Immunological Design Of Commensal Communities To Treat Intestinal Infection And Inflammation

Author summaryThe symbiotic bacteria that colonize the human intestine are major regulators of the immune system. While the collective ability of these organisms to shape immune function is clear the individual impact of different symbionts on immunity is poorly delineated. To address this, we have systematically characterized the immunological properties of an extensive panel of commensals from the major taxa in the human intestinal microbiota. We have uncovered the unique complement of pattern recognition receptors, intracellular signaling components and transcription factors through which each symbiotic species exerts their effect on the innate immune system. This allowed us to identify, for the first time, taxonomic patterns of commensal regulation of immunity and uncover a unique role for canonical NF-kappa B signaling in acting as a rheostat calibrating the degree of immune stimulation symbionts elicit. We used the immunological profiles of these symbionts to guide the construction of therapeutic symbiont communities to combat both AMR infection and pathological intestinal inflammation. Previously, harnessing the power of symbiotic microbes to combat disease was largely a trial-and-error process, and predicting how changes in microbiota composition will impact immunity was almost impossible. Our study addresses both of these challenges and provides a unique scientific resource to guide the rational design of symbiotic microbial communities to treat myriad diseases and reveals how loss of different symbionts will impact host health.The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-kappa B signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-kappa B signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation.