From intestinal messenger to next-generation therapeutics: A review on mechanisms and prospects of host metabolic regulation mediated by P9, a secreted protein from Akkermansia muciniphila.

P9, a protein secreted by Akkermansia muciniphila (A. muciniphila), serves as a key bioactive effector and exhibits promising therapeutic potential for metabolic disorders. This review systematically elucidates the molecular mechanisms by which P9 mediates microbe-host interactions through activation of the intercellular adhesion molecule-2 (ICAM-2) and interleukin-6 (IL-6) signaling pathways. It also summarizes recent advances in P9 biomanufacturing, summarizing advances in its heterologous expression in Escherichia coli (E. coli) and Lactobacillus lactis (L. lactis), and proposes innovative delivery strategies using engineered probiotics or nanocarriers to bypass gastrointestinal barriers. In addition, we explore the modular structure of P9 proteins predicted by AlphaFold, revealing potential domains amenable to functional optimization through protein engineering. By combining mechanistic insights with bioengineering approaches, this review positions engineered P9 as a multifunctional candidate for developing oral, targeted, and sustained-release therapies against obesity and type 2 diabetes mellitus (T2DM). This strategy offers new avenues for linking fundamental gut microbiome research with translational metabolic medicine applications.