Microbiota-derived indole metabolites inhibit rotavirus infection in vitro and in vivo and in human infants
Wirusanti, N. I.; van Schajik, Y.; Kim, J.; Frempong, J. F.; Simkhada, N.; Fisher, S.; Pucci, N.; Piedade, G. J.; Luchen, C. C.; Chibuye, M.; Simuyandi, M.; Chisenga, C.; Silwamba, S.; Chibesa, K.; Nzangwa, B. T.; Kuntawala, D. H.; Ramani, S.; Mende, D.; Baldridge, M. T.; Sovran, B.; Harris, V. C.
Show abstract
Rotavirus (RV) is the leading cause of life-threatening gastroenteritis in children under five despite effective RV vaccines availability, necessitating novel protective strategies for high-risk populations. Gut microbiota can modulate RV susceptibility and vaccine immunogenicity, yet underlying mechanisms are poorly characterized. Here, we demonstrate that microbiota-derived indole metabolites confer protection against RV infection. In healthy adults, higher fecal indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) levels associated with reduced fecal RV shedding following challenge. In human intestinal enteroids (HIEs), IAA pre-treatment inhibited human RV Wa G1P[8] replication via the aryl hydrocarbon receptor (AhR) pathway. In mice, treatment with AhR agonist indole-3-carbinol (I3C) significantly reduced fecal shedding of murine RV strain EDIM-Cambridge. Finally, Zambian infants with active RV infection exhibited lower fecal IAA and IPA levels than age-matched healthy controls. These findings demonstrate that microbiota-derived AhR ligands consistently inhibit RV infection across three experimental models and hold promise for protecting at-risk pediatric populations.
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