Abstract
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-κB 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-κB 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.
Highlights
The microbiota is well established as a major regulator of immune development and functional maturation[1,2,3,4]
Identification of potent immunostimulatory commensals from the human microbiota To understand the impact of different commensal taxa on immunity, we cultured a broad panel of organisms from the major phyla from the human intestinal microbiota: the Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria[6]
We chose macrophages as a model because in vivo these cells are heavily influenced by signals from the microbiota[26], they are positioned within tissues at the interface with the microbiota[27], and express a broad complement of pattern recognition receptors (PRRs)[28]
Summary
The microbiota is well established as a major regulator of immune development and functional maturation[1,2,3,4]. The most significant microbiota colonizing humans, in terms of microbial mass, species diversity and influence on immunity, is found within the intestine[5]. The intestinal microbiota is dominated by commensal bacteria from two phyla: the Firmicutes and the Bacteroidetes, with species from the Actinobacteria and Proteobacteria phyla comprising the majority of the remaining species[5,6]. While the collective ability of these organisms to regulate immunity has been thoroughly investigated, the individual contributions of different commensal species within the microbiota to the regulation of immunity is poorly understood [1,7,8]. Delineating the immunostimulatory properties of different commensal species will allow rational approaches to microbiota reengineering to combat disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
