Studying Drug-microbiome interactions by metaproteomics.

Maintaining human microbiome in vitro to test for the effects of drugs and other compounds.

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Our lab focuses on developing and optimizing metaproteomic workflows as well as applying our techniques for microbiome-host and microbiome-drug interactions. We have very little information on the effects of the vast majority of drugs and compounds on the gut microbiome. In vitro models could provide timely and cost-efficient solutions to understand drug-microbiome interactions and as drug assays. For such model to be representative, it is essential to maintain not only the taxonomic composition, but also the function of the microbiome constituents. Although there have been attempts to culture the gut microbiome, no maintenance of microbiome functionality has been reported.  We also didn’t know whether the previously cultured gut microbiota could capture the actual functional responses to drugs in vivo. In this study, we developed and validated a culture model that maintains taxon-specific functional activities and recapitulates in vivo drug response. The model is scalable and could be used for medium to high-throughput drug screening.  Moreover, the approach can be coupled to metagenomics, metatranscriptomics, metaproteomics and metabolomics.

In this manuscript we primarily used metaproteomics to monitor the functional changes in the microbiome.  If you are not familiar with metaproteomics you might not appreciate what it can provide. I’ve always liked this analogy: imagine that I’m a member of a bacterial community, using 16S rDNA sequencing you’ll know my name, using metagenomics you’ll get a list of my abilities, and using metaproteomics you’ll know what I’m doing right now. A microbiome with the same taxonomic composition can have different functionality when the environmental conditions are different. It has been estimated that only ~ 40% of genes are expressed under specific conditions.  Recent work in E. coli has shown that some mRNAs are expressed but don’t lead to proteins right away.  Instead, they are there in anticipation of environmental changes.  The remaining mRNAs predicted by genomic sequencing are not actually present unless activated by certain conditions. Therefore, bacteria count and mRNA levels are not sufficient to accurately represent the function of the microbiome.
In the last few years, we have seen an explosion of microbiome studies linked to different diseases.  However, understanding the function of the microbiome and understanding whether drugs and other compounds change the function of the microbiome remains a challenge.  In vitro assays linked to different readouts, such as functional metaproteomics, will help in better understanding how microbiomes respond to different stimuli including drugs and other compounds.