Gut microbiome structure and metabolic activity in inflammatory bowel disease

Abstract

The inflammatory bowel diseases (IBD), 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 LC-MS 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 subjects. Metabolomic and metagenomic profiles were broadly correlated with fecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant (DA) in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While >50% of DA metabolite features were uncharacterized, many could be assigned putative roles through metabolomic “guilt-by-association” (covariation with known metabolites). DA 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 DA species and well-characterized DA 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.

Predictive Metagenomic Analysis of Autoimmune Disease Identifies Robust Autoimmunity and Disease Specific Microbial Signatures

“…Further, many of the taxa we identified as being predictive of autoimmune disease were correlated with metabolites that have been previously found to be associated with autoimmunity and inflammation. Recent publications have identified a number of bile acids, triacylglycerols 66 , vitamin B, and acylcarnitine 60 metabolites altered in IBD compared with a control population, many of which we also found to be significantly associated with our most predictive taxa.…”

Dynamic Bayesian networks for integrating multi-omics time-series microbiome data

“…This generated 1, 785 stool samples, 651 intestinal biopsies, and 529 blood samples. In addition to multi-omics data (e.g., metatranscriptomics [22] and metabolomics [6,17]), we also included clinical information.…”

M2IA: a Web Server for Microbiome and Metabolome Integrative Analysis

“…Thus, the microbiota-metabolites interactions are important to maintain the host health and wellbeing. Integrative data analysis of gut microbiome and metabolome can offer deep insights on the impact of lifestyle and dietary factors on chronic and acute diseases (e.g., autoimmune diseases, inflammatory bowel disease [5] , cancers [6] , type 2 diabetes and obesity [7] , cardiovascular disorders, and non-alcoholic fatty liver disease [8] ), and provide potential diagnostic and therapeutic targets [9] .…”