Human milk oligosaccharides reduce necrotizing enterocolitis induced-neuroinflammation and cognitive impairment in mice

Autor: Chhinder P. Sodhi, Raheel Ahmad, William B. Fulton, Carla Lopez, Benjamin Eke, Daniel Scheese, Johannes Duess, Steven Steinway, Zachariah Raouf, Hannah Moore, Koichi Tsuboi, Maame Sampah, Hee-Seong Jang, Rachael H. Buck, David R. Hill, Grace M. Niemiro, Thomas Prindle, Sanxia Wang, Meghan Wang, Hongpeng Jia, Jonathan Catazaro, Peng Lu, David J. Hackam
Rok vydání: 2023
Předmět:
Zdroj: American Journal of Physiology-Gastrointestinal and Liver Physiology.
ISSN: 1522-1547
0193-1857
DOI: 10.1152/ajpgi.00233.2022
Popis: Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality in premature infants. One of the most devastating complications of NEC is the development of NEC-induced brain injury, which manifests as impaired cognition that persists beyond infancy, and which represents a pro-inflammatory activation of the gut-brain axis. Given that oral administration of the human milk oligosaccharides (HMOs) 2'-fucosyl lactose (2'-FL) or 6'-sialyslactose (6'-SL) significantly reduced intestinal inflammation in mice, we now hypothesize that oral administration of these HMOs will reduce NEC-induced brain injury, and sought to determine the mechanisms involved. We now show that the administration of either 2'-FL or 6'-SL significantly attenuated NEC-induced brain injury, reversed myelin loss in the corpus callosum and midbrain of newborn mice, and prevented the impaired cognition observed in mice with NEC-induced brain injury. In seeking to define the mechanisms involved, 2'-FL or 6'-SL administration resulted in a restoration of the blood-brain barrier in newborn mice, and also had a direct anti-inflammatory effect on the brain as revealed through the study of brain organoids. Metabolites of 2'-FL were detected in the infant mouse brain by Nuclear Magnetic resonance (NMR), whereas intact 2'-FL was not. Strikingly, the beneficial effects of 2'-FL or 6'-SL against NEC-induced brain injury required the release of the neurotrophic factor BDNF, as mice lacking BDNF were not protected by these HMOs from the development of NEC-induced brain injury. These findings reveal that the HMOs 2'-FL or 6'-SL interrupt the gut-brain inflammatory axis and reduce the risk of NEC-induced brain injury.
Databáze: OpenAIRE
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