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The Role of Gut Microbiota-Derived Butyrate in Inflammation and Neurological Outcomes after Neonatal Hypoxic-Ischemic Encephalopathy

Award Number: K08HD120866
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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The Role of Gut Microbiota-Derived Butyrate in Inflammation and Neurological Outcomes after Neonatal Hypoxic-Ischemic Encephalopathy - PROJECT SUMMARY Neonatal hypoxic-ischemic encephalopathy (nHIE) is a leading cause of pediatric neurodevelopmental disabilities worldwide. Therapeutic hypothermia, the only treatment, must be initiated within six hours of birth, is limited to specialized centers, and primarily targets acute inflammation. Chronic inflammation, driven by T- lymphocytes in the periphery and microglia in the brain, persists for years, hindering brain development. Targeting chronic inflammation presents a unique opportunity to improve long-term nHIE outcomes. The gut microbiota plays a critical role in shaping the immune system, with its metabolites like butyrate promoting anti-inflammatory immune responses. My preliminary studies using the Rice-Vannucci model of nHIE showed a significant decline in short-chain fatty acid-producing bacteria, including butyrate producers, which persisted for 5 months post-injury. Butyrate is lower in the stool and brain of mice with brain injury compared to controls, suggesting that chronic butyrate deficiency may drive persistent inflammation. Fecal microbiota transplantation (FMT) from healthy mice reversed anxiety and hyperactivity in nHIE mice, while FMT from nHIE mice induced depressive behavior in naïve recipients. I will define how gut microbiota-derived butyrate modulates both peripheral and central inflammation, enhancing regulatory T cell maturation and promoting an anti-inflammatory microglial polarization, ultimately improving long- term outcomes after nHIE. In Aim 1: I will determine how chronic gut microbiota alterations following nHIE affect neurological outcomes. We will use FMT and shotgun metagenomics to assess microbial changes and correlate butyrate levels with behavioral outcomes. In Aim 2, I will analyze how butyrate modulates peripheral inflammation by promoting Treg maturation. We will combine FMT, butyrate administration, and Treg depletion (using DEREG mice) to assess systemic inflammatory responses. In Aim 3, I will determine how butyrate influences central inflammation and microglial activation. We will use butyrate treatment and microglia depletion (in Tmem119-DTR mice) to assess microglial phenotypes and inflammatory markers in the brain, correlating these with outcomes. This K08 award will close key knowledge gaps in 1) integrative analysis of the gut-brain axis, 2) immune modulation in brain injury, and 3) laboratory team leadership skills. These short-term goals will equip me to integrate microbiota, immune, and brain research into an independent program aimed at developing novel treatment strategies for nHIE.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $162,000 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	1	5/1/2026	NEW	$0
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	3/27/2026	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $162,000

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The Role of Gut Microbiota-Derived Butyrate in Inflammation and Neurological Outcomes after Neonatal Hypoxic-Ischemic Encephalopathy

Award Number: K08HD120866

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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