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Abstract
Background Next-generation live biotherapeutics are promising to aid the treatment of obesity. We investigated the role of a novel bacterium, R. hominis, in preventing diet-induced obesity.
Methods We measured R. hominis abundance in human stool samples (metagenomic sequencing and qPCR) from 100 subjects (57 obese; 43 normal controls). The impact of R. hominis 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 R. hominis 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.
Results R. hominis 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). In vivo, R. hominis 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<0.05). Treatment of R. hominis led to the enrichment of lean-associated species, such as Faecalibacterium prausnitzii and Dysosmobacter welbionis, higher levels of amino acids, bile acids, indole and its derivates, and lower levels of oxidated lipids. In vitro, 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.
(A), p=0.0357: (B, C), p<0.05
Conclusions R.hominis protects against diet-induced metabolic disorder by procuring functional metabolite. R. hominis is a promising candidate for the development of next-generation live biotherapeutics for the treatment of obesity and metabolic diseases.