Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

Diego F. Niño; Qinjie Zhou; Yukihiro Yamaguchi; Laura Y. Martin; Sanxia Wang; William B. Fulton; Hongpeng Jia; Peng Lu; Thomas Prindle; Fan Zhang; Joshua Crawford; Zhipeng Hou; Susumu Mori; Liam L. Chen; Andrew Guajardo; Ali Fatemi; Mikhail Pletnikov; Rangaramanujam M. Kannan; Sujatha Kannan; Chhinder P. Sodhi; David J. Hackam

doi:10.1126/scitranslmed.aan0237

Research ArticleGASTROINTESTINAL DISEASE

Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

View ORCID ProfileDiego F. Niño¹,²,
View ORCID ProfileQinjie Zhou¹,²,
Yukihiro Yamaguchi¹,²,
Laura Y. Martin¹,²,
Sanxia Wang¹,²,
View ORCID ProfileWilliam B. Fulton¹,²,
View ORCID ProfileHongpeng Jia¹,²,
Peng Lu¹,²,
Thomas Prindle Jr.¹,²,
View ORCID ProfileFan Zhang³,
Joshua Crawford⁴,
View ORCID ProfileZhipeng Hou⁵,
Susumu Mori⁵,
Liam L. Chen⁶,
Andrew Guajardo⁶,
Ali Fatemi ⁷,
View ORCID ProfileMikhail Pletnikov⁴,⁸,
View ORCID ProfileRangaramanujam M. Kannan ⁹,
Sujatha Kannan ¹⁰,
Chhinder P. Sodhi¹,²,* and
View ORCID ProfileDavid J. Hackam ¹,²,*

¹Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
²Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
³Program of Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁵Department of Biomedical Engineering and The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁶Division of Neuropathology, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁷Departments of Neurology and Pediatrics, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, MD 21205, USA.
⁸Department of Molecular and Comparative Pathobiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21205, USA.
⁹Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁰Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

↵*Corresponding author. Email: dhackam1{at}jhmi.edu (D.J.H.); csodhi{at}jhmi.edu (C.P.S.)

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Science Translational Medicine 12 Dec 2018:
Vol. 10, Issue 471, eaan0237
DOI: 10.1126/scitranslmed.aan0237

Diego F. Niño

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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ORCID record for Diego F. Niño

Qinjie Zhou

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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ORCID record for Qinjie Zhou

Yukihiro Yamaguchi

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Laura Y. Martin

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Sanxia Wang

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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William B. Fulton

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Hongpeng Jia

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Peng Lu

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Thomas Prindle Jr.

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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Fan Zhang

3Program of Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

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Joshua Crawford

4Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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Zhipeng Hou

5Department of Biomedical Engineering and The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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Susumu Mori

5Department of Biomedical Engineering and The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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Liam L. Chen

6Division of Neuropathology, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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Andrew Guajardo

6Division of Neuropathology, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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Ali Fatemi

7Departments of Neurology and Pediatrics, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, MD 21205, USA.

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Mikhail Pletnikov

4Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

8Department of Molecular and Comparative Pathobiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21205, USA.

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Rangaramanujam M. Kannan

9Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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Sujatha Kannan

10Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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Chhinder P. Sodhi

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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For correspondence: dhackam1@jhmi.edu csodhi@jhmi.edu

David J. Hackam

1Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

2Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

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ORCID record for David J. Hackam
For correspondence: dhackam1@jhmi.edu csodhi@jhmi.edu

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The gut-brain conNECtion

Necrotizing enterocolitis (NEC) is a gastrointestinal disorder affecting premature infants. Newborns with NEC often develop cognitive impairments. The mechanisms leading to cognitive disabilities remain unclear. Niño et al. show that increased oxidative stress in the brain triggered NEC-associated cognitive impairments in mice. The release of the proinflammatory molecule high-mobility group box 1 from the injured intestine activated Toll-like receptor 4 on microglial cells in the brain, resulting in accumulation of reactive oxygen species. Oral administration of microglia-targeting antioxidants prevented cognitive impairments in a mouse model of NEC. The results suggest that reducing microglial activation might be a strategy to protect patients from cognitive impairments associated with NEC.

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Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

The gut-brain conNECtion

Science Translational Medicine

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