Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis

Vishal Singh, Beng San Yeoh, Benoit Chassaing, Benyue Zhang, Piu Saha, Xia Xiao, Deepika Awasthi, Rangaiah Shashidharamurthy, Madhu Dikshit, Andrew Gewirtz, Matam Vijay Kumar

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background & Aims: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with the extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. Methods: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. Wild-type (WT) and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S ribosomal RNA gene pyrosequencing, and their colitogenic potential by co-housing with interleukin (Il)10KO mice. Acute (dextran sodium sulfate) and chronic (IL10R neutralization and T-cell adoptive transfer) colitis were induced in WT and Lcn2KO mice with or without antibiotics. Results: Lcn2 expression was dramatically induced on inflammation and was dependent on the presence of a gut microbiota and MyD88 signaling. Use of bone marrow-chimeric mice showed that nonimmune cells are the major contributors of circulating Lcn2. Lcn2KO mice showed increased levels of entA-expressing gut bacteria burden, and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T cells and showed exacerbated colitis on exposure to DSS or neutralization of IL10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il10KO mice. Conclusions: Lcn2 is a bacterially induced, MyD88-dependent protein that plays an important role in gut homeostasis and a pivotal role on challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.

Original languageEnglish (US)
Pages (from-to)482-498.e6
JournalCMGH
Volume2
Issue number4
DOIs
StatePublished - Jul 1 2016

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Siderophores
Microbiota
Carrier Proteins
Homeostasis
Colitis
Knockout Mice
Inflammation
Myeloid Differentiation Factor 88
Dysbiosis
16S Ribosomal RNA
Anti-Bacterial Agents
T-Lymphocytes
Lipocalin-2
Dextran Sulfate
Adoptive Transfer
Bacterial Load
Interleukins
rRNA Genes
Interleukin-10
Bone Marrow

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Singh, V., Yeoh, B. S., Chassaing, B., Zhang, B., Saha, P., Xiao, X., ... Kumar, M. V. (2016). Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis. CMGH, 2(4), 482-498.e6. https://doi.org/10.1016/j.jcmgh.2016.03.007
Singh, Vishal ; Yeoh, Beng San ; Chassaing, Benoit ; Zhang, Benyue ; Saha, Piu ; Xiao, Xia ; Awasthi, Deepika ; Shashidharamurthy, Rangaiah ; Dikshit, Madhu ; Gewirtz, Andrew ; Kumar, Matam Vijay. / Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis. In: CMGH. 2016 ; Vol. 2, No. 4. pp. 482-498.e6.
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abstract = "Background & Aims: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with the extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. Methods: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. Wild-type (WT) and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S ribosomal RNA gene pyrosequencing, and their colitogenic potential by co-housing with interleukin (Il)10KO mice. Acute (dextran sodium sulfate) and chronic (IL10R neutralization and T-cell adoptive transfer) colitis were induced in WT and Lcn2KO mice with or without antibiotics. Results: Lcn2 expression was dramatically induced on inflammation and was dependent on the presence of a gut microbiota and MyD88 signaling. Use of bone marrow-chimeric mice showed that nonimmune cells are the major contributors of circulating Lcn2. Lcn2KO mice showed increased levels of entA-expressing gut bacteria burden, and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T cells and showed exacerbated colitis on exposure to DSS or neutralization of IL10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il10KO mice. Conclusions: Lcn2 is a bacterially induced, MyD88-dependent protein that plays an important role in gut homeostasis and a pivotal role on challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.",
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Singh, V, Yeoh, BS, Chassaing, B, Zhang, B, Saha, P, Xiao, X, Awasthi, D, Shashidharamurthy, R, Dikshit, M, Gewirtz, A & Kumar, MV 2016, 'Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis', CMGH, vol. 2, no. 4, pp. 482-498.e6. https://doi.org/10.1016/j.jcmgh.2016.03.007

Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis. / Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit; Zhang, Benyue; Saha, Piu; Xiao, Xia; Awasthi, Deepika; Shashidharamurthy, Rangaiah; Dikshit, Madhu; Gewirtz, Andrew; Kumar, Matam Vijay.

In: CMGH, Vol. 2, No. 4, 01.07.2016, p. 482-498.e6.

Research output: Contribution to journalArticle

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T1 - Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal Homeostasis

AU - Singh, Vishal

AU - Yeoh, Beng San

AU - Chassaing, Benoit

AU - Zhang, Benyue

AU - Saha, Piu

AU - Xiao, Xia

AU - Awasthi, Deepika

AU - Shashidharamurthy, Rangaiah

AU - Dikshit, Madhu

AU - Gewirtz, Andrew

AU - Kumar, Matam Vijay

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Background & Aims: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with the extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. Methods: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. Wild-type (WT) and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S ribosomal RNA gene pyrosequencing, and their colitogenic potential by co-housing with interleukin (Il)10KO mice. Acute (dextran sodium sulfate) and chronic (IL10R neutralization and T-cell adoptive transfer) colitis were induced in WT and Lcn2KO mice with or without antibiotics. Results: Lcn2 expression was dramatically induced on inflammation and was dependent on the presence of a gut microbiota and MyD88 signaling. Use of bone marrow-chimeric mice showed that nonimmune cells are the major contributors of circulating Lcn2. Lcn2KO mice showed increased levels of entA-expressing gut bacteria burden, and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T cells and showed exacerbated colitis on exposure to DSS or neutralization of IL10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il10KO mice. Conclusions: Lcn2 is a bacterially induced, MyD88-dependent protein that plays an important role in gut homeostasis and a pivotal role on challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.

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