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

Today we are sharing a study led by Professor Oluf Pedersen from the University of Copenhagen, published in Nature Microbiology. This research, for the first time, discovered two novel peptides, RORDEP1 and RORDEP2, produced by the human gut commensal bacterium Ruminococcus torques(RT). These peptides are present in human circulation, show a negative correlation with obesity, and significantly improved glucose tolerance, increased bone density, and reduced fat accumulation in pre-clinical models. This provides new mechanistic insights and therapeutic potential for host metabolism regulation by microbially derived peptides.

Fig. 1 | Identification of RUMTOR_00181 and RORDEPs

01 Research Background​

The human gut microbiome is a functionally rich "organ," encoding a proteome far exceeding the human genome in size. However, how microbial-derived proteins directly regulate host metabolism remains poorly understood. Ruminococcus torques(RT) is a common and abundant commensal bacterium in the human gut, but its specific role in host metabolic regulation has not been clearly defined. Recent discoveries of microbially derived hormone-like peptides have offered new avenues for metabolic disease treatment. Nevertheless, systematically identifying bacterially derived peptides with metabolic regulatory functions and elucidating their mechanisms remains a significant challenge in the field.

02 Innovative Highlights​

First discovery and functional validation of metabolically active peptides from a gut commensal: Moving beyond previous correlative studies in the field, this research clearly identifies the RORDEP1/RORDEP2 peptides produced by Ruminococcus torques(RT) as active molecules directly regulating host metabolism. Their abundance was found to be negatively correlated with obesity in human populations, and their multiple benefits—including improved glucose tolerance and increased bone density—were confirmed in animal models.

Reveals a new cross-organ "microbiota-peptide-host" pathway: The study systematically elucidates a novel molecular pathway: how peptides produced by gut bacteria enter the circulatory system and systemically improve host metabolism by modulating gut hormones (e.g., reducing GIP, elevating GLP-1) and directly enhancing liver insulin sensitivity. This provides a new paradigm for understanding microbiota-host interactions.

Provides novel "microbial peptide" drug candidate targets for metabolic diseases: This study demonstrates the significant therapeutic potential of peptides derived from common commensal bacteria. It not only opens up a new direction—"microbial peptides"—for the prevention and treatment of metabolic diseases but also lays a solid foundation for developing next-generation therapies based on bacterial active molecules.

03 Results and Discussion​

• Discovery and Structural Features of RORDEPs​

Through bioinformatic screening of 118 human ligands and their precursor proteins, it was found that the RUMTOR_00181 protein encoded by the RT ATCC 27756 strain contains two FN3 domains, which can be cleaved by proteases to release RORDEP1 and RORDEP2. Phylogenetic analysis showed that RORDEPs are homologous to human Irisin (FNDC5) but share low sequence identity (~24%), suggesting they are independently evolved bacterial functional peptides.​

• Association of RORDEP levels with metabolic phenotypes in humans

In 59 healthy adults, RT strains carrying the RUMTOR_00181 gene were detected in all individuals (abundance spanning 5 orders of magnitude), and their absolute abundance was significantly negatively correlated with BMI and body fat percentage (Fig. 2a-d). This negative correlation was further validated in the LifeLines DEEP cohort (n=1,135; β= -0.151, P=0.002). Using targeted mass spectrometry absolute quantification (AQUA) technology, RORDEP1 (average 176 pM) and RORDEP2 (average 210 pM) were detected for the first time in human plasma (Fig. 2e-f), and their concentrations were highly positively correlated.

Fig. 2 | RT strain abundance and plasma RORDEPs and their host correlatives

• RT Strain Intervention Improves Metabolic Phenotypes in Mice​

After 8 weeks of gavage with RT strains expressing RORDEPs (RT2) in high-fat diet-fed mice, compared to the PBS control group, the live RT2 treatment group showed significantly improved glucose tolerance, slowed weight gain, reduced adipose tissue weight and adipocyte size, increased lean mass, and increased femoral cortical thickness (Fig. 3a-j). Mechanistically, RT2 treatment activated the expression of genes related to thermogenesis (Ucp1, Cidea, Dio2) and lipolysis in inguinal white adipose tissue, while suppressing genes involved in lipogenesis (Fasn, Scd1) and inflammation (Tnf).

