The NQR Complex Regulates the Immunomodulatory Function of Bacteroides thetaiotaomicron

Abstract

The gut microbiome and intestinal immune system are engaged in a dynamic interplay that provides myriad benefits to host health. However, the microbiome can also elicit damaging inflammatory responses, and thus establishing harmonious immune–microbiome interactions is essential to maintain homeostasis. Gut microbes actively coordinate the induction of anti-inflammatory responses that establish these mutualistic interactions. Despite this, the microbial pathways that govern this dialogue remain poorly understood. We investigated the mechanisms through which the gut symbiont Bacteroides thetaiotaomicron exerts its immunomodulatory functions on murine- and human-derived cells. Our data reveal that B. thetaiotaomicron stimulates production of the cytokine IL-10 via secreted factors that are packaged into outer membrane vesicles, in a TLR2- and MyD88-dependent manner. Using a transposon mutagenesis-based screen, we identified a key role for the B. thetaiotaomicron–encoded NADH:ubiquinone oxidoreductase (NQR) complex, which regenerates NAD+ during respiration, in this process. Finally, we found that disruption of NQR reduces the capacity of B. thetaiotaomicron to induce IL-10 by impairing biogenesis of outer membrane vesicles. These data identify a microbial pathway with a previously unappreciated role in gut microbe–mediated immunomodulation that may be targeted to manipulate the capacity of the microbiome to shape host immunity.

A molecular toolkit for heterologous protein secretion across Bacteroides species

“…These features, together with the predicted size limit and post-secretion distribution that we observed, suggest that unknown lipoprotein transportation, sorting, and secretion systems exist in Bacteroides . Indeed, recent transposon mutagenesis studies in B. theta have revealed novel systems involved OMV production 90,91 , however, whether these systems are involved in lipoprotein sorting and protein packing into OMVs remains unclear and further investigation is required before these mechanisms can be exploited to improve secretion output.…”