Abstract
Hosts must control symbiont abundance to ensure stable associations with their beneficial microbes, while also minimizing potentially harmful unrestricted microbial proliferation. Yet, the microbial stimuli and involved host responses that shape this colonization control, are usually unknown, in spite of their central role in shaping host-microbe and, more broadly, host-microbiota interactions. Here, using the natural association between Caenorhabditis elegans and its symbiont Pseudomonas lurida MYb11, we combine an unbiased bacterial genetic screen with a host response reporter to identify the biosurfactant massetolide as a key regulator of host-microbe interaction. Our subsequent host functional genetic analyses revealed that massetolide triggers host TGF-beta and serotonergic signaling to promote intestinal peristalsis, limiting colonization. Indeed, massetolide deficiency enhances colonization, while its presence specifically facilitates serotonin-dependent expulsion. Together, our findings reveal a symbiont-derived biosurfactant that links host neuroimmune control of intestinal peristalsis with bacterial susceptibility to expulsion, coupling host and microbial physiology to regulate symbiont abundance.