Bennett E. Roth

A Modular Organization of the Human Intestinal Mucosal Microbiota and Its Association with Inflammatory Bowel Disease

Abnormalities of the intestinal microbiota are implicated in the pathogenesis of Crohns disease (CD) and ulcerative colitis (UC), two spectra of inflammatory bowel disease (IBD). However, the high complexity and low inter-individual overlap of intestinal microbial composition are formidable barriers to identifying microbial taxa representing this dysbiosis. These difficulties might be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We sequenced 16S ribosomal RNA genes from 179 endoscopic lavage samples from different intestinal regions in 64 subjects (32 controls, 16 CD and 16 UC patients in clinical remission). CD and UC patients showed a reduction in phylogenetic diversity and shifts in microbial composition, comparable to previous studies using conventional mucosal biopsies. Analysis of weighted co-occurrence network revealed 5 microbial modules. These modules were unprecedented, as they were detectable in all individuals, and their composition and abundance was recapitulated in an independent, biopsy-based mucosal dataset 2 modules were associated with healthy, CD, or UC disease states. Imputed metagenome analysis indicated that these modules displayed distinct metabolic functionality, specifically the enrichment of oxidative response and glycan metabolism pathways relevant to host-pathogen interaction in the disease-associated modules. The highly preserved microbial modules accurately classified IBD status of individual patients during disease quiescence, suggesting that microbial dysbiosis in IBD may be an underlying disorder independent of disease activity. Microbial modules thus provide an integrative view of microbial ecology relevant to IBD.

Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis: A decision analytic model

OBJECTIVE:Current guidelines recommend upper endoscopic screening for patients with hepatic cirrhosis and primary prophylaxis with a nonselective β-blocker for those with large varices. However, only 25% of cirrhotics develop large varices. Thus, the aim of this study is to evaluate the most cost-effective approach for primary prophylaxis of variceal hemorrhage.METHODS:Using a Markov model, we compared the costs and clinical outcomes of three strategies for primary prophylaxis of variceal bleeding. In the first strategy, patients were given a β-blocker without undergoing upper endoscopy. In the second strategy, patients underwent upper endoscopic screening; those found to have large varices were treated with a β-blocker. In the third strategy, no prophylaxis was used. Selected sensitivity analyses were performed to validate outcomes.RESULTS:Our results show screening prophylaxis was associated with a cost of

A Metaproteomic Approach to Study Human-Microbial Ecosystems at the Mucosal Luminal Interface

37,300 and 5.72 quality-adjusted life yr (QALYs). Universal prophylaxis was associated with a cost of

Host–microbe relationships in inflammatory bowel disease detected by bacterial and metaproteomic analysis of the mucosal–luminal interface

34,100 and 6.65 QALYs. The no prophylaxis strategy was associated with a cost of

A nationwide 2010-2012 analysis of U.S. health care utilization in inflammatory bowel diseases.

36,600 and 4.84 QALYs. The incremental cost-effectiveness ratio was

Association of Systemic Sclerosis With a Unique Colonic Microbial Consortium.

800/QALY for the endoscopic strategy relative to the no prophylaxis strategy. Screening endoscopy was cost saving when the compliance, bleed risk without β-blocker, and variceal bleed costs were increased, and when the discount rate, bleed risk on β-blockers, and cost of upper endoscopy were decreased. In contrast, the universal prophylaxis strategy was persistently cost saving relative to the no prophylaxis strategy. In comparing the strategies, sensitivity analysis on the death rates from variceal hemorrhage did not alter outcomes.CONCLUSIONS:Our results provide economic and clinical support for primary prophylaxis of esophageal variceal bleeding in patients with hepatic cirrhosis. Universal prophylaxis with β-blocker is preferred because it is consistently associated with the lowest costs and highest QALYs.

