Exploiting Ruminococcus gnavus and Limosilactobacillus reuteri to strengthen host immunity and treat infections

Abstract

While millions of years of coevolution between the host and intestinal microbiota have fostered a predominantly symbiotic relationship, the intestinal epithelium is tasked with balancing immune tolerance and anti-pathogen immunity. One way in which the mucosal epithelium maintains healthy host-microbiota interactions is by producing antimicrobial peptides (AMPs). Epithelium-derived AMPs represent an evolutionarily ancient defense mechanism against pathogens. Reg3, the archetypal intestinal antimicrobial peptide, is critical for maintaining host–microbe interactions. Expression of Reg3 is known to be regulated by the microbiota through two different pathways, though it remains unknown whether specific Reg3-inducing bacteria act via one or both of these pathways. In recent work, we identified Ruminococcus gnavus and Limosilactobacillus reuteri as commensal bacteria able to induce Reg3g expression. As discussed in more detail in Chapter 2, we found that R. gnavus and L. reuteri require Myd88 and group 3 innate lymphoid cells (ILC3s) for induction of Reg3. Interestingly, R. gnavus and L. reuteri suppress Reg3 in the absence of either Myd88 or ILC3s. Additionally, we demonstrated that colonization by these bacteria is not required for induction of Reg3, which occurs several days after transient exposure to the organisms. Chapter 3 begins to investigate the protective nature of R. gnavus and L. reuteri against clinically significant antimicrobial-resistant pathogens. Herein, we demonstrate that vancomycin-resistant enterococcal (VRE) infection is limited after treatment with either organism. Taken together, our results highlight the use of microbiota-based therapies to modulate favorable immune responses in combating antimicrobial resistant infections.