A functional immune-based platform for donor-recipient matching in faecal microbiota transplantation for inflammatory bowel disease

Background: Faecal microbiota transplantation (FMT) shows variable efficacy in inflammatory bowel disease (IBD), and current donor selection strategies rely primarily on microbiome characteristics, while host immune responses to donor microbiota remain largely unexplored. Here, we investigated whether recipient-specific immune responses to donor microbiota could be leveraged to develop a personalised donor-recipient matching strategy for FMT in IBD. Methods: We developed a proof-of-concept (POC) assay, termed Gut Microbiota-Leukocyte Reaction (GMLR), to assess immune compatibility between donor microbiota and recipients with IBD. Lamina propria mononuclear cells isolated from intestinal biopsies were exposed ex vivo to microbiota from healthy donors, and cytokines relevant to IBD pathophysiology were measured. Findings: Donor microbiota clustered into distinct groups associated with differential immune signatures, including significant IL-22 induction (p = 0.033), whereas IL-17 showed a non-significant trend toward reduction (p = 0.054) that was not consistently observed across immune cell subsets. However, immune responses were highly individualised across recipients, with substantial inter-patient variability. Based on these responses, we developed an algorithm to generate donor-recipient compatibility scores, providing a framework to prioritise potential donor-recipient pairs. Interpretation: Our findings suggest that donor-recipient immune compatibility is highly personalised and may represent a key determinant of FMT efficacy, challenging the "super-donor" paradigm. This ex vivo proof-of-concept platform may help prioritise donor-recipient pairs and should be prospectively validated against clinical FMT outcomes. Funding: This work was supported by the Italian Ministry of Health, Associazione Italiana per la Ricerca sul Cancro (AIRC), the European Union-NextGeneration EU (HEAL ITALIA project), and the Italian Ministry of Education and Research (MUR).