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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 symbiontBacteroides thetaiotaomicronexerts its immunomodulatory functions. Our data reveal thatB. thetaiotaomicronstimulates 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 theB. thetaiotaomicronencoded NQR complex, which regenerates NAD+ during respiration, in this process. Finally, we found that disruption of NQR reduces the capacity ofB. thetaiotaomicronto 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.Key pointsTheB. thetaNQR complex coordinates OMV-driven TLR2-dependent IL-10 expression.