Summary
In a mouse study reported as a bioRxiv preprint, IL-10 mRNA in lipid nanoparticles restored microbiota-transplant engraftment and subsequent resolution of C. difficile infection.
An IL-10 messenger-RNA treatment helped fecal microbiota transplants (FMT) take hold and resolve Clostridioides difficile infection in mice that otherwise did not respond, according to a bioRxiv preprint. The study links transplant success to the intestine’s immune environment and reports that boosting IL-10 signalling can make that environment more receptive to transplanted microbes.
How inflammation can impede a transplant
FMT introduces beneficial gut bacteria intended to establish themselves in the intestine and help control infection. That establishment is called engraftment. In the mouse models described in the preprint, deficient IL-10 signalling was associated with poor FMT engraftment and failure to resolve C. difficile infection.
The researchers describe a sequence involving immune regulation. Foxp3-positive regulatory T cells produce IL-10, which limits signalling by interferon-gamma (IFN-γ). Without that restraint, increased intestinal IFN-γ signalling was linked to greater production of reactive oxygen and nitrogen species (ROS/RNS) by neutrophils and intestinal epithelial cells. The authors report that these reactive molecules support inflammation-tolerant microbes, while making conditions less favourable for the transplanted community to establish.
Several interventions that interrupted parts of this pathway restored FMT treatment success in mice: antibody-mediated blockade of IFN-γ signalling, depletion of neutrophils, and inhibition of ROS/RNS production. These results support the researchers’ account of how inflammation can interfere with microbiome-based treatment.
IL-10 mRNA restored FMT response in mice
The team also tested an immunotherapy made from Il10 mRNA packaged in lipid nanoparticles (LNPs). The particles deliver mRNA, which cells can use to produce the encoded protein. In mice classified as FMT non-responders, administration of the Il10-mRNA-LNP treatment restored transplant engraftment and was followed by resolution of C. difficile infection, the abstract reports.
The findings suggest that FMT response may depend not only on the microbes being transplanted but also on whether the host intestine allows them to establish. In this study, modifying immune signalling improved that local environment in mice. The evidence is preclinical: the reported work does not establish that the treatment will improve FMT outcomes in people.
The preprint’s competing-interest statement says the University of Pennsylvania submitted a provisional patent application covering the Il10 mRNA-LNP. It also discloses that co-author Mohamad-Gabriel Alameh is a scientific adviser to AfriGen Biologics and has an ownership stake in RNA Technologies.