The NQR pathway regulates the immunomodulatory function ofBacteroides thetaiotaomicron

Abstract

AbstractThe gut microbiome and intestinal immune system are engaged in a dynamic interplay that provides myriad benefits to host health. However, the microbiome also has the capacity to elicit damaging inflammatory responses, and thus the establishment of harmonious immune-microbiome interactions is essential to maintain homeostasis. Gut microbes actively coordinate the induction of anti-inflammatory immune responses that establish and sustain these mutualistic interactions. Despite this, the microbial pathways that govern this dialogue remain poorly understood. We investigated the mechanisms through which the gut symbiontBacteroides thetaiotaomicron(B. theta), a known modulator of intestinal immune function, exerts its immunomodulatory functions. Our data reveal thatB. thetastimulates production of the cytokine IL-10 in a Toll-like receptor 2 dependent manner, independent of its known capsular polysaccharides. This process depends on an intact NQR pathway, which regenerates NAD+ during respiration. Deletion ofnqrgenes significantly reduces the capacity ofB. thetato induce IL-10 by impairing biogenesis of outer membrane vesicles. These data identify a microbial pathway that may be targeted to intentionally manipulate the immunomodulatory capacity of the microbiome.