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PhD thesis_Ricky .pdf
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- (en) The global rise of metabolic disorders, including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD), has highlighted the need to understand the gut microbiota’s role in host health. While traditional probiotics target a few taxa, "Next-Generation Probiotics" (NGPs) focus on abundant gut microbes with specific protective functions. This thesis investigates the human gut commensal Dysosmobacter welbionis J115ᵀ, from its discovery to its prevalence, metabolism, and taxonomy. Analysis of metagenomic data from UK and Chinese cohorts showed that Dysosmobacter welbionis is highly prevalent in gthe eneral population (72-81%). In three cohorts with MASLD phenotypes, its abundance was lower in patients with liver fat accumulaton, and inversely correlated with fibrosis scores, suggesting a protective role against disease severity. In vivo, supplementation of Dysosmobacter welbionis J115ᵀ in high-fat diet (HFD) fed mice reduced liver weightsteatosiss markers, and improved glycemic control, demonstrating its causal role in mitigating early MASLD and metabolic dysfunction. Mechanistic studies revealed a novel myo-inositol-to-butyrate fermentation pathway. Using carbon utilization assays, NMR metabolomics, and proteomics, we found that Dysosmobacter welbionis J115ᵀ preferentially metabolizes myo-inositol into butyrate, a key short-chain fatty acid for gut and metabolic health. This pathway is driven by a conserved iol gene cluster, a species-wide metabolic signature. We also expanded the genus by isolating 19 additional strains and identifying a new species, Dysosmobacter phytatis sp. nov. (strain PhyT). Taxonomic revisions included reclassifying Oscillibacter acetigenes as a synonym of Dysosmobacter welbionis and Pusillibacter faecalis as Dysosmobacter hominis, providing a clearer framework for research. Safety assessment showed that while J115ᵀ carries a mobile tet(W) gene, other isolates like Dysosmobacter welbionis W28 lack mobile resistance elements and remain sensitive to vancomycin. This strain collection supports potential regulatory approval. Overall, this thesis demonstrates that Dysosmobacter welbionis is a key gut microbe with a specialized metabolic niche, offering promising potential for developing new therapies targeting metabolic and liver diseases.
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Lee, C.-h. (n.d.). Discovery of a novel myo-inositol to butyrate fermentation pathway and taxonomic expansion of the genus Dysosmobacter in the human gut. https://hdl.handle.net/2078.5/275837