Abstract: Derived from gut microbiota that can intervene in human diseases, next generation probiotics are one of the novel drug candidates available for the treatment of intestinal inflammation, immune dysfunction, metabolic disorders and cancer. Several biopharmaceuticals developed for next generation probiotics have entered the stage of preclinical or clinical studies, however, insufficient efficacy and uncontrollable dosage are the challenges in the development of next generation probiotics into drugs. To solve these problems, intestinal colonization making next generation probiotics controllable is a possible way. This review introduces the clinical progress of next generation probiotics based on drug development, focusing on the factors and their mechanisms affecting the intestinal colonization of next generation probiotics, and summarizes the strategies to enhance the intestinal resilience of next generation probiotics, aiming to provide some ideas for solving the current problems in clinical development of next generation probiotics.