Not by (Good) Microbes Alone: Towards Immunocommensal Therapies

Commensal bacteria have been identified as critical drivers of host resilience to pathogen invasion. The resulting 'competitive exclusion' of pathogens by commensals can arise via multiple mechanisms, including direct competition for sites of colonization, production of metabolic products that inhibit pathogen growth, and modulation of host immune responses (including differential targeting of pathogens). Nonetheless, suppression of pathogens through the combined action of commensals and host immunity is far from inevitable. Here, we utilize a simple, within-host ecosystem model to explore the microbiological and immunological conditions that govern the fate of pathogen colonization. Model analysis leads to the hypothesis that robust elimination of pathogens requires a synergy between host immune defense and commensal bacteria. That is, pathogens can proliferate and establish persistent infections if either the state of the microbiota or the host immune defense falls below critical levels. Leveraging these findings, we advocate for improved integration of nonlinear dynamic models in efforts to understand infection dynamics in an immunological context. Doing so may provide new opportunities to establish baseline indicators for healthy microbiomes and to develop improved therapeutics through targeted modification of feedback amongst commensals and between commensals and the immune system.