association between the use of antibiotics and the onset and development of both type 1 and type 2 diabetes, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, as well as coeliac disease and eosinophilic oesophagitis. We discuss the key findings of epidemiological studies, provide mechanistic insights into the pathways by which the gut microbiota might contribute to these diseases, and assess clinical trials investigating the effects of antibiotics. Such studies indicate that antibiotic exposures, varying in type, timing and dosage, could explain differences in disease risk. There seems to be a critical window in early life in which perturbation of the microbiome has a substantial effect on disease development. Identifying the antibiotic-perturbed gut microbiota as a factor that contributes to the pathophysiology of these inflammatory disorders might stimulate new approaches to prevention, diagnosis and treatment.

Integrated Analysis of Biopsies from Inflammatory Bowel Disease Patients Identifies SAA1 as a Link Between Mucosal Microbes with TH17 and TH22 Cells.

BACKGROUND: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. METHODS: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort. RESULTS: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4 T cells. These SAA1-linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort. CONCLUSIONS: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types.

Perceptions of fecal microbiota transplantation for Clostridium difficile infection: factors that predict acceptance.

BACKGROUND: Despite the effectiveness of fecal microbiota transplantation (FMT) for treating recurrent Clostridium difficile (C. difficile) infection, some patients are reluctant to accept this therapy. Our study examined attitudes towards FMT and factors that contribute to patients' acceptance of this treatment. METHODS: We distributed patient surveys at a Veterans Affairs hospital, a public hospital, and an academic faculty practice. Multivariable logistic regression was performed, adjusting for factors associated with FMT acceptance on univariate analysis and prior experience with C. difficile infection. RESULTS: Of 267 patients, only 12% knew of FMT prior to the survey, but 77% would undergo the procedure if medically indicated. On multivariable analysis, those with children and with college degrees or higher were more likely to agree to FMT (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.02-4.35; OR 2.27, 95% CI 1.11-4.60 respectively). Sixty-five respondents (71%) chose colonoscopy as the preferred vehicle for FMT, while nasogastric tube was least preferred. Disease transmission was the most common concern (30%, n=242), and FMT success rate was the least selected concern (9.1%). CONCLUSIONS: Most patients in a diverse sample of gastroenterology clinics had no prior knowledge of FMT, but were receptive to the procedure. Having children and higher education levels were predictors for FMT acceptance. Our findings suggest that barriers to FMT utilization may be overcome with counseling about safety concerns. More data on the risk of transmitting diseases or clinical characteristics, such as obesity, through FMT are needed and will be important for the acceptance of this procedure.

Isolation and cytokine analysis of lamina propria lymphocytes from mucosal biopsies of the human colon.

Much of our understanding of gut-microbial interactions has come from mouse models. Intestinal immunity is complex and a combination of host genetics and environmental factors play a significant role in regulating intestinal immunity. Due to this complexity, no mouse model to date gives a complete and accurate representation of human intestinal diseases, such as inflammatory bowel diseases. However, intestinal tissue from patients undergoing bowel resection reflects a condition of severe disease that has failed treatment; hence a more dynamic perspective of varying inflammatory states in IBD could be obtained through the analyses of pinch biopsy material. Here we describe our protocol for analyzing mucosal pinch biopsies collected predominantly during colonoscopies. We have optimized flow cytometry panels to analyze up to 8 cytokines produced by CD4+ and CD8+ cells, as well as for characterizing nuclear proteins and transcription factors such as Ki67 and Foxp3. Furthermore, we have optimized approaches to analyze the production of cytokines, including TGF-beta from direct ex vivo cultures of pinch biopsies and LPMCs isolated from biopsies. These approaches are part of our workflow to try and understand the role of the gut microbiota in complex and dynamic human intestinal diseases.

Urticaria due to polyethylene glycol-3350 and electrolytes for oral solution in a patient with jejunal nodular lymphoid hyperplasia.

Both jejunal nodular lymphoid hyperplasia (NLH) and polyethylene glycol (PEG)-3350 hypersensitivity are extremely rare. We describe a 30-year-old female who had previously taken a PEG-3350 bowel preparation without adverse effects, and presented for evaluation of chronic diarrhea. An upper and lower gastrointestinal endoscopy, and small bowel series were scheduled. PEG-3350 and electrolytes for oral solution was prescribed for bowel cleansing. During consumption of the bowel preparation she developed urticarial hypersensitivity. An alternative bowel preparation was used. Colonoscopy and upper endoscopy were normal, but small bowel series revealed innumerable sand-like lucencies in the jejunum. NLH was confirmed on biopsy from antegrade enteroscopy. This is the first case report on the pathological jejunal NLH in association with the PEG-3350 urticarial hypersensitivity. The potential pathophysiological etiology of this association is discussed.

A program to enhance completion of screening colonoscopy among urban minorities.

BACKGROUND & AIMS: Although colonoscopy is becoming the preferred screening test for colorectal cancer, screening rates, particularly among minorities, are low. Little is known about the uptake of screening colonoscopy or the factors that predict colonoscopy completion among minorities. This study investigated the use of patient navigation within an open-access referral system and its effects on colonoscopy completion rates among urban minorities. METHODS: This was a cohort study that took place at a teaching hospital in New York. Participants were mostly African Americans and Hispanics directly referred for screening colonoscopy by primary care clinics from November 2003 to May 2006. Once referred, a bilingual Hispanic female patient navigator facilitated the colonoscopy completion. Completion rates, demographic factors associated with completing colonoscopy, endoscopic findings, and patient satisfaction were analyzed. RESULTS: Of 1169 referrals, 688 patients qualified for and 532 underwent navigation. Two thirds (66%) of navigated patients completed screening colonoscopies, 16% had adenomas, and only 5% had inadequate bowel preps. Women were 1.31 times more likely to complete the colonoscopy than men (P = .014). Hispanics were 1.67 times more likely to complete the colonoscopy than African Americans (P = .013). Hispanic women were 1.50 times more likely to complete the colonoscopy than Hispanic men (P = .009). Patient satisfaction was 98% overall, with 66% reporting that they definitely or probably would not have completed their colonoscopy without navigation. CONCLUSIONS: By using a patient navigator, the majority of urban minorities successfully completed their colonoscopies, clinically significant pathology was detected, and patient satisfaction was enhanced. This approach may help increase adherence with screening colonoscopy efforts in other clinical settings.