Resetting the Gut Microbiome Offers Potential Treatment for Rare Autoimmune Disease

Defective regulatory T cells (Tregs) alter the gut microbiome, leading to a variety of autoimmune diseases. New findings suggest that replacing absent gut bacteria or restoring a key metabolite could help treat children with IPEX syndrome.

IPEX syndrome is a rare and often fatal autoimmune disease that occurs when mutations in the transcription factor, Foxp3, disrupts Treg function. Patients who do not receive a stem cell transplant usually die before 2 years of age.

In a study published in The Journal of Experimental Medicine, investigators discovered that mice carrying a mutant version of the Foxp3 gene showed changes in their gut microbiome, around the same time they developed autoimmune symptoms.

Most notably, the mice had lower levels of bacteria from the genus Lactobacillus. When investigators fed the mice Lactobacillus reuteri, they could reset the gut microbiome and reduce inflammation, thereby, significantly extending the animals’ survival.

Bacteria can secrete metabolic molecules that largely affect their hosts. In study mice that lacked Foxp3, the levels of the metabolite inosine was reduced. However, the levels were restored to normal after the investigators reset the gut microbiome with L. reuteri.

The results of the study showed that when inosine binds to the cell surface proteins, called adenosine A2A receptors, the metabolite inhibits the production of Th1 and Th2 cells. In Foxp2-deficient mice, these pro-inflammatory T cell types are elevated. However, they are diminished when treated with either L. reuteri or inosine itself, resulting in reduced inflammation and an extension of the animals’ life span.

“Our findings suggest that probiotic L. reuteri, inosine, or other A2A receptor agonists could be used therapeutically to control T cell-mediated autoimmunity,” said lead investigator Yuying Liu.