Systems biology in inflammatory bowel diseases

Purpose of review: Ulcerative colitis (UC) and Crohn’s Disease (CD) are the two predominant types of inflammatory bowel disease (IBD), affecting over 1.4 million individuals in the US. IBD results from complex interactions between pathogenic components, including genetic and epigenetic factors, the immune response and the microbiome through an unknown sequence of events. The purpose of this review is to describe a system biology approach to IBD as a novel and exciting methodology aiming at developing novel IBD therapeutics based on the integration of molecular and cellular "omics" data. Recent Findings: Recent evidence suggested the presence of genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations in IBD patients. Furthermore, several studies have shown that different cell types, including fibroblasts, epithelial, immune and endothelial cells together with the intestinal microbiota are involved in IBD pathogenesis. Novel computational methodologies have been developed aiming to integrate high - throughput molecular data. Summary: A systems biology approach could potentially identify the central regulators (hubs) in the IBD interactome and improve our understanding of the molecular mechanisms involved in IBD pathogenesis. The future IBD therapeutics should be developed on the basis of targeting the central hubs in the IBD network

Media consumption and creation in attitudes toward and knowledge of inflammatory bowel disease: web-based survey

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition affecting over 5 million people globally and 1.6 million in the United States but currently lacks a precisely determined cause or cure. The range of symptoms IBD patients experience are often debilitating, and the societal stigmas associated with some such symptoms can further degrade their quality of life. Better understanding the nature of this public reproach then is a critical component for improving awareness campaigns and, ultimately, the experiences of IBD patients. OBJECTIVE: The objective of this study was to explore and assess the public's awareness and knowledge of IBD, as well as what relationship, if any, exists between the social stigma surrounding IBD, knowledge of the disease, and various media usage, including social media. METHODS: Utilizing a Web-based opt-in platform, we surveyed a nationally representative sample (n=1200) with demographics mirroring those of the US Census figures across baseline parameters. Using constructed indices based on factor analysis, we were able to build reliable measures of personal characteristics, media behaviors, and perceptions and knowledge of IBD. RESULTS: Among the American public, IBD is the most stigmatized of seven diseases, including genital herpes and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Additionally, IBD knowledge is generally low with 11.08% (133/1200) of the sample indicating no familiarity with the disease and 85.50% (1026/1200) of participants inaccurately answering two-thirds of the IBD index questions with which their knowledge was assessed. Increased knowledge of IBD is associated with lower levels of stigma. However, social media use is currently related to lower levels of IBD knowledge (P<.05). Furthermore, findings indicate that participants who most frequently engaged in producing social media content are less knowledgeable about IBD (P<.10), highlighting the potential for a dangerous cycle should they be contributing to a Web-based IBD dialogue. CONCLUSIONS: Greater efforts must be taken to stymie IBD misinformation across all media, but especially in social media channels, to increase IBD knowledge and reduce stigma surrounding IBD. These findings pave the way for further research qualitatively examining the pervasiveness of specific IBD messages found in today's social media landscape and their impact on enacted stigmas so as to better equip providers and patient advocacy organizations with impactful communication solutions

Conflation of short identity-by-descent segments bias their inferred length distribution

Identity-by-descent (IBD) is a fundamental concept in genetics with many applications. In a common definition, two haplotypes are said to contain an IBD segment if they share a segment that is inherited from a recent shared common ancestor without intervening recombination. Long IBD segments (> 1cM) can be efficiently detected by a number of algorithms using high-density SNP array data from a population sample. However, these approaches detect IBD based on contiguous segments of identity-by-state, and such segments may exist due to the conflation of smaller, nearby IBD segments. We quantified this effect using coalescent simulations, finding that nearly 40% of inferred segments 1-2cM long are results of conflations of two or more shorter segments, under demographic scenarios typical for modern humans. This biases the inferred IBD segment length distribution, and so can affect downstream inferences. We observed this conflation effect universally across different IBD detection programs and human demographic histories, and found inference of segments longer than 2cM to be much more reliable (less than 5% conflation rate). As an example of how this can negatively affect downstream analyses, we present and analyze a novel estimator of the de novo mutation rate using IBD segments, and demonstrate that the biased length distribution of the IBD segments due to conflation can lead to inflated estimates if the conflation is not modeled. Understanding the conflation effect in detail will make its correction in future methods more tractable

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

Background: Inflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host metabolic changes in IBD dogs. Twenty-three dogs diagnosed with IBD and ten healthy control dogs were included. Dogs with IBD were given a clinical score using the canine chronic enteropathy clinical activity index (CCECAI). Faecal short-chain fatty acids (SCFA) and ammonia concentrations were measured and quantitative PCR was performed. The concentration of plasma amino acids, acylcarnitines, serum folate, cobalamin, and indoxyl sulfate was determined. Results: No significant differences in the abundance of a selection of bacterial groups and fermentation metabolites were observed between the IBD and control groups. However, significant negative correlations were found between CCECAI and the faecal proportion of Lactobacillus as well as between CCECAI and total SCFA concentration. Serum folate and plasma citrulline were decreased and plasma valine was increased in IBD compared to control dogs. Increased plasma free carnitine and total acylcarnitines were observed in IBD compared with control dogs, whereas short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and, methylmalonylcarnitine) to free carnitine ratios decreased. Dogs with IBD had a higher 3-hydroxyisovalerylcarnitine + isovalerylcarnitine to leucine ratio compared to control dogs. Conclusions: Canine IBD induced a wide range of changes in metabolic profile, especially for the plasma concentrations of short-chain acylcarnitines and amino acids, which could have evolved from tissue damage and alteration in host metabolism. In addition, dogs with more severe IBD were characterised by a decrease in faecal proportion of Lactobacillus

The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease.

