Microbiome-Based Therapies Hold Promise for Chronic Diseases

By Deborah Borfitz

September 4, 2025 | Researchers in Denmark report finding a potential new route for developing microbiome-based therapies by providing “a concrete example” of how specific bacterial proteins might be used in the treatment of chronic metabolic diseases, according lead author Yong Fan, Ph.D., assistant professor at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. Specifically, they identified a common gut bacterium capable of producing hormone-like proteins measurably influencing weight, bone density, and blood sugar regulation in preclinical models. 

Those proteins, known as RORDEP1 and RORDEP2, could serve as a foundation for a new class of drugs known as “pharmabiotics,” says Fan. It’s a concept referring to live microbial therapeutics that would need to be clinically validated for their safety and efficacy and approved for marketing by regulatory authorities. 

Up to now, efforts in the rapidly progressing microbiome field have focused largely on metabolites or changes in broad microbial communities, Fan says. Here, researchers have instead discovered these unique RORDEP-proteins and mapped their influence on host physiology at a mechanistic level. “This mechanistic clarity, combined with translational potential, is what makes RORDEPs unique in the microbiome therapeutics landscape.” 

The proteins have been likened to irisin, providing a biological anchor to the well-studied hormone “known to be released by muscles during exercise, playing a role in fat metabolism, and energy regulation,” says Fan. The partial resemblance “strengthens the rationale that these proteins can act as signaling molecules with broad effects on host metabolism. It connects our discovery to a well-established physiological pathway while opening a new microbial dimension to hormone regulation.” 

In human samples, researchers observed a large variation in RORDEP-producing bacteria—"up to 100,000-fold differences between individuals, with higher levels associated with a leaner phenotype,” he reports. In rodent experiments, they also demonstrated that either introducing RORDEP-producing bacteria or administering the purified proteins consistently led to the beneficial metabolic effects (Nature Microbiology, DOI:  10.1038/s41564-025-02064-x). 

The paper described how RORDEP proteins increase the body’s own production of hormones such as glucagon-like peptide-1 (GLP-1) and pancreatic polypeptide (PYY), which help regulate appetite and blood sugar, as well as insulin, which is essential for maintaining stable blood sugar levels. They also suppress the gastric inhibitory polypeptide (GIP) that can contribute to weight gain and directly enhance fat burning. 

Therapeutic Directions

The preclinical stage biotech company GutCRINE, a spinout from the University of Copenhagen, is now advancing two first-in-human clinical trials. Fan cofounded GutCRINE two years ago with Professor Oluf Pedersen, M.D., senior study author and group leader at Human Genomics and Metagenomics in Metabolism, Center for Basic Metabolic Research, at the university. 

In one study, healthy volunteers are being given live RORDEP-producing bacteria to evaluate safety and biological activity, says Fan. In the other study, purified RORDEP1 protein is being tested directly in humans. The trials are both “designed to establish safety, tolerability, and biological effects.” 

The vision of GutCRINE is to develop two complementary therapeutic platforms, one of which will be “second-generation probiotics based on RORDEP-producing bacteria as a dietary supplement to help prevent common chronic diseases,” Fan says. “Biological drugs based on RORDEP proteins, either in their natural or chemically modified form,” will also be developed as medicines for conditions such as diabetes, obesity, cardiovascular disease, and osteoporosis. 

“From a business and clinical perspective, both paths are valuable,” says Fan. “Probiotics offer a preventive and accessible strategy, while protein-based therapeutics provide a more controlled pharmaceutical approach.” 

The proof-of-concept work will admittedly take years, and clinical translation upwards of a decade, he adds. To date, research has been supported by the University of Copenhagen and external collaborations. Additional funding partnerships to advance the clinical programs are being actively built. 

It is important to understand that “our gut bacteria are not just passive passengers—they can actively shape our hormonal balance and metabolic health,” Fan says. “By uncovering RORDEP proteins, we have revealed a new layer of communication between microbes and humans, with the potential to transform how we prevent and treat some of the most pressing chronic diseases of our time.”