Microbial therapeutics for acute colitis based on genetically modifiedLactococcus lactishypersecreting IL-1Ra in mice

Inflammatory bowel disease: Training bugs to deliver drugs Genetically reprogrammed bacteria can facilitate the efficient delivery of a therapeutic protein for treating inflammatory bowel disease (IBD). Interleukin 1 receptor antagonist (IL-1Ra) inhibits the immune cells that attack the intestinal lining in IBD patients, but current administration strategies are associated with serious side effects. Takeshi Shimosato and colleagues at Shinshu University in Nagano, Japan, have engineered the microbeLactococcus lactisto secrete high levels of IL-1Ra. The researchers dosed mice orally with these bacteria, which released IL-1Ra into the intestinal tissue. This treatment proved safe and effectively reduced inflammation and associated symptoms in a mouse model of ulcerative colitis.L. lactishas previously been tested as a probiotic in clinical trials, and may therefore offer an appealing alternative to subcutaneous administration of IBD drugs in human patients. The increased incidence of inflammatory bowel disease (IBD) in Western and rapidly Westernizing developing countries poses a global pandemic threat. The development of affordable drugs for treating IBD worldwide is thus a priority. Genetically modified lactic acid bacteria (gmLAB) as microbial therapeutics are inexpensive protein producers suitable for use as carriers of protein to the intestinal mucosa. Here, we successfully constructed gmLAB hypersecreting interleukin 1 receptor antagonist (IL-1Ra). Oral administration of these gmLAB suppressed body weight reduction and exacerbation of the disease activity index score in mice with acute colitis and decreased the number of CD4(+)IL-17A(+)cells in the mesenteric lymph nodes. These data suggest that the gmLAB deliver IL-1Ra to the colon, where it inhibits IL-1 signaling. We thus developed a novel IBD therapeutic that blocks IL-1 signaling using a gmLAB protein delivery system. This system could be an inexpensive oral microbial therapeutic.