BACKGROUND: Patients with primary sclerosing cholangitis associated with inflammatory bowel disease (PSC-IBD) have a very high risk of developing colorectal neoplasia. Alterations in the gut microbiota and/or gut bile acids could account for the increase in this risk. However, no studies have yet investigated the net result of cholestasis and a potentially altered bile acid pool interacting with a dysbiotic gut flora in the inflamed colon of PSC-IBD. AIM: The aim of this study was to compare the gut microbiota and stool bile acid profiles, as well as and their correlation in patients with PSC-IBD and inflammatory bowel disease alone. METHODS: Thirty patients with extensive colitis (15 with concomitant primary sclerosing cholangitis) were prospectively recruited and fresh stool samples were collected. The microbiota composition in stool was profiled using bacterial 16S rRNA sequencing. Stool bile acids were assessed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: The total stool bile acid pool was significantly reduced in PSC-IBD. Although no major differences were observed in the individual bile acid species in stool, their overall combination allowed a good separation between PSC-IBD and inflammatory bowel disease. Compared with inflammatory bowel disease alone, PSC-IBD patients demonstrated a different gut microbiota composition with enrichment in Ruminococcus and Fusobacterium genus compared with inflammatory bowel disease. At the operational taxonomic unit level major shifts were observed within the Firmicutes (73%) and Bacteroidetes phyla (17%). Specific microbiota-bile acid correlations were observed in PSC-IBD, where 12% of the operational taxonomic units strongly correlated with stool bile acids, compared with only 0.4% in non-PSC-IBD. CONCLUSIONS: Patients with PSC-IBD had distinct microbiota and microbiota-stool bile acid correlations as compared with inflammatory bowel disease. Whether these changes are associated with, or may predispose to, an increased risk of colorectal neoplasia needs to be further clarified.info:eu-repo/semantics/publishedVersio

Genome-wide association studies of inflammatory bowel disease in German shepherd dogs

Canine Inflammatory Bowel Disease (IBD) is considered a multifactorial disease caused by complex interactions between the intestinal immune system, intestinal microbiota and environmental factors in genetically susceptible individuals. Although IBD can affect any breed, German shepherd dogs (GSD) in the UK are at increased risk of developing the disease. Based on previous evidence, the aim of the present study was to identify single nucleotide polymorphisms (SNPs), which may confer genetic susceptibility or resistance to IBD using a genome-wide association study (GWAS). Genomic DNA was extracted from EDTA blood or saliva samples of 96 cases and 98 controls. Genotyping of cases and controls was performed on the Canine Illumina HD SNP array and data generated was analyzed using PLINK. Several SNPs and regions on chromosomes 7,9,11 and 13 were detected to be associated with IBD using different SNP-by-SNP association methods and FST windows approach. Searching one Mb up-and down-stream of the most significant SNPs, as identified by single SNP analysis as well as 200Kb before and after the start and the end position of the associated regions identified by FST windows approach, we identified 63 genes. Using a combination of pathways analysis and a list of genes that have been reported to be involved in human IBD, we identified 16 candidate genes potentially associated with IBD in GSD

The variance of identity-by-descent sharing in the Wright-Fisher model

Widespread sharing of long, identical-by-descent (IBD) genetic segments is a hallmark of populations that have experienced recent genetic drift. Detection of these IBD segments has recently become feasible, enabling a wide range of applications from phasing and imputation to demographic inference. Here, we study the distribution of IBD sharing in the Wright-Fisher model. Specifically, using coalescent theory, we calculate the variance of the total sharing between random pairs of individuals. We then investigate the cohort-averaged sharing: the average total sharing between one individual and the rest of the cohort. We find that for large cohorts, the cohort-averaged sharing is distributed approximately normally. Surprisingly, the variance of this distribution does not vanish even for large cohorts, implying the existence of "hyper-sharing" individuals. The presence of such individuals has consequences for the design of sequencing studies, since, if they are selected for whole-genome sequencing, a larger fraction of the cohort can be subsequently imputed. We calculate the expected gain in power of imputation by IBD, and subsequently, in power to detect an association, when individuals are either randomly selected or specifically chosen to be the hyper-sharing individuals. Using our framework, we also compute the variance of an estimator of the population size that is based on the mean IBD sharing and the variance in the sharing between inbred siblings. Finally, we study IBD sharing in an admixture pulse model, and show that in the Ashkenazi Jewish population the admixture fraction is correlated with the cohort-averaged sharing.Comment: Includes Supplementary Materia