IDDF2024-ABS-0326 Roseburia hominis improves host metabolism in obesity by production of nicotinamide riboside

<h3>Background</h3> Next-generation live biotherapeutics are promising to aid the treatment of obesity. We investigated the role of a novel bacterium, <i>R. hominis</i>, in preventing diet-induced obesity. <h3>Methods</h3> We measured <i>R. hominis</i> abundance in human stool samples (metagenomic sequencing and qPCR) from 100 subjects (57 obese; 43 normal controls). The impact of <i>R. hominis</i> on body weight and metabolism was assessed in obese mice induced by the high-fat diet. Metagenomic sequencing evaluated colonization and fecal microbiota composition. The effect of <i>R. hominis</i> conditional medium (RHCM) was validated in a palmitic acid (PA)-induced L-02 cell model. Metabolomic profiling and RNA sequencing identified functional metabolites and host gene regulation. <h3>Results</h3> <i>R. hominis</i> was depleted in stool samples of obese subjects compared with lean controls (IDDF2024-ABS-0326 Figure 1 (A), p=0.0357) and correlated with higher levels of BMI (R=-0.26, p=0.0082) and serum triglycerides (R=-0.40, p=0.051). <i>In vivo</i>, <i>R. hominis</i> prevented HFD-induced weight gain, improved insulin resistance, and reduced serum lipid and lipid accumulation in liver and adipose tissue compared with vehicle control (IDDF2024-ABS-0326 Figure 1 (B, C), p&lt;0.05). Treatment of <i>R. hominis</i> led to the enrichment of lean-associated species, such as <i>Faecalibacterium prausnitzii</i> and <i>Dysosmobacter welbionis</i>, higher levels of amino acids, bile acids, indole and its derivates, and lower levels of oxidated lipids. <i>In vitro</i>, RHCM prevented PA-induced lipid accumulation in L-02 cells by regulating metabolism pathways, such as the mTOR pathway, thermogenesis, and insulin signaling pathways. Treatment with proteinase K did not abolish the preventive role of RHCM on lipid accumulation. We identified a metabolite produced by RH that could prevent lipid accumulation in cells treated with PA. Mechanistically, this metabolite converts into NAD+ to induce its activity through SIRT1/mTOR signaling. Inhibitor of SIRT1, EX527, partially abolished the preventive role of RHCM on PA-induced lipid accumulation in L-02 cells. <h3>Conclusions</h3> <i>R.hominis</i> protects against diet-induced metabolic disorder by procuring functional metabolite. <i>R. hominis</i> is a promising candidate for the development of next-generation live biotherapeutics for the treatment of obesity and metabolic diseases.