Polypeptides synthesized by common bacteria in the human gut improve rodent metabolism.

Summary

Two circulating peptides (RORDEP1/2) produced by Ruminococcus torques inversely associate with human adiposity and causally improve rodent metabolism. In mice, RORDEP-expressing strains improved glucose tolerance, increased bone density, and reduced fat mass; recombinant RORDEP1 enhanced incretin responses and insulin action while suppressing hepatic gluconeogenesis and glycogenolysis.

Key Findings

• Identified two circulating human peptides (RORDEP1/2) produced by gut commensal Ruminococcus torques that inversely correlate with adiposity.
• RORDEP-expressing strains improved glucose tolerance, increased bone density, and reduced fat mass in both HFD-fed lean and DIO mice, with thermogenesis/lipolysis gene upregulation.
• Recombinant RORDEP1 decreased GIP and increased GLP-1, PYY, and insulin in rats.
• Intestinal delivery of RORDEP1 potentiated insulin-mediated suppression of hepatic glucose production and reprogrammed hepatic gene expression toward glycogenesis/glycolysis.

Clinical Implications

Though preclinical, RORDEPs or RORDEP-expressing probiotics could be developed to enhance GLP-1/PYY signaling, reduce adiposity, and improve hepatic insulin sensitivity; safety, immunogenicity, and durability require clinical testing.

Limitations

• Preclinical rodent data; human efficacy and safety are unknown.
• Potential variability among R. torques strains and peptide bioavailability/stability in humans.

Future Directions

Phase 1 studies of RORDEP1 pharmacokinetics, safety, and incretin responses in humans; standardized RORDEP-producing probiotic development; biomarker-guided trials in obesity/NAFLD/T2D.