<b>Self-aggregating</b> <i> <b>Lactiplantibacillus plantarum</b> </i> <b>enhances type-I interferon responses via the cytosolic sensors NOD2 and cGAS</b>

The gut microbiome plays a critical role in health, disease and immunity. To date, we have access to large datasets describing how the microbial diversity present in the gut correlates with many clinical conditions. However, the microbiome composition is taxonomically complex; influenced by many environmental factors; and variable between individuals and communities, thereby limiting functional and mechanistic insights into the microbiota‒host interactions. We are still unsure of the molecular mechanisms by which gut commensal microbes intrinsically possess to interact with the immune system and induce beneficial responses. This study has addressed this important question by revealing that only certain members of <i>Lactobacillaceae</i>, a bacterial family very well known for its probiotic properties, interact very intimately with macrophages because of their ability to simultaneously overexpress adhesive cell wall proteins and to self-aggregate, leading to significant production of type I interferon (IFN-I) cytokines. IFN-I cytokines are essential to confer protection against viral infections and auto-immune disorders. Specifically, we have proved that this enhanced IFN-I feature is strain-dependent and predominantly driven by cGAS, a molecule that activates the cytosolic sensor STING upon the recognition of bacterial DNA. Furthermore, another cytosolic sensor, NOD2, seems to be an additional stimulus to amplify IFN-I production, suggesting the involvement of successive molecular events for a prominent probiotic response. Our findings provide insight into how specific molecules of probiotic bacteria modulate or stimulate host responses, providing a better understanding of the molecular crosstalk between the microbiome and immune cells.