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Linking Inflammatory Bowel Disease Symptoms to Changes in the Gut Microbiome Structure and Function.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract that is often characterized by abdominal pain, rectal bleeding, inflammation, and weight loss. Many studies have posited that the gut microbiome may play an integral role in the onset and exacerbation of IBD. Here, we present a novel computational analysis of a previously published IBD dataset. This dataset consists of shotgun sequence data generated from fecal samples collected from individuals with IBD and an internal control group. Utilizing multiple external controls, together with appropriate techniques to handle the compositionality aspect of sequence data, our computational framework can identify and corroborate differences in the taxonomic profiles, bacterial association networks, and functional capacity within the IBD gut microbiome. Our analysis identified 42 bacterial species that are differentially abundant between IBD and every control group (one internal control and two external controls) with at least a twofold difference. Of the 42 species, 34 were significantly elevated in IBD, relative to every other control. These 34 species were still present in the control groups and appear to play important roles, according to network centrality and degree, in all bacterial association networks. Many of the species elevated in IBD have been implicated in modulating the immune response, mucin degradation, antibiotic resistance, and inflammation. We also identified elevated relative abundances of protein families related to signal transduction, sporulation and germination, and polysaccharide degradation as well as decreased relative abundance of protein families related to menaquinone and ubiquinone biosynthesis. Finally, we identified differences in functional capacities between IBD and healthy controls, and subsequently linked the changes in the functional capacity to previously published clinical research and to symptoms that commonly occur in IBD.

SUBMITTER: Hassouneh SA

PROVIDER: S-EPMC8326577 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome-the molecular interface between host and microbiota-are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (n = 155) and validation (n = 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic 'guilt by association' (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome-metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.

Project description:The gut microbiome is of utmost importance to human health. While a healthy microbiome can be represented by a variety of structures, its functional capacity appears to be more important. Gene content of the community can be assessed by "shotgun" metagenomics, but this approach is still too expensive. High-throughput amplicon-based surveys are a method of choice for large-scale surveys of links between microbiome, diseases, and diet, but the algorithms for predicting functional composition need to be improved to achieve good precision. Here we show how feature engineering based on microbial phenotypes, an advanced method for functional prediction from 16S rRNA sequencing data, improves identification of alterations of the gut microbiome linked to the disease. We processed a large collection of published gut microbial datasets of inflammatory bowel disease (IBD) patients to derive their community phenotype indices (CPI)-high-precision semiquantitative profiles aggregating metabolic potential of the community members based on genome-wide metabolic reconstructions. The list of selected metabolic functions included metabolism of short-chain fatty acids, vitamins, and carbohydrates. The machine-learning approach based on microbial phenotypes allows us to distinguish the microbiome profiles of healthy controls from patients with Crohn's disease and from ones with ulcerative colitis. The classifiers were comparable in quality to conventional taxonomy-based classifiers but provided new findings giving insights into possible mechanisms of pathogenesis. Feature-wise partial dependence plot (PDP) analysis of contribution to the classification result revealed a diversity of patterns. These observations suggest a constructive basis for defining functional homeostasis of the healthy human gut microbiome. The developed features are promising interpretable candidate biomarkers for assessing microbiome contribution to disease risk for the purposes of personalized medicine and clinical trials.

Project description:Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn's disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study's results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.

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Linking Inflammatory Bowel Disease Symptoms to Changes in the Gut Microbiome Structure and Function.

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