Systemic sclerosis is associated with a unique colonic microbial consortium

Aberrant interactions between the host and the intestinal bacteria are thought to contribute to the pathogenesis of many digestive diseases. However, studying the complex ecosystem at the human mucosal-luminal interface (MLI) is challenging and requires an integrative systems biology approach. Therefore, we developed a novel method integrating lavage sampling of the human mucosal surface, high-throughput proteomics, and a unique suite of bioinformatic and statistical analyses. Shotgun proteomic analysis of secreted proteins recovered from the MLI confirmed the presence of both human and bacterial components. To profile the MLI metaproteome, we collected 205 mucosal lavage samples from 38 healthy subjects, and subjected them to high-throughput proteomics. The spectral data were subjected to a rigorous data processing pipeline to optimize suitability for quantitation and analysis, and then were evaluated using a set of biostatistical tools. Compared to the mucosal transcriptome, the MLI metaproteome was enriched for extracellular proteins involved in response to stimulus and immune system processes. Analysis of the metaproteome revealed significant individual-related as well as anatomic region-related (biogeographic) features. Quantitative shotgun proteomics established the identity and confirmed the biogeographic association of 49 proteins (including 3 functional protein networks) demarcating the proximal and distal colon. This robust and integrated proteomic approach is thus effective for identifying functional features of the human mucosal ecosystem, and a fresh understanding of the basic biology and disease processes at the MLI.

Local thrombolysis: A newer approach to treating inflammatory bowel disease-related thromboembolism

Background: Host–microbe interactions at the intestinal mucosal–luminal interface (MLI) are critical factors in the biology of inflammatory bowel disease (IBD). Methods: To address this issue, we performed a series of investigations integrating analysis of the bacteria and metaproteome at the MLI of Crohns disease, ulcerative colitis, and healthy human subjects. After quantifying these variables in mucosal specimens from a first sample set, we searched for bacteria exhibiting strong correlations with host proteins. This assessment identified a small subset of bacterial phylotypes possessing this host interaction property. Using a second and independent sample set, we tested the association of disease state with levels of these 14 “host interaction” bacterial phylotypes. Results: A high frequency of these bacteria (35%) significantly differentiated human subjects by disease type. Analysis of the MLI metaproteomes also yielded disease classification with exceptional confidence levels. Examination of the relationships between the bacteria and proteins, using regularized canonical correlation analysis (RCCA), sorted most subjects by disease type, supporting the concept that host–microbe interactions are involved in the biology underlying IBD. Moreover, this correlation analysis identified bacteria and proteins that were undetected by standard means‐based methods such as analysis of variance, and identified associations of specific bacterial phylotypes with particular protein features of the innate immune response, some of which have been documented in model systems. Conclusions: These findings suggest that computational mining of mucosa‐associated bacteria for host interaction provides an unsupervised strategy to uncover networks of bacterial taxa and host processes relevant to normal and disease states. (Inflamm Bowel Dis 2012;)

Portal hypertensive enteropathy in a patient with polycystic liver disease: A unique endoscopic finding

Background:Implementation of the 2010 Affordable Care Act (ACA) calls for a collaborative effort to transform the U.S. health care system toward patient-centered and value-based care. To identify how specialty care can be improved, we mapped current U.S. health care utilization in patients with inflammatory bowel diseases (IBD) using a national insurance claims database. Methods:We performed a cross-sectional study analyzing U.S. health care utilization in 964,633 patients with IBD between 2010 and 2012 using insurance claims data, including pharmacy and medical claims. Frequency of IBD-related care utilization (medication, tests, and treatments) and their charges were evaluated. Subsequently, outcomes were put into the framework of current U.S. guidelines to identify areas of improvement. Results:A disproportionate usage of aminosalicylates in Crohns disease (42%), frequent corticosteroid use (46%, with 9% long-term users), and low rates of corticosteroid-sparing drugs (thiopurines 15%; methotrexate 2.7%) were observed. Markers for inflammatory activity, such as C-reactive protein or fecal calprotectin were not commonly used (8.8% and 0.13%, respectively). Although infrequently used (11%), anti-TNF antibody therapy represents a major part of observed IBD charges. Conclusions:This analysis shows 2010–2012 utilization and medication patterns of IBD health care in the United States and suggests that improvement can be obtained through enhanced guidelines adherence.

The current health care environment and stages of market development.

To compare colonic microbial composition in systemic sclerosis (SSc) patients and healthy controls and to determine whether certain microbial genera are associated with gastrointestinal (GI) tract symptoms in patients with SSc.