Microbiota-derived SCFAs Promote Chronic Neurogenesis and Anti-inflammatory Gene Expression after Traumatic Brain Injury (P1-6.008)

Abstract

<h3>Objective:</h3> To evaluate whether short-chain fatty acids (SCFAs) will benefit the long-term recovery of traumatic brain injury (TBI) in mice. <h3>Background:</h3> SCFAs, including acetate and butyrate, are the main metabolites generated by gut microbiota consuming dietary fiber in the colon. SCFAs have pleotropic effects throughout the body including influences on immunity and neurogenesis. We hypothesized that SCFAs could influence recovery from TBI. <h3>Design/Methods:</h3> Adult C57BL6/J mice (n=4/group) were randomized to standard high-amylose maize starch (HAMS) chow or acetylated- and butyrylated-HAMS (HAMS-AB). Fermentation of HAMS-AB by gut bacteria releases acetate and butyrate in the intestinal lumen. The controlled cortical impact (CCI) model of TBI (6m/s, 2.2mm depth, 50msec dwell) was performed. Sham mice received anesthesia and skin incision without craniotomy. At 6 months post-injury, mice were sacrificed and single-cell mRNA from pericontusional tissue sequenced following the 10X Genomics protocol. After pre-processing by <i>CellRanger</i> and SCT normalization by <i>Seurat</i>, cells were annotated based on canonical markers. Cell subtype gene modules were clustered by weighted gene co-expression network analysis (WGCNA) and enriched at gene-ontology (GO) pathways. The GO pathway and regulon activity were evaluated by <i>AUCell</i> and <i>SCENIC</i> respectively. <h3>Results:</h3> In a total of 116,134 cells, consisting of 12 cell types, from 3 groups (41,509 from sham_control, 36,409 from injury_control, 38,216 from injury_SCFA,) passed the quality control and doublet filtering. Both the cell composition and transcriptome were different in each group. SCFAs decreased gene expression associated with neuronal activity and increased the immature neuron frequency. During immature neuron differentiation, SCFAs downregulated neurodegenerative disease-related genes expression in injured mice. In addition, SCFAs decreased chronic microglia/macrophage activation and promoted an M2-like phenotype. Lastly, SCFAs attenuated T cell activation and cytotoxic-related pathways. <h3>Conclusions:</h3> SCFAs impact gene expression in multiple cell types at 6 months after TBI. The pathways affected suggest a beneficial role for gut-derived SCFA administration for recovery after TBI. <b>Disclosure:</b> Dr. Xiong has nothing to disclose. Mrs. Nelson has nothing to disclose. Mr. Sneiderman has nothing to disclose. Ms. Feldman has nothing to disclose. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Johns Hopkins Health System. The institution of Patrick M. Kochanek, MD, MCCM has received research support from Chuck Noll Foundation. The institution of Patrick M. Kochanek, MD, MCCM has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received publishing royalties from a publication relating to health care. Dr. Rajasundaram has nothing to disclose. Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. An immediate family member of Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Legal fees. The institution of Dr. Jha has received research support from NIH/NINDS, Chuck Noll Foundation, University of Pittsburgh, Barrow Neurological Foundation. The institution of Dr. Kohanbash has received research support from NIH. Dr. Simon has nothing to disclose.