The purpose of this notice of funding opportunity (NOFO) is to support highly innovative mechanistic research to accelerate precision probiotic interventions using a milestone-driven, biphasic award mechanism, R61/R33 Phased Innovation Award. The ultimate goal of this NOFO is to identify, understand, and develop strategies to address barriers in precision probiotic therapies to account for the heterogenicity in humans that causes inconsistent probiotic responses. • The first phase, funded by the R61, will provide up to 2 years to identify unique host biological patterns that are correlated with heterogeneity of probiotic clinical effects. • The second phase, funded under the R33, will support studies to assess the ability of the unique patterns determined in the R61 phase to detect the improvement of probiotic responsiveness in rigorously designed mechanistic studies. • The combined R61/R33 should not exceed 5 years. • Transition from the R61 to the R33 phase of the award will be administratively reviewed and will be determined based on successful completion of Transition Milestones that need to be clearly specified in the R61 phase application.