Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation

Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many gene...

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Autores principales:	Amy M. Tsou, Jeremy A. Goettel, Bin Bao, Amlan Biswas, Yu Hui Kang, Naresh S. Redhu, Kaiyue Peng, Gregory G. Putzel, Jeffrey Saltzman, Ryan Kelly, Jordan Gringauz, Jared Barends, Mai Hatazaki, Sandra M. Frei, Rohini Emani, Ying Huang, Zeli Shen, James G. Fox, Jonathan N. Glickman, Bruce H. Horwitz, Scott B. Snapper
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Intestinal inflammation Wiskott-Aldrich syndrome Immune dysregulation Gut microbiota Defined consortium Pathobiont Microbial ecology QR100-130
Acceso en línea:	https://doaj.org/article/5dc4ac88ab5f400b9de6cbbeae362a98
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spelling	oai:doaj.org-article:5dc4ac88ab5f400b9de6cbbeae362a982021-11-07T12:12:25ZUtilizing a reductionist model to study host-microbe interactions in intestinal inflammation10.1186/s40168-021-01161-32049-2618https://doaj.org/article/5dc4ac88ab5f400b9de6cbbeae362a982021-11-01T00:00:00Zhttps://doi.org/10.1186/s40168-021-01161-3https://doaj.org/toc/2049-2618Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was −/− ) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was −/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was −/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was −/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was −/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was −/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was −/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was −/− compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstractAmy M. TsouJeremy A. GoettelBin BaoAmlan BiswasYu Hui KangNaresh S. RedhuKaiyue PengGregory G. PutzelJeffrey SaltzmanRyan KellyJordan GringauzJared BarendsMai HatazakiSandra M. FreiRohini EmaniYing HuangZeli ShenJames G. FoxJonathan N. GlickmanBruce H. HorwitzScott B. SnapperBMCarticleIntestinal inflammationWiskott-Aldrich syndromeImmune dysregulationGut microbiotaDefined consortiumPathobiontMicrobial ecologyQR100-130ENMicrobiome, Vol 9, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Intestinal inflammation Wiskott-Aldrich syndrome Immune dysregulation Gut microbiota Defined consortium Pathobiont Microbial ecology QR100-130
spellingShingle	Intestinal inflammation Wiskott-Aldrich syndrome Immune dysregulation Gut microbiota Defined consortium Pathobiont Microbial ecology QR100-130 Amy M. Tsou Jeremy A. Goettel Bin Bao Amlan Biswas Yu Hui Kang Naresh S. Redhu Kaiyue Peng Gregory G. Putzel Jeffrey Saltzman Ryan Kelly Jordan Gringauz Jared Barends Mai Hatazaki Sandra M. Frei Rohini Emani Ying Huang Zeli Shen James G. Fox Jonathan N. Glickman Bruce H. Horwitz Scott B. Snapper Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
description	Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was −/− ) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was −/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was −/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was −/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was −/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was −/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was −/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was −/− compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract
format	article
author	Amy M. Tsou Jeremy A. Goettel Bin Bao Amlan Biswas Yu Hui Kang Naresh S. Redhu Kaiyue Peng Gregory G. Putzel Jeffrey Saltzman Ryan Kelly Jordan Gringauz Jared Barends Mai Hatazaki Sandra M. Frei Rohini Emani Ying Huang Zeli Shen James G. Fox Jonathan N. Glickman Bruce H. Horwitz Scott B. Snapper
author_facet	Amy M. Tsou Jeremy A. Goettel Bin Bao Amlan Biswas Yu Hui Kang Naresh S. Redhu Kaiyue Peng Gregory G. Putzel Jeffrey Saltzman Ryan Kelly Jordan Gringauz Jared Barends Mai Hatazaki Sandra M. Frei Rohini Emani Ying Huang Zeli Shen James G. Fox Jonathan N. Glickman Bruce H. Horwitz Scott B. Snapper
author_sort	Amy M. Tsou
title	Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
title_short	Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
title_full	Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
title_fullStr	Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
title_full_unstemmed	Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
title_sort	utilizing a reductionist model to study host-microbe interactions in intestinal inflammation
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5dc4ac88ab5f400b9de6cbbeae362a98
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Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation

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