Maternal helminths rewire the microbiota to promote offspring antiviral immunity

Maternal environmental exposures can alter microbiome composition and lead to changes in offspring immunity. Industrialization has led to significant shifts in the microbiome, but whether these have transgenerational impacts remains unclear. Here, we discovered that maternal helminths, an evolutionarily conserved mammalian partner lost in industrialized societies, confer broad and lasting protection against respiratory viruses in offspring. This heterologous antiviral immunity is mediated by helminth-induced changes in the maternal microbiota. The tryptophan metabolite indole-3-propionic acid (IPA), derived from helminth-altered microbiota, induces lung epithelial IFN-I responses and is sufficient to protect offspring from respiratory syncytial virus (RSV) and influenza A virus infections. Analysis of chronically helminth-infected human populations reveals gut microbiota enriched for tryptophan metabolic capacity. Additionally, IPA treatment is sufficient to enhance antiviral IFN-I signaling in human bronchial epithelial cells. Collectively, this work uncovers the importance of maternal helminth-driven trans-kingdom crosstalk across generations and highlights microbial metabolites as actionable strategies to strengthen antiviral defense. • Maternal helminths promote offspring antiviral immunity via the microbiota • Helminth-altered microbiota produce IPA, which drives antiviral protection • IPA induces lung epithelial type I interferon responses to promote antiviral immunity • Helminth-endemic human microbiota are enriched in the tryptophan metabolism pathway Fernandes et al. show that maternal helminths, long-standing mammalian partners, confer antiviral immunity to offspring via the microbiota-derived metabolite indole-3-propionic acid (IPA). This work reveals helminth-driven trans-kingdom crosstalk across generations and highlights microbiota-derived metabolites as potential strategies to enhance antiviral defense.