Fig. 3 | The RT2 strain expressing both RORDEPs improves mouse metabolism.

• Engineered Bacteria Delivering RORDEP1 Recapitulate Metabolic Benefits​

To exclude interference from other components of the RT strain itself, researchers constructed engineered Escherichia coliNissle 1917 expressing RORDEP1 (EcN-RORDEP1). In high-fat diet-induced obese mice, short-term gavage with EcN-RORDEP1 significantly improved glucose tolerance and reduced weight gain , demonstrating that RORDEP1 itself is sufficient to mediate the metabolic protective effects.

• Systemic Metabolic Regulation Mechanism of Recombinant RORDEP1​

Intraperitoneal injection of recombinant RORDEP1 (r-RORDEP1) significantly lowered blood glucose after an oral glucose load and altered plasma hormone profiles: GIP decreased by 50%, while GLP-1, PYY, and insulin increased (Fig. 4a-g). In db/db diabetic model mice, consecutive 10-day intraperitoneal injection of r-RORDEP1 significantly improved glucose tolerance (Fig. 4h-i). Using scrambled-sequence RORDEP1 as a control confirmed that the effect is sequence-specific.

Fig. 4 | Peritoneal delivery of r-RORDEP1 improves the metabolism of rats and mice

• Intestinal Delivery of RORDEP1 Enhances Liver Insulin Sensitivity​

In hyperinsulinemic-euglycemic clamp experiments, intraduodenal infusion of r-RORDEP1 dose-dependently increased the glucose infusion rate, up to 4 times that of the control group at the highest dose (Fig. 5a-c). Using isotope-labeled glucose tracing, it was further confirmed that r-RORDEP1 acts by inhibiting hepatic glucose production (decreased by ~40%) without affecting peripheral glucose uptake (Fig. 5d-g).

Fig. 5 | Intestinal delivery of r-RORDEP1 enhances the insulin sensitivity of hepatic glucose output in rats

• Liver Transcriptomics and Proteomics Reveal Molecular Mechanisms​

Multi-omics analysis of livers from rats receiving intraduodenal r-RORDEP1 infusion showed downregulation of genes/proteins related to gluconeogenesis, glycogenolysis, and lipogenesis, and upregulation of insulin signaling, glycogen synthesis, and glycolysis pathways (Fig. 6a-e). Phosphoproteomic analysis indicated activation of metabolic pathways such as those involving PPAR, systematically revealing the molecular network through which RORDEP1 coordinately improves hepatic insulin sensitivity via multiple targets.

Fig. 6 | Intestinal delivery of r-RORDEP1 to rats changes the expression of key liver genes involved in metabolism and insulin signalling

04 Conclusion​

Through innovative computational biology screening combined with multi-level experimental validation, this study is the first to report that the RORDEP1 and RORDEP2 peptides secreted by the human gut commensal Ruminococcus torquesare important host metabolic regulators. Both population epidemiology and pre-clinical experiments indicate that RORDEPs not only improve glucose homeostasis and body fat distribution but also increase bone density. Their mechanism of action involves multiple regulations of the gut hormone axis (inhibiting GIP, promoting GLP-1/PYY/insulin secretion) and liver insulin signaling pathways. Although RORDEPs share low homology with human Irisin and were not found to act directly through integrin receptors, they exhibit potent metabolic improvement potential through indirect mechanisms. This work not only opens up the new field of "microbial peptidomics" as a source for discovering functional molecules but also lays a solid theoretical foundation for developing next-generation metabolic disease treatment strategies based on microbially derived peptides. As the authors state, subsequent efforts are necessary to explore the receptors for RORDEPs and their long-term application effects, and clinical trials should be initiated promptly to validate their translational value in preventing and treating human metabolic diseases.

Original Article:

Fan Y, Lyu L, Vazquez-Uribe R, et al. Polypeptides synthesized by common bacteria in the human gut improve rodent metabolism[J]. Nature Microbiology, 2025: 1-22.

https://www.nature.com/articles/s41564-025-02064-x