An engineered probiotic bacterium that produces the peptide iberiotoxin in the gut achieved systemic delivery and treated rheumatoid arthritis in rats as effectively as injected peptide.
Oral = Injected efficacyEngineered probiotic bacteria delivering iberiotoxin orally achieved the same arthritis treatment efficacy as direct peptide injection in rats — a potential breakthrough for oral peptide delivery
What the researchers found
Oral administration of engineered L. reuteri secreting iberiotoxin (LrIbTX) achieved comparable efficacy to injected IbTX in treating collagen-induced arthritis in rats. Both treatments significantly improved clinical joint swelling and histologic inflammation versus controls.
IbTX was detected in the sera of healthy rats after oral gavage with LrIbTX, confirming systemic absorption of the intestinally-produced peptide. The oral and injected routes were also equivalent in inhibiting a delayed-type hypersensitivity reaction. No anti-IbTX antibodies were detected with either delivery method, suggesting good tolerability.
Why it matters
One of the biggest challenges in peptide therapeutics is oral delivery — most peptides are destroyed by stomach acid and digestive enzymes, forcing patients to rely on injections. This study demonstrates a fundamentally new approach: using engineered probiotic bacteria as living factories that produce and secrete therapeutic peptides directly in the gut, where they can be absorbed systemically. If this platform generalizes to other peptides, it could transform how peptide drugs are delivered.
How the study worked
Researchers constructed a plasmid for inducible secretion of iberiotoxin and transformed it into probiotic L. reuteri to create LrIbTX. The engineered bacteria were characterized for growth rate and fecal recovery after oral gavage. Systemic IbTX delivery was confirmed using a competitive binding assay in rat serum. Efficacy was tested in the collagen-induced arthritis (CIA) rat model, comparing oral LrIbTX to injected IbTX and control bacteria. Outcomes included clinical joint scores, histologic inflammation, bone density, anti-collagen antibodies, and anti-IbTX antibodies. A delayed-type hypersensitivity model was also used.
What this study cannot tell us
This is a preclinical study in rats, and oral-to-systemic peptide delivery through engineered bacteria faces significant challenges in translation to humans, including differences in gut physiology, immune responses, and regulatory hurdles for live biotherapeutics. The specific serum levels of IbTX achieved were not quantified with standard pharmacokinetic methods. Long-term safety of chronically administering engineered bacteria that produce bioactive peptides in the gut is unknown. The collagen-induced arthritis model, while standard, does not fully recapitulate human rheumatoid arthritis.
How to read the evidence
This is a preclinical animal study demonstrating proof of concept for a novel drug delivery platform. While the results are compelling and the methodology is rigorous, the technology is at an early stage and significant hurdles remain before human translation.
When this study was published
Published in 2025, this is a very recent study at the cutting edge of engineered probiotic and peptide delivery research. The field of live biotherapeutics is rapidly evolving.
The bigger picture
This study represents the convergence of two hot fields: engineered probiotics and peptide therapeutics. The demonstration that a gut bacterium can produce a peptide that reaches therapeutic levels in the bloodstream is a proof of concept with broad implications. Many peptide drugs — from insulin to GLP-1 agonists to antimicrobial peptides — currently require injection. An oral probiotic delivery platform could dramatically improve patient compliance and reduce healthcare costs for peptide-based treatments across many diseases.
Questions still open
- Can the L. reuteri oral delivery platform be adapted to deliver other therapeutic peptides that currently require injection, such as insulin or GLP-1 analogs?
- What are the long-term safety implications of colonizing the gut with bacteria engineered to continuously produce bioactive peptides?
- How would this approach perform in humans, where gut pH, transit time, and immune surveillance differ significantly from rats?
Common questions
How can bacteria in the gut deliver a drug to the whole body?
What is iberiotoxin and why target potassium channels for arthritis?
Read the original research
Limosilactobacillus reuteri enables oral-to-systemic absorption of iberiotoxin for treatment of collagen-induced arthritis in rats.
Microbial cell factories, 24(1), 177
Citation
Kady, Mohamed R; Elston, R Nicholas; Snyder, Lauren J; Fleischman, Jorie D; Brandt, Madilyn J; Zhu, Duolong; Britton, Robert A; Beeton, Christine. (2025). Limosilactobacillus reuteri enables oral-to-systemic absorption of iberiotoxin for treatment of collagen-induced arthritis in rats.. Microbial cell factories, 24(1), 177. https://doi.org/10.1186/s12934-025-02800-2