A helminth-microbiota metabolic relay promotes disease tolerance

Persistent infection by helminths requires limiting inflammatory damage despite incomplete pathogen clearance, yet how helminths mobilize resident microbiota to establish this state remains unclear. Here we identify a cross-kingdom metabolic relay through which Trichinella spiralis promotes systemic disease tolerance. Infection selectively expanded Ligilactobacillus murinus and redirected microbial tryptophan metabolism toward indole-3-lactic acid (ILA), a direct ligand of the aryl hydrocarbon receptor (AhR). Antibiotic perturbation abrogated ILA production, AhR activation and Treg-Th17 remodeling, whereas transfer of helminth-conditioned fecal preparations or supplementation with L. murinus or ILA restored these responses. Pharmacological inhibition or genetic deletion of AhR eliminated the protection conferred by T. spiralis, L. murinus and ILA against endotoxin-induced lung injury. In lethal SARS-CoV-2 infection, oral ILA improved survival and limited pulmonary immunopathology without reducing viral burden, thereby uncoupling host protection from pathogen control. In a human COVID-19 cohort, ILA relative abundance remained inversely associated with IFN-γ after adjustment for available clinical covariates. These findings reveal that helminths can reprogram commensal metabolism to govern systemic immune tolerance and identify microbial ILA production as a tractable postbiotic strategy for limiting inflammatory tissue damage.