Personalized Gut-Liver Microphysiological System Maps Donor-Specific Tissue-Resident Immunity and Reveals a Conserved Metabolic Crosstalk.

Tissue-resident immune (TRI) niches are unique to tissues and greatly vary between individuals. We built a personalized gut-liver microphysiological system (MPS) to recapitulate these profiles, combining primary colon epithelium, hepatocytes, and autologous CD45⁺ TRI cells of two donors. Single-cell RNA-seq of colon and liver revealed distinct TRI profiles and predicted responses distinct between donors. Co-culture established organ and donor-specific immune programs: colonic epithelium induced Th1/Th17 polarization in Donor 1 but B cell differentiation in Donor 2. Gut-liver crosstalk in all donors converged on a retinoid-bile acid metabolic axis with a muted inflammatory set-point, indicating that circulating metabolites can override baseline immune differences. Microbial agonist challenges of gut compartments revealed distinct liver responses: Poly(I:C) induced a uniform type-I/III interferon burst, LPS triggered a stronger response in Donor 1, and 5-OP-RU selectively activated Donor 2. Our personalized, immune-competent gut-liver MPS demonstrates that a conserved metabolic dialogue coexists with and is modulated by TRI profiles. This work provides a blueprint for exploring immunometabolic diseases and precision therapeutics in multi-organ models reflecting human immune diversity.