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New Research Reveals How Gut Bacteria Colonize the Human Gut

Gut Bacteria – Researchers have discovered that Bacteroides thetaiotaomicron, a commensal bacterium, requires a specific protein domain for survival in mammalian gut. This protein, Rho, contains an intrinsically disordered domain (IDR) which sequesters Rho molecules into an intracellular compartment. This mechanism increases Rho termination activity while altering gene expression patterns to enable B. thetaiotaomicron to colonize successfully the gut.

New Research Reveals How Gut Bacteria Colonize the Human Gut
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Researchers engineered a B. thetaiotaomicron strain without Rho IDR and discovered it is viable in laboratory media but outcompeted by its wild-type parental strain in germ free mice’s gut.

Furthermore, when exposed to 13 species representing primary phyla in human gut bacteria, researchers observed no difference between them or either DIDR strain. These results demonstrate that Rho requires its IDR for fitness in mammalian gut.

Rho phase separation occurs both in vitro and in vivo, depending on IDR determination. WT Rho formed droplets depending on salt and protein concentrations as well as presence of RNA; DIDR Rho did not, even at protein concentrations 20 times higher.

Purified IDR also formed droplets but only when exposed to RNA; similarly WT Rho would only do so when facing carbon starvation or harvested from murine cecums. Immunofluorescence experiments identified Rho condensates in WT B. thetaiotaiomicron facing carbon starvation or harvested from murine cecum.

Researchers conducted in vitro transcription termination assays using different templates, purified WT Rho and DIDR Rho, under both phase-separating and non-phase separating conditions.

WT Rho terminated transcription more efficiently under phase separating conditions than DIDR Rho did; certain templates only experienced termination under certain conditions while others experienced both conditions simultaneously. Sequestering WT Rho into a phase separated compartment increased Rho’s termination activity which proved crucial for certain templates.

Finally, an RNA-seq analysis of isogenic WT and DIDR Rho strains harvested from the murine cecum identified hundreds of genes regulated by IDR, including several essential for gut fitness. These discoveries illustrate how a single domain within a highly conserved protein could have evolved without altering its core biochemical function, yet now plays an integral role in organismal physiology.

This research offers insight into the factors and mechanisms that make beneficial bacteria successful gut colonizers. It may have potential applications for clinical trials aiming to manipulate the gut microbiota to treat various diseases. Furthermore, it sheds light on how one acquired domain within a highly conserved protein can play an essential role in an organism’s physiology without altering its core biochemical function.

Source- DOI: 10.1126/science.abn7229

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