Cargando…

Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations

Numerous studies of knockout mice find impacts on microbiota composition that influence host phenotype. However, such differences can vanish when KO mice are compared directly to WT littermates, suggesting these differences do not reflect the genetic deletion per se but microbiota composition drifti...

Descripción completa

Detalles Bibliográficos
Autores principales: Viennois, Emilie, Pujada, Adani, Sung, Junsik, Yang, Chunhua, Gewirtz, Andrew T., Chassaing, Benoit, Merlin, Didier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374158/
https://www.ncbi.nlm.nih.gov/pubmed/32694535
http://dx.doi.org/10.1038/s41522-020-0137-y
_version_ 1783561635673145344
author Viennois, Emilie
Pujada, Adani
Sung, Junsik
Yang, Chunhua
Gewirtz, Andrew T.
Chassaing, Benoit
Merlin, Didier
author_facet Viennois, Emilie
Pujada, Adani
Sung, Junsik
Yang, Chunhua
Gewirtz, Andrew T.
Chassaing, Benoit
Merlin, Didier
author_sort Viennois, Emilie
collection PubMed
description Numerous studies of knockout mice find impacts on microbiota composition that influence host phenotype. However, such differences can vanish when KO mice are compared directly to WT littermates, suggesting these differences do not reflect the genetic deletion per se but microbiota composition drifting over generations. Hence, our hypothesis that absence of di/tri-peptide transporter PepT1 altered microbiota composition resulting in resistance to colitis compelled scrutiny. In this study, we used PepT1(−/−) and WT founder mice bred separately for multiple generations. Such mice were then bred to each other to generate F1 PepT1(−/−) and WT littermates, which were then bred within their genotype to generate F2, F3, and F4, offspring. Here we report that founder PepT1(−/−) mice were, relative to their WT counterparts, resistant to DSS colitis. Such resistance was associated with alterations in gut microbiota, which, when transplanted to germfree mice, was sufficient to transfer resistance to colitis. Such differences were not observed when comparing F1 PepT1(−/−) to F1 WT littermates but rather, returned gradually over subsequent generations such that, relative to their F4 WT controls, F4 PepT1(−/−) displayed microbiota composition and colitis-resistant phenotype nearly identical to the founder PepT1(−/−) mice. Our findings indicate a role for PepT1 in influencing microbiota composition and, consequently, proneness to colitis and cancer. Overall, our study indicates that littermate-controlled experiments can be insufficient for assessing microbiota-dependent phenotypes and prevent a full comprehension of genotype-driven phenomena. Rather, impact of a single genetic alteration on microbiota and host phenotype may take generations to manifest.
format Online
Article
Text
id pubmed-7374158
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-73741582020-07-24 Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations Viennois, Emilie Pujada, Adani Sung, Junsik Yang, Chunhua Gewirtz, Andrew T. Chassaing, Benoit Merlin, Didier NPJ Biofilms Microbiomes Article Numerous studies of knockout mice find impacts on microbiota composition that influence host phenotype. However, such differences can vanish when KO mice are compared directly to WT littermates, suggesting these differences do not reflect the genetic deletion per se but microbiota composition drifting over generations. Hence, our hypothesis that absence of di/tri-peptide transporter PepT1 altered microbiota composition resulting in resistance to colitis compelled scrutiny. In this study, we used PepT1(−/−) and WT founder mice bred separately for multiple generations. Such mice were then bred to each other to generate F1 PepT1(−/−) and WT littermates, which were then bred within their genotype to generate F2, F3, and F4, offspring. Here we report that founder PepT1(−/−) mice were, relative to their WT counterparts, resistant to DSS colitis. Such resistance was associated with alterations in gut microbiota, which, when transplanted to germfree mice, was sufficient to transfer resistance to colitis. Such differences were not observed when comparing F1 PepT1(−/−) to F1 WT littermates but rather, returned gradually over subsequent generations such that, relative to their F4 WT controls, F4 PepT1(−/−) displayed microbiota composition and colitis-resistant phenotype nearly identical to the founder PepT1(−/−) mice. Our findings indicate a role for PepT1 in influencing microbiota composition and, consequently, proneness to colitis and cancer. Overall, our study indicates that littermate-controlled experiments can be insufficient for assessing microbiota-dependent phenotypes and prevent a full comprehension of genotype-driven phenomena. Rather, impact of a single genetic alteration on microbiota and host phenotype may take generations to manifest. Nature Publishing Group UK 2020-07-21 /pmc/articles/PMC7374158/ /pubmed/32694535 http://dx.doi.org/10.1038/s41522-020-0137-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Viennois, Emilie
Pujada, Adani
Sung, Junsik
Yang, Chunhua
Gewirtz, Andrew T.
Chassaing, Benoit
Merlin, Didier
Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title_full Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title_fullStr Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title_full_unstemmed Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title_short Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations
title_sort impact of pept1 deletion on microbiota composition and colitis requires multiple generations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374158/
https://www.ncbi.nlm.nih.gov/pubmed/32694535
http://dx.doi.org/10.1038/s41522-020-0137-y
work_keys_str_mv AT viennoisemilie impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT pujadaadani impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT sungjunsik impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT yangchunhua impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT gewirtzandrewt impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT chassaingbenoit impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations
AT merlindidier impactofpept1deletiononmicrobiotacompositionandcolitisrequiresmultiplegenerations