Traumatic brain injury (TBI)-related neurodegeneration (TReND) is increasingly recognized as a major health
concern and cause of cognitive decline. Neuroinflammation, a proposed mechanism of TReND, may persist for
years after the primary injury. We propose that chronic intestinal dysbiosis after TBI, specifically the depletion of
“healthy” commensal bacteria capable of fermenting dietary fiber to produce the short chain fatty acid (SCFA)
acetate, leads to a maladaptive state of the microbiome-gut-brain axis. Microbially-derived acetate is the most
abundant SCFA in the gut, enters the circulation, and is critical to brain and immune function. Depletion of
acetate-producing bacteria is a consistent finding in critically ill humans and corresponding murine models.
Restoration of depleted bacteria or their metabolites has the potential to reverse dysbiosis-associated
phenotypes. Through a unique collaboration between internationally recognized centers for TBI and microbiome
research, The Safar Center for Resuscitation Research, The Center for Medicine and the Microbiome, and the
Neurotrauma Clinical Trials Center at the University of Pittsburgh, and The Biomedical Discovery Institute at
Monash University, we have generated exciting data which demonstrates (1) depletion of acetate-producing
bacterial populations in the gut after severe TBI in patients and controlled cortical impact (CCI) TBI in mice, (2)
a marked reduction in fecal acetate after CCI, (3) progressive and sustained disruption of commensal bacteria
and acetate production weeks after injury, (4) repletion in drinking water or a dietary strategy to target gut
microbiota to deliver SCFAs is protective. Thus, we propose a translational study to discover if TReND and
chronic neuroinflammation after TBI is fueled by depletion of commensal bacteria and deficient fermentation of
dietary fiber. In Aim 1, we will address the hypothesis that deficiency of microbially-derived acetate contributes
to TReND up to 6 months from injury. We will employ CCI in male and female mice and compare untreated
controls (acetate deficient) to mice repleted using acetylated-fiber or gavage of acetate-producing bacteria.
Assessments of lesion volume, memory, surviving neurons, and brain energy metabolism will be performed. Gut
microbiome structure and function and acetate level in brain tissue, serum, and feces will be analyzed. In Aim
2, we will determine whether deficiency of acetate promotes chronic microglial activation and polarization to a
tissue-destructive phenotype as assessed by immunohistochemistry and RNA-Seq. In Aim 3, we will address
the hypothesis that TBI results in a reproducible, progressive, and sustained decrease in gut derived acetate.
We will perform an observational study of adults with moderate and severe TBI. Clinical information including
injury severity, antibiotics, diