Helminth reshapes host gut microbiota and immunoregulation by deploying an antimicrobial program of innate immunity

Helminths can manipulate their host's gut microbiota, with the expansion of the lactobacilli population being a common feature. This process profoundly influences host immunoregulation, yet the underlying mechanisms remain almost unknown. Using a tissue-dwelling helminth model (larval <i>Echinococcus multilocularis</i>) while validating key findings from other helminth infections, we show that helminths harness the antibacterial program of host innate immunity to transform the host gut microbiome and control gut microbiota-mediated immunity. Using multifaceted techniques, we elucidate that cathelicidin-related antimicrobial peptide (CRAMP), derived from the expanded CD11b⁺CD206⁺ macrophages rather than the intestinal epithelial cells, is the key component that enters into the gut ecological system and enhances the fitness of <i>Lactobacillus</i> by selectively killing gram-negative microbes like enterobacteria. Furthermore, through <i>in vitro</i> cell culturing and <i>in vivo</i> dietary intervention experiments, we demonstrate that this regulation from innate immunity is boosted via toll-like receptor signaling by helminth's secretory products, which could be sufficiently tuned down by dietary vitamin D through its receptor and cyp27b1. Importantly, using microbiota-targeted treatment methods, we prove that this signaling bolsters gut microbiota-mediated host intestinal Foxp3⁺ Treg cell expansion and parasite survival and that therapies targeting this signaling are effective in treating infection. We outline a dietary micronutrient-dependent mechanism by which helminths leverage host innate immunity to edit the host gut microbiome and thereby control immunosuppression precisely.