Landmark study tracks how microorganisms and metabolites change over time in inflammatory bowel disease

An ambitious new study followed 132 patients suffering from inflammatory bowel disease (IBD) for one year, in order to generate longitudinal molecular profiles of host and microbial activity. In doing so it captured the most comprehensive description to date of host and microbe activities in IBD.

Inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease, are the result of chronic inflammation in the gut, with affected individuals experiencing cycles of disease activity and remission. IBD affects millions of people worldwide and severely impacts quality of life. This new study was part of the Integrative Human Microbiome Project—a follow-up to the landmark Human Microbiome Project—and was carried out by a group of universities and medical schools in the USA. It was co-supervised by Microbiome Insights Scientific Advisory Board member Curtis Huttenhower of the Harvard T.H. Chan School of Public Health, USA. According to the authors, the study was designed to specifically go beyond previously reported metagenomic profiles of those with IBD.

Sampling of each participant was done up to 24 times throughout the year, resulting in a total of 2965 stool, biopsy, and blood specimens. Along with these a multi-omics view was enabled by characterizing the metagenomes, proteomes, metabolomes, and viromes.

This revealed changes over time in the microbiomes of IBD patients, changes that included characteristic increases in facultative anaerobes at the expense of obligate ones, as well as alterations in microbial gene expression, metabolite pools, and levels of antibodies in host serum. During periods of disease activity, microbiomes were also more variable and underwent taxonomic, functional, and biochemical shifts. Host, microbial, and biochemical factors were all central to this dysregulation.

Previous work had described some of these changes, such as the taxonomic shifts to aerotolerant, pro-inflammatory clades. However, this work yielded several new insights such as the changes in gene expression, particularly by clostridia. There was also an unexpected stability of the relative abundance of P. copri among IBD patients, and an unclassified Subdoligranulum species was markedly reduced and its importance was highlighted through its association with a wide range of IBD-linked metabolites. A result like this was only possible, according to investigators, by using the multi-omics approach. Interestingly, this species was recently shown to form a complex of new species-level clades, which likely contains butyrate producers considered to be beneficial, particularly in IBD. Investigators therefore believe that further isolation of additional species in tandem with the associated metabolites will show how these species interact with host physiology and the immune system, revealing the consequences of their reduction during IBD.

Authors also noted that several other host and microbial features were singled out for follow-up because of the multi-omics data integration. For example, strain-level profiling of implicated microorganisms, specifically those associated with the host epithelium, is possible with this dataset. This might help to identify the organisms responsible for IBD-associated accumulation of primary unconjugated bile acids and the depletion of secondary bile acids. Expanding the range of species known to carry appropriate metabolic genes could lead to new therapeutic targets.

The study authors do stress that, “it has not yet been determined whether these multi-omic features of the microbiome can predict disease events before their occurrence and that the disease-relevant time scales of distinct molecular events have not been identified.” They suggest that searching for the earliest signs of departure from a subject-specific baseline state might be predictive and is one avenue to pursue. More importantly though, they recommended that these results are taken back to the clinic as better predictive biomarkers of IBD progression and outcomes, and as a new set of host-microbe interactions that can be developed into targets for therapy in broad IBD populations.

The study’s infrastructure resources, results, and data are made available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org).

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