This report summarizes the deliberations of a working group convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) at their 2025 annual meeting to identify the key targets that mediate the host response to biotics. Probiotics, prebiotics, synbiotics, and postbiotics have been explored in numerous contexts, but results of clinical trials are mixed. In most studies performed to date, a therapeutic product and its dose and administration strategy were selected based on factors other than rigorous mechanistic evidence. Given recent advances in our understanding of interactions between biotics, the host, and the gut microbiome, we sought to determine whether a more rational, informed approach might now guide the more precise selection of a biotic for a specific indication. The panel addressed biotic modulation of the immune system, host metabolism, the enteric nervous system, human commensal microbes, and the gut-brain axis and developed five recommendations to increase the likelihood that biotic interventions will lead to meaningful clinical impacts. Interventions should: (1) strive to modulate or refine, rather than "boost," host metabolism and the immune system to achieve specific outcomes; (2) consider the human metabolome, in addition to the microbiome, as a readout and therapeutic target; (3) determine context-dependent responses to biotics in terms of spatial location within the gut, host genetics, environmental influences, and diet; (4) explore a wide range of microbial fermentation substrates that yield biologically active products in addition to prebiotic fibers; and (5) leverage new approach methods including ex vivo human tissue-based approaches, novel in vitro methods, and advanced computational tools including artificial intelligence to complement human studies. The roadmap proposed by this panel aims to accelerate the translation of biotic research into discoveries that will more readily impact clinical practice.
