Introduction In USA and Europe, it is estimated that more than 3 million people are suffering from inflammatory bowel disease (IBD) and another 1.7 million cancer patients treated with checkpoint inhibitors (ICI) are diagnosed with manifest ICI‐induced colitis. The current treatments with steroids and available biologics act systemically and possess limitations with loss of response and severe adverse events and may even limit the effect of the ICI therapy. Thus, new local‐acting therapies are needed to serve the full unmet need amongst these patients. We have recently published that oral administration of L. reuteriR2LC to mice increases IgA production in Peyer’s patches, resulting in modified gut microbiota, altered physiology and immune cell phenotype in the colon and prophylactic administration reduced inflammation in the DSS‐induced colitis. Methods , the novel drug candidate, ILP100, which is a genetically modified lactic acid bacteria that express the chemokine CXCL12 were generated and evaluated as a therapeutic in two different models of colitis, the DSS‐model and a model of checkpoint inhibitor induced colitis (using aPD1 and aPDL1). Results , Peroral administration of ILP100 to mice with overt colitis interrupts disease progression and improves symptoms assessed as disease activity index (DAI) and colon shortening. Further analysis showed that treatment with ILP100 increased infiltrating immune cells expressing TGF‐ß and IL‐10 as well as other tolerogenic immune cell populations including Treg and Tr1 in the colonic lamina propria. There were no changes in the small intestinal lamina propria or mesenteric lymph nodes and there was no systemic exposure detected. Further, efficacy comparison studies demonstrate a reduced severity and a faster recovery of the ILP100 treated mice compared to TNF‐α inhibitor and α4β7‐inhibitor treated mice. The findings have been confirmed over a large dose range. Even though the ICI‐induced colitis did not manifest in symptoms such as body weight loss or blood in feces, fibrosis was developed measured as a reduction of the mean colon length of 12‐18 % in the ICI‐treated groups compared to control, with a tendency to a reduced colon shortening in the ICI + ILP100‐treated groups. Histological analysis of intestines samples from the checkpoint inhibitor is currently ongoing. In conclusion , we demonstrate that peroral administration of ILP100 efficiently ameliorate overt colitis in the DSS‐model by inducing healing through a local shift into an anti‐inflammatory and tolerogenic immune signature in the colon mucosa. Further, our data suggest that peroral administration of ILP100 ameliorate colitis in an ICI model.