Coexist or eliminate? Antibody-based functional silencing versus eradication in gut microbiome- targeted therapy

Dominant anti-infective strategies equate therapeutic success with pathogen eradication, yet in the gut most clinically relevant "pathogens" are pathobionts that cause disease only under specific ecological conditions. Antibiotics resolve infection but decimate commensal communities and select for resistance.

We review antibody-based interventions, native mucosal antibodies (IgA, IgM), monoclonal antibodies, and immunoglobulin Y (IgY), as mechanistic test cases for a functional silencing paradigm, in which pathobiont virulence is attenuated through non-bactericidal mechanisms while preserving community architecture.

Drawing on randomized trial data (bezlotoxumab in Clostridioides difficile recurrence prevention, MODIFY I/II, n = 2,655), preclinical and early clinical IgY studies in enteric infections, and long-term IgY deployment in aquaculture, we find that functional silencing delivers durable benefit when disease is driven by discrete virulence factors. However, evolutionary risks, including phase variation, conformational switching, and the theoretical framework of "imperfect immunity", identify conditions under which retained pathobionts may re-emerge as threats.

Eradication and functional silencing are best understood as complementary strategies whose optimal deployment depends on host immune status, barrier integrity, and the nature of pathobiont virulence. Defining the boundary between safe coexistence and evolutionary rebound constitutes the field's central unresolved challenge.