Name
Microbiota-derived indole metabolites inhibit rotavirus infection in vitro, in vivo, and in humans
Presenter
Vanessa Harris, Amsterdam University Medical Centers
Co-Author(s)
Nurul I Wirusanti1*, Yannick van Schajik2*, Jongchan Kim1, Jo Frempong3,4, Nagina Simkhada1, Sydney Fisher1, Nicholas Pucci5, Goncalo Piedade1, Charlie C Luchen1,6, Mwelwa Chibuye1,6, Michelo Simuyandi6, Caroline Chisenga6, Sasirekha Ramani7, Megan T Baldridge3,4, Adithya Sridhar8,9+, Katja Wolthers8+, Bruno Sovran 2,9,10+, Vanessa C Harris1
1 Department of Global Health (AIGHD), Amsterdam University Medical Center, Academic Medical Center, Amsterdam, the Netherlands; 2 Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, Amsterdam, the Netherlands; 3 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; 4 Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; 5 Department of Medical Microbiology and Infection Control, Amsterdam University Medical Center, Amsterdam, the Netherlands; 6 Enteric Disease and Vaccine Research Unit, Center for Infectious Disease Research in Zambia, Lusaka, Zambia; 7 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA; 8 OrganoVIR Labs, Department of Medical Microbiology, Amsterdam University Medical Center, Amsterdam, the Netherlands; 9 Emma Children’s Hospital, Department of Pediatric Infectious Diseases, Amsterdam University Medical Center, The Netherlands; 10 Department of Pediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Abstract Category
Vaccines
Abstract
Rotavirus (RV) remains the leading cause of severe gastroenteritis and diarrheal deaths in children from low-and middle-income countries, necessitating novel treatment strategies tailored for this population. We have previously shown that gut microbiota composition can alter RV infection and vaccine immunogenicity. Mechanistically, the gut microbiota may modulate RV infection through the production of microbial-derived metabolites. Of particular interest is the microbial metabolism of dietary tryptophan produces indole metabolites, essential for gut barrier functions and immune regulation. Disruptions in microbiota composition can shift tryptophan metabolism from microbiota-derived indole pathway toward the host-derived kynurenine pathway.
In the present study, we uncovered the association between microbiota-derived indole metabolites and protection against RV infection. In an adult discovery cohort, following antibiotic treatment and RV vaccine challenge, individuals with fecal RV vaccine shedding (n=20) exhibited a lower relative abundance of microbiota-derived indole-3-acetic acid (IAA) compared to those without RV shedding (n=43). This was confirmed in a Zambian infant cohort, where RV-positive infants (n=35) had significantly lower IAA levels than their RV-negative (n=35) counterparts. In vitro, IAA pre-treatment reduced RV replication in both adult and infant human intestinal enteroids. RNA-seq analysis suggested that this suppression is mediated by the aryl hydrocarbon receptor (AhR) pathway, a key regulator of gut immunity and barrier function. In vivo, AhR agonist supplementation (indole-3-carbinol) significantly reduced fecal RV shedding in mice. This study serves as a proof-of-principle that microbiota-derived metabolites can be leveraged as a novel treatment strategy in RV disease treatment and prevention.
In the present study, we uncovered the association between microbiota-derived indole metabolites and protection against RV infection. In an adult discovery cohort, following antibiotic treatment and RV vaccine challenge, individuals with fecal RV vaccine shedding (n=20) exhibited a lower relative abundance of microbiota-derived indole-3-acetic acid (IAA) compared to those without RV shedding (n=43). This was confirmed in a Zambian infant cohort, where RV-positive infants (n=35) had significantly lower IAA levels than their RV-negative (n=35) counterparts. In vitro, IAA pre-treatment reduced RV replication in both adult and infant human intestinal enteroids. RNA-seq analysis suggested that this suppression is mediated by the aryl hydrocarbon receptor (AhR) pathway, a key regulator of gut immunity and barrier function. In vivo, AhR agonist supplementation (indole-3-carbinol) significantly reduced fecal RV shedding in mice. This study serves as a proof-of-principle that microbiota-derived metabolites can be leveraged as a novel treatment strategy in RV disease treatment and prevention.