Microbial production of short-chain fatty acids attenuates long-term neurologic impairment after traumatic brain injury
Document Type
Article
Abstract
BACKGROUND: Traumatic brain injury (TBI) triggers persistent gut microbiome dysbiosis characterized by depletion of short-chain fatty acid (SCFA)-producing bacteria. However, the link between SCFA depletion and long-term neurologic impairment (LTNI) after TBI remains unclear. Previously, we and others noted the involvement of metabolite-sensing receptors and SCFA ligands in mouse models of neurodegenerative diseases, including Alzheimer's. Here, we further investigated SCFA-mediated neuroprotection in LTNI at both microbiome and single-cell resolution using the controlled cortical impact (CCI) model of TBI with a high-yielding SCFA diet to examine their mechanistic role in pathogenesis. METHODS: C57BL6/J mice were randomized to CCI (6 m/s, 2 mm) or sham surgery. Following surgery, mice were randomized to a study diet based on a balanced modification of the AIN93-G diet containing either 15% high amylose maize starch (HAMS) control diet or acetylated and butyrylated HAMS (HAMSAB) for 6 months to model increased SCFA production by bacterial fermentation in the gut. Morris water maze test and nesting assessment were performed at 1, 3, and 6 months after injury. The longitudinal gut microbiome changes were investigated by 16 S rRNA amplicon and metagenomic sequencing of fecal pellets at baseline, 1 month, and 6 months post-injury. At 6 months, pericontusional tissue was collected for single-cell RNA-sequencing following the 10X Genomics protocol or histologic analysis. RESULTS: Compared to the HAMS control diet, HAMSAB diet remodeled the CCI murine gut microbiome at an early phase, increased various SCFA-producing taxa, and attenuated neurologic deficits up to 6 months after CCI. In mice fed HAMSAB diet, single-cell transcriptomics and pathway analysis identified the promotion of neurogenesis, including increased doublecortin-positive immature neurons. In myeloid cells, HAMSAB induced an anti-inflammatory phenotype, inhibiting pro-inflammatory signaling interaction such as midkine signaling, and promoted differentiation to disease-associated microglia (DAM). Simultaneously, SCFAs reduced neurodegenerative pathway activity in neurons and glial cells and reduced phosphorylated tau deposition in pericontusional cortex. CONCLUSIONS: Diet-facilitated microbial production of acetate and butyrate attenuates behavioral deficits of LTNI after TBI and produces enduring benefits at the single-cell level on the neuro-inflammatory and neuro-progenitor responses. This therapeutic approach could have a broader potential to prevent neurodegenerative disease.
Medical Subject Headings
Animals; Brain Injuries, Traumatic (metabolism, complications); Mice; Mice, Inbred C57BL; Fatty Acids, Volatile (metabolism, biosynthesis); Gastrointestinal Microbiome (physiology); Male
Publication Date
12-9-2025
Publication Title
Journal of neuroinflammation
E-ISSN
1742-2094
Volume
22
Issue
1
First Page
285
PubMed ID
41366428
Digital Object Identifier (DOI)
10.1186/s12974-025-03615-z
Recommended Citation
Xiong, Zujian; Dodson, Brittany P.; Rogers, Matthew B.; Sneiderman, Chaim T.; Janesko-Feldman, Keri; Vagni, Vincent; Manole, Mioara; Li, Xuejun; Rajasundaram, Dhivyaa; Clark, Robert S.; Raphael, Itay; Morowitz, Michael J.; Mariño, Eliana; Kochanek, Patrick M.; Jha, Ruchira M.; Kohanbash, Gary; and Simon, Dennis W., "Microbial production of short-chain fatty acids attenuates long-term neurologic impairment after traumatic brain injury" (2025). Neurology. 2035.
https://scholar.barrowneuro.org/neurology/2035