Metabolomic Changes With Acetate and Butyrate Supplementation After Controlled Cortical Impact

Sunday, February 23, 2025

10:45am – 11:45am Eastern Time

Location: Connections Central Theater 1

Amanda Dave, MD, MS

Children's Hospital of Pittsburgh of UPMC

Disclosure(s): No relevant financial relationship(s) to disclose.
KF

Keri Feldman, n/a

BS
Safar Center for Resuscitation Research

Disclosure information not submitted.
VV

Vincent Vagni, n/a

BS
Safar Center for Resuscitation Research

Disclosure information not submitted.
RC

Robert Clark, MD, FCCM

MD
Childrens Hospital of Pittsburgh of UPMC

Disclosure information not submitted.
Michael J. Morowitz, MD

MD
University of Pittsburgh School of Medicine

Disclosure information not submitted.
Patrick M. Kochanek, MD, MCCM

Distinguished Professor of Critical Care Medicine
UPMC Presbyterian

Disclosure information not submitted.
HB

Hulya Bayir, n/a

MD
n/a

Disclosure information not submitted.
MC

Mona Chatrizeh, n/a

PhD
n/a

Disclosure information not submitted.
JT

Jianmin Tian, n/a

PhD
Children's Hospital of Pittsburgh Department of Surgery

Disclosure information not submitted.
DS

Dennis Simon, MD

Childrens Hospital of Pittsburgh of UPMC

Disclosure(s): No relevant financial relationship(s) to disclose.

Disclosure(s):

Amanda Dave, MD, MS: No relevant financial relationship(s) to disclose.

Dennis Simon, MD: No relevant financial relationship(s) to disclose.

Introduction: Short chain fatty acids (SCFA) are produced by microbial fermentation of dietary fiber and serve as an energy substrate for glial cells through the tricarboxylic acid (TCA) cycle. In the controlled cortical impact (CCI) model of traumatic brain injury (TBI), SCFAs are reduced in the gut after injury and SCFA supplementation is protective and anti-inflammatory. We hypothesized that SCFA supplementation increases production of the potent anti-inflammatory TCA metabolites 2-hydroxyglutarate and itaconate.

Methods: CCI was performed in adult male C57BL6/J mice (6m/s, 2.0mm). Shams received anesthesia and skin incision. Mice (n=7/group) were randomized to SCFA supplemented water (0.067M acetate, 0.047M butyrate) or standard drinking water provided ad libitum 14 days before CCI and continued until sacrifice 7 days post-injury. Relative quantification of TCA metabolites in pericontusional brain tissue was performed using liquid chromatography-mass spectrometry and data were normalized to vehicle treated shams (Sham-Veh). IL-10 levels were analyzed by Meso scale discovery platform.

Results: CCI and SCFA supplementation were associated with multiple changes in TCA metabolites in pericontusional brain tissue. 2-hydroxyglutarate decreased 31% after CCI (Sham-Veh 0.99±0.29 vs. CCI-Veh 0.68±0.22; p< 0.05). SCFA supplementation did not impact 2-hydroxyglutarate levels (CCI-Veh 0.68±0.22 vs. CCI-SCFA 0.83±0.35; p=0.38). Itaconate showed a trend towards lower concentration after CCI (Sham-Veh 0.99±0.14 vs. CCI-Veh 0.87±0.1; p=0.09). SCFA supplementation showed a trend towards increasing itaconate concentration to sham levels (CCI-Veh 0.87±0.1 vs. CCI-SCFA 1.00±0.13; p=0.06). IL-10 increased 25% after CCI (Sham-Veh 0.99±0.19 vs. CCI-Veh 1.24±0.11; p< 0.05) and increased an additional 24% after SCFA supplementation (CCI-Veh 1.24±0.11 vs. CCI-SCFA 1.48 ±0.14; p< 0.01).

Conclusions: In this exploratory study, CCI injury and SCFA supplementation impacted the concentration of anti-inflammatory metabolites 2-hydroxyglutarate and itaconate. The anti-inflammatory cytokine IL-10 was increased after SCFA supplementation. Further studies are needed to confirm these results, delineate the pathway implications, and identify whether this impacts neuroinflammation in response to TBI and neurologic outcomes.