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Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dys...

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Autores principales: Guijas, Carlos, Horton, Lucy E., Hoang, Linh, Domingo-Almenara, Xavier, Billings, Elizabeth M., Ware, Brian C., Sullivan, Brian, Siuzdak, Gary
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317520/
https://www.ncbi.nlm.nih.gov/pubmed/35888769
http://dx.doi.org/10.3390/metabo12070645
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author Guijas, Carlos
Horton, Lucy E.
Hoang, Linh
Domingo-Almenara, Xavier
Billings, Elizabeth M.
Ware, Brian C.
Sullivan, Brian
Siuzdak, Gary
author_facet Guijas, Carlos
Horton, Lucy E.
Hoang, Linh
Domingo-Almenara, Xavier
Billings, Elizabeth M.
Ware, Brian C.
Sullivan, Brian
Siuzdak, Gary
author_sort Guijas, Carlos
collection PubMed
description The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8(+) T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.
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spelling pubmed-93175202022-07-27 Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression Guijas, Carlos Horton, Lucy E. Hoang, Linh Domingo-Almenara, Xavier Billings, Elizabeth M. Ware, Brian C. Sullivan, Brian Siuzdak, Gary Metabolites Article The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8(+) T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection. MDPI 2022-07-14 /pmc/articles/PMC9317520/ /pubmed/35888769 http://dx.doi.org/10.3390/metabo12070645 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guijas, Carlos
Horton, Lucy E.
Hoang, Linh
Domingo-Almenara, Xavier
Billings, Elizabeth M.
Ware, Brian C.
Sullivan, Brian
Siuzdak, Gary
Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title_full Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title_fullStr Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title_full_unstemmed Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title_short Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
title_sort microbial metabolite 3-indolepropionic acid mediates immunosuppression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317520/
https://www.ncbi.nlm.nih.gov/pubmed/35888769
http://dx.doi.org/10.3390/metabo12070645
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