Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth
Summary: Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight i...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723006915 |
| _version_ | 1797791874634743808 |
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| author | Lisa J. Funkhouser-Jones Rui Xu Georgia Wilke Yong Fu Lawrence A. Schriefer Heyde Makimaa Rachel Rodgers Elizabeth A. Kennedy Kelli L. VanDussen Thaddeus S. Stappenbeck Megan T. Baldridge L. David Sibley |
| author_facet | Lisa J. Funkhouser-Jones Rui Xu Georgia Wilke Yong Fu Lawrence A. Schriefer Heyde Makimaa Rachel Rodgers Elizabeth A. Kennedy Kelli L. VanDussen Thaddeus S. Stappenbeck Megan T. Baldridge L. David Sibley |
| author_sort | Lisa J. Funkhouser-Jones |
| collection | DOAJ |
| description | Summary: Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6 precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impairs host mitochondrial function and reduces total cellular ATP, as well as directly reducing the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole-producing bacteria, delays life cycle progression of the parasite in vitro and reduces the severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites impair mitochondrial function and contribute to colonization resistance to Cryptosporidium infection. |
| first_indexed | 2024-03-13T02:25:02Z |
| format | Article |
| id | doaj.art-59e6a266f8ee48cab18b8af576086baf |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T02:25:02Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-59e6a266f8ee48cab18b8af576086baf2023-06-30T04:21:52ZengElsevierCell Reports2211-12472023-07-01427112680Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growthLisa J. Funkhouser-Jones0Rui Xu1Georgia Wilke2Yong Fu3Lawrence A. Schriefer4Heyde Makimaa5Rachel Rodgers6Elizabeth A. Kennedy7Kelli L. VanDussen8Thaddeus S. Stappenbeck9Megan T. Baldridge10L. David Sibley11Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USADepartment of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USADepartment of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USADepartment of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USADepartment of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USADepartment of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA; Corresponding authorSummary: Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6 precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impairs host mitochondrial function and reduces total cellular ATP, as well as directly reducing the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole-producing bacteria, delays life cycle progression of the parasite in vitro and reduces the severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites impair mitochondrial function and contribute to colonization resistance to Cryptosporidium infection.http://www.sciencedirect.com/science/article/pii/S2211124723006915CP: Microbiology |
| spellingShingle | Lisa J. Funkhouser-Jones Rui Xu Georgia Wilke Yong Fu Lawrence A. Schriefer Heyde Makimaa Rachel Rodgers Elizabeth A. Kennedy Kelli L. VanDussen Thaddeus S. Stappenbeck Megan T. Baldridge L. David Sibley Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth Cell Reports CP: Microbiology |
| title | Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth |
| title_full | Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth |
| title_fullStr | Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth |
| title_full_unstemmed | Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth |
| title_short | Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth |
| title_sort | microbiota produced indole metabolites disrupt mitochondrial function and inhibit cryptosporidium parvum growth |
| topic | CP: Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723006915 |
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