Intestinal microbiota modulates neuroinflammatory response and brain injury after neonatal hypoxia-ischemia

ABSTRACT

Premature infants lack a normal intestinal microbial community and also at risk of perinatal hypoxic-ischemic (HI) brain injury, which is considered to be one of the major factors for motor, sensory, and cognitive deficits. We hypothesized that neonatal gut microbiota composition modulated the immune reaction and severity of neonatal H-I brain injury. Neonatal C57BL/6J mouse pups were exposed to H-I protocol consisting of permanent left carotid artery ligation, followed by 8% hypoxia for 60 min. Microbial manipulation groups included 1) antibiotic treatment, E18 (maternal) to P5; 2) antibiotic treatment E18 to P5 + E. coli gavage; 3) antibiotic treatment E18 to P5 + B. infantis gavage; and 4) saline to pups with dams getting fresh water. The extent of brain injury and recovery was measured on MRI. Edematous injury volume was significantly higher in E. coli group than that in B. infantis group and in fresh water group. Gene expression in brains of pro-inflammatory cytokines (IL1β, IL6, IL2, TNF-α and toll-like receptors 2–6) were elevated to a greater extent in the E. coli group at P10, no injury, and at P13, 72 hours after H-I relative to sham control and B. infantis groups. Significant effects of microbiome and brain injury and interaction of these factors were found in abundance of major phyla. The neuroinflammatory response and brain injury after neonatal hypoxia-ischemia are affected by intestinal microbiota, providing opportunities for therapeutic intervention through targeting the early colonization and development of the gut microbiota.

KEYWORDS:

• Gut-brain interaction
• neuroinflammation
• hypoxia-ischemia
• perinatal brain injury

Acknowledgments

D. Gascoigne– review & editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

A. Drobyshevsky, M. Caplan – conceptualization, analysis, writing, S. Synowiec, I. Goussakov, J. Lu, R. Fabres – data acquisition. All authors reviewed the manuscript.

Availability of data and materials

All sequencing data are available on NCBI (bioproject ID: PRJNA1001342).

Ethics approval

The study received approval by the Institutional Animal Care and Use Committee of NorthShore University HealthSystem.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2333808

Additional information

Funding

This study was funded by NIH grants 1R01NS091278-01A1, 1R21NS062367-01A1.