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

Microbiome

Ying Huang¹  James G. Fox²  Zeli Shen²  Ryan Kelly³  Jordan Gringauz³  Jeffrey Saltzman³  Jared Barends³  Kaiyue Peng⁴  Sandra M. Frei⁵  Amlan Biswas⁵  Yu Hui Kang⁵  Rohini Emani⁵  Bin Bao⁵  Naresh S. Redhu⁵  Bruce H. Horwitz⁶  Scott B. Snapper⁷  Jeremy A. Goettel⁸  Amy M. Tsou⁹  Jonathan N. Glickman^1,10  Gregory G. Putzel^1,11  Mai Hatazaki^1,11 

[1] Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China;Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Division of Emergency Medicine, Boston Children’s Hospital, Boston, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, NY, USA;Division of Pediatric Gastroenterology and Nutrition, Weill Cornell Medical College, New York, NY, USA;Harvard Medical School, Boston, MA, USA;Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA;Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, NY, USA;

关键词: Intestinal inflammation;    Wiskott-Aldrich syndrome;    Immune dysregulation;    Gut microbiota;    Defined consortium;    Pathobiont;   

DOI  :  10.1186/s40168-021-01161-3

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWas−/− 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.ConclusionsThese 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.EtQioPqacpXxmFoWy2LpqYVideo abstract

【 授权许可】

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