Signed, sealed, delivered: a generalizable model for living biotherapeutic dosing and metabolism.

Abstract

Living Biotherapeutic Products (LBPs) offer a promising therapeutic strategy for metabolic disorders rooted in gut microbiome dysfunction, yet quantitative frameworks for predicting their efficacy remain underdeveloped. We introduce the Bacterial Compartment Absorption and Transit (BCAT) model, a pharmacokinetic-pharmacodynamic framework that couples probiotic transit, endogenous microbiome metabolism, and enzymatic transformation within a unified dose-optimization setting. Building on the classical CAT model, BCAT incorporates mechanistically-derived colon compartments and treats dosing time as a control variable. We validate BCAT against clinical data for native choline metabolism and SYNB1618 probiotic trials, achieving 5% mean prediction error compared to ~30% for prior two-compartment models. Applying BCAT to trimethylaminuria (TMAU), we predict that ~10 9 CFU of engineered probiotic, administered 3-4 h before meals, achieves 95% reduction in systemic trimethylamine, matching healthy hepatic clearance. Global sensitivity analysis identifies enzyme expression level as the dominant design parameter, enforcing the broad applicability of this model. The BCAT framework generalizes to any gut microbiome-mediated metabolic disorder and provides quantitative dosing targets to guide live biotherapeutic development.