Bacterial endosymbiont suppresses detoxification through folate-mediated DNA methylation in Nilaparvata lugens

Symbiont-derived metabolites can regulate host physiology, but how they affect xenobiotic detoxification remains poorly understood. Here, we provide evidence that the endosymbiont Arsenophonus nilaparvatae increases insecticide susceptibility in Nilaparvata lugens through a folate-associated DNA methylation pathway. Specifically, A. nilaparvatae enhances folate biosynthesis through metabolic complementation with host alkaline phosphatase, while folate supplementation reduces P450 expression and monooxygenase activity. Metabolomics reveals an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM/SAH). Consistent with this shift, symbiont infection and folate treatment are accompanied by increased NlDNMT3 expression and global 5-methylcytosine (5mC) levels. Moreover, genome-wide and targeted bisulfite analyses identify increased promoter-associated methylation at NlCYP6ER1, coinciding with reduced transcription. Importantly, inhibiting DNA methylation partially reverses these molecular and phenotypic effects. Finally, folate-associated sensitization is observed with high-folate transgenic rice and in other tested insects. Together, these findings support a symbiont-folate-DNA methylation axis regulating host detoxification and suggest folate metabolism as a potential target for insect control.