Our intestinal tract offers an attractive environment for both beneficial and pathogenic bacteria. The beneficial bacteria of our microbiota feast on undigested foods and provide numerous health benefits. Enteric pathogens see this environment as an entry point for infection. Both groups influence each other, creating a tripartite interaction with us, the host. Understanding the regulatory processes that decide on the outcome of these encounters represents an emerging research area to combat infectious diseases. While the field has focused on protein-mediated processes, our group investigates the role of RNA-centric mechanisms in controlling microbial interactions in the gut.
The anaerobic Gram-negative bacterium Bacteroides thetaiotaomicron represents a predominant member of the human gut microbiota and emerged as the model bacterium for functional microbiota research. By compiling a high-resolution transcriptome annotation for this bacterium (‘Theta-Base’: https://bacteroides.helmholtz-hzi.de/), we recently identified hundreds of novel small regulatory RNAs (sRNAs), whose functional and mechanistic characterization represents one major focus of the group. For example, we pursue a unique, multi-pronged strategy to identify and understand in vivo-relevant Bacteroides sRNAs in a systematic manner. To this end, we combine cross-species RNA-seq approaches (metatranscriptomics, dual and triple RNA-seq) and multiplexed CRISPR-based sRNA knockdown with advanced human colon models.
Most known sRNAs do not operate in isolation, but depend on assisting RNA chaperones to fulfill their regulatory functions. In the absence of homologs of classical global RNA-binding proteins, we combine computational and experimental screens to search for alternative global RNA binders in Bacteroides. Recent findings from the lab, for instance, suggest a Bacteroides cold-shock protein as an RNA-binder and to contribute to bacterial colonization of the host mucous layer.
In summary, biological insights gained from these studies will improve our knowledge of the functions of regulatory RNA molecules and their protein partners in a predominant member of the human intestinal microbiota. This will lay the groundwork needed to exploit microbiota RNA biology for diagnostics and therapy against enteric infections and microbial disorders in our gut.