Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota

ABSTRACT Many studies have demonstrated the importance of the gut microbiota in healthy and disease states. However, establishing the causality of host-microbiota interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced...

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Autores principales:	Allison L. Richards, Michael B. Burns, Adnan Alazizi, Luis B. Barreiro, Roger Pique-Regi, Ran Blekhman, Francesca Luca
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	complex traits gene expression genetics host response host-microbiota interaction Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1b2384dcb70a4a7a84714da723aebaee
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spelling	oai:doaj.org-article:1b2384dcb70a4a7a84714da723aebaee2021-12-02T19:48:49ZGenetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota10.1128/mSystems.00067-162379-5077https://doaj.org/article/1b2384dcb70a4a7a84714da723aebaee2016-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00067-16https://doaj.org/toc/2379-5077ABSTRACT Many studies have demonstrated the importance of the gut microbiota in healthy and disease states. However, establishing the causality of host-microbiota interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiota for human cells and to shed light on the molecular mechanisms underlying host-gut microbiota interactions. In primary human colonic epithelial cells, we identified over 6,000 genes whose expression changed at various time points following coculturing with the gut microbiota of a healthy individual. Among the differentially expressed genes we found a 1.8-fold enrichment of genes associated with diseases that have been previously linked to the microbiome, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host single nucleotide polymorphisms (SNPs) that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiota. Of these 12 genes, 8 have been associated with diseases linked to the gut microbiota, specifically colorectal cancer, obesity, and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiota interactions and can be used to identify putative mechanisms for the interplay between host genetics and the microbiota in health and disease. IMPORTANCE The study of host-microbiota interactions in humans is largely limited to identifying associations between microbial communities and host phenotypes. While these studies have generated important insights on the links between the microbiota and human disease, the assessment of cause-and-effect relationships has been challenging. Although this relationship can be studied in germfree mice, this system is costly, and it is difficult to accurately account for the effects of host genotypic variation and environmental effects seen in humans. Here, we have developed a novel approach to directly investigate the transcriptional changes induced by live microbial communities on human colonic epithelial cells and how these changes are modulated by host genotype. This method is easily scalable to large numbers of host genetic backgrounds and diverse microbiota and can be utilized to elucidate the mechanisms of host-microbiota interactions. Future extensions may also include colonic organoid cultures.Allison L. RichardsMichael B. BurnsAdnan AlaziziLuis B. BarreiroRoger Pique-RegiRan BlekhmanFrancesca LucaAmerican Society for Microbiologyarticlecomplex traitsgene expressiongeneticshost responsehost-microbiota interactionMicrobiologyQR1-502ENmSystems, Vol 1, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	complex traits gene expression genetics host response host-microbiota interaction Microbiology QR1-502
spellingShingle	complex traits gene expression genetics host response host-microbiota interaction Microbiology QR1-502 Allison L. Richards Michael B. Burns Adnan Alazizi Luis B. Barreiro Roger Pique-Regi Ran Blekhman Francesca Luca Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
description	ABSTRACT Many studies have demonstrated the importance of the gut microbiota in healthy and disease states. However, establishing the causality of host-microbiota interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiota for human cells and to shed light on the molecular mechanisms underlying host-gut microbiota interactions. In primary human colonic epithelial cells, we identified over 6,000 genes whose expression changed at various time points following coculturing with the gut microbiota of a healthy individual. Among the differentially expressed genes we found a 1.8-fold enrichment of genes associated with diseases that have been previously linked to the microbiome, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host single nucleotide polymorphisms (SNPs) that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiota. Of these 12 genes, 8 have been associated with diseases linked to the gut microbiota, specifically colorectal cancer, obesity, and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiota interactions and can be used to identify putative mechanisms for the interplay between host genetics and the microbiota in health and disease. IMPORTANCE The study of host-microbiota interactions in humans is largely limited to identifying associations between microbial communities and host phenotypes. While these studies have generated important insights on the links between the microbiota and human disease, the assessment of cause-and-effect relationships has been challenging. Although this relationship can be studied in germfree mice, this system is costly, and it is difficult to accurately account for the effects of host genotypic variation and environmental effects seen in humans. Here, we have developed a novel approach to directly investigate the transcriptional changes induced by live microbial communities on human colonic epithelial cells and how these changes are modulated by host genotype. This method is easily scalable to large numbers of host genetic backgrounds and diverse microbiota and can be utilized to elucidate the mechanisms of host-microbiota interactions. Future extensions may also include colonic organoid cultures.
format	article
author	Allison L. Richards Michael B. Burns Adnan Alazizi Luis B. Barreiro Roger Pique-Regi Ran Blekhman Francesca Luca
author_facet	Allison L. Richards Michael B. Burns Adnan Alazizi Luis B. Barreiro Roger Pique-Regi Ran Blekhman Francesca Luca
author_sort	Allison L. Richards
title	Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
title_short	Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
title_full	Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
title_fullStr	Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
title_full_unstemmed	Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota
title_sort	genetic and transcriptional analysis of human host response to healthy gut microbiota
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/1b2384dcb70a4a7a84714da723aebaee
work_keys_str_mv	AT allisonlrichards geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT michaelbburns geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT adnanalazizi geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT luisbbarreiro geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT rogerpiqueregi geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT ranblekhman geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota AT francescaluca geneticandtranscriptionalanalysisofhumanhostresponsetohealthygutmicrobiota
_version_	1718375946317201408

Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota

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