IBD Multiomics Database May Be Rich Source of New Treatment Targets
Key findings
- The new Inflammatory Bowel Disease Multiomics Database catalogs new relationships between multiomic features that have been identified as being potentially central during inflammatory bowel disease (IBD)
- In a yearlong study of 132 patients, characterization of dysbiotic periods of IBD identified greater variation in metagenomic species than the overall IBD phenotype did
- Novel findings included increased gene expression by clostridia during dysbiotic IBD and reduction in an unclassified Subdoligranulum species that is associated with a wide range of IBD-linked metabolites
- The temporal stability of multiple microbiome measurements differed across IBD phenotypes and disease activity, with distinct effects on molecular components of the microbiome including unexpected stability of Prevotella copri in IBD patients
- These and many other findings in the report may be useful to develop prognostic markers in IBD and identify new therapeutic targets
More than 200 variants in the human genome drive the risk of inflammatory bowel disease (IBD). Many of them are responsible for the host-microbe interactions that result in the relapsing-remitting inflammation that is characteristic of the disease.
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Ramnik J. Xavier, MD, PhD, director of the Center for the Study of Inflammatory Bowel Disease, and colleagues are part of the Integrative Human Microbiome Project (iHMP), which recently generated longitudinal molecular profiles of host and microbial activity for individuals with and without IBD. The work integrated taxonomic, metagenomic, metatranscriptomic, metaproteomic and metabolic data on the gut microbiome. Researchers compiled the results of the study into the Inflammatory Bowel Disease Multiomics Database, which is expected to be useful for diagnosis, prognosis and treatment of IBD.
In an article published in Nature, Dr. Xavier and his colleagues discuss the nature of their work on the iHMP, their findings and their insights into potential uses for the data they've collected.
Study Participants and Samples
The researchers studied 132 children and adults who underwent colonoscopy for routine screening or work-up of gastrointestinal symptoms. Individuals not diagnosed with IBD were classified as controls.
Over one year, the participants contributed a total of 651 colon biopsy specimens, 529 blood samples and 1,785 stool samples (shipped from home every two weeks). They completed symptom questionnaires throughout the study, and a subgroup of those with greater fluctuations in disease activity were asked to contribute blood and stool samples more frequently.
Multiomic Gut Microbiome Changes
Over the course of the study, researchers observed the gut microbiome through metabolomic, metagenomic and metatranscriptomic lenses. They identified the following changes in the gut microbiome between patients with IBD and controls.
Metabolomics: Differences between IBD patients and controls were most apparent in the metabolome. Metabolite pools were less diverse in individuals with IBD, and certain compounds were more abundant including polyunsaturated fatty acids and vitamins B5 and B3.
Metagenomics: Contradicting several previous studies, no metagenomic species were significantly different between IBD patients and controls. The reason may have been that unlike most studies, this one included IBD patients with relatively inactive disease.
Analysis of Dysbiosis: The researchers applied the term dysbiotic to samples whose taxonomic compositions were highly unlike those of control samples. Dysbiotic periods corresponded to a larger fraction of variation in metagenomic species than the overall IBD phenotype did, which may reflect a clearer delineation between active and less active disease over time.
Dysbiosis also distinguished between independent host measures, such as serum levels of various antibodies. Furthermore, 117 of 548 tested metabolites differed in individuals with dysbiotic IBD. Some of the differences, such as the reduction in short-chain fatty acids, are known to occur in IBD patients.
However, several previously undescribed taxonomic changes were observed during dysbiosis. For example, some species, including Clostridium hathewayi, C. bolteae and Ruminococcus gnavus, increased significantly in transcriptional activity as well as showing significantly increased expression during dysbiosis. Their roles in IBD may be more pronounced than suggested solely by their differences in genomic abundance.
Gut Microbiome Stability
Each subject's microbiome tended to diverge from baseline with respect to metagenomic, metatranscriptomic and metabolomic profiles. These changes were most pronounced for IBD patients, in whom the microbiome sometimes had almost no species in common with itself from an earlier time point.
In controls and IBD patients, gene family transcripts, metabolites and proteins sometimes changed as much within two weeks as over longer time periods.
The researchers evaluated large-scale temporal differences by searching for shifts in the microbiome between consecutive time points (dissimilarities more similar to those between different people than within one person). In metagenomic taxonomic profiles, there were 166 such shifts, which in IBD patients mainly concerned Escherichia coli.
Among controls, shifts occurred primarily in those with high levels of Prevotella copri, an organism that unexpectedly remained more stable in IBD patients.
Microbiome-associated Host Factors
The research group identified 1,008 unique genes that were differentially expressed in biopsy specimens from IBD patients compared with controls. Certain immune-related pathways, including the IL-17 signaling pathway and the complement cascade, were overrepresented in upregulated differentially expressed genes.
Multiomic Microbiome Interactions
To find host-microbial molecular interactions that might underlie IBD activity, the researchers constructed an association network that incorporated metagenomic species, species-level transcription ratios, functional profiles, metabolites, host transcription, serology and fecal calprotectin.
Faecalibacterium prausnitzii accounted for some of the strongest associations within the network, including expression of numerous gene families downregulated in dysbiosis. E. coli and to a lesser extent Haemophilus parainfluenzae accounted for a large fraction of upregulated gene families.
Members of the Roseburia genus were associated with bile acids and a number of acylcarnitines, suggesting that Roseburia are involved in the carnitine and bile acid dysregulation observed in IBD.
An unclassified Subdoligranulum species was both markedly reduced in IBD and central to the functional network. It associated with a wide range of IBD-linked metabolites both identifiable (e.g., bile acids and polyunsaturated fatty acids) and unidentifiable.
Uses for the Data
It is still unknown whether these multiomic features of the microbiome can predict disease activity. Members of the iHMP plan to investigate whether the data can be used to develop better predictive biomarkers of IBD progression and outcome, as well as identify new host-microbe interaction targets for novel interventions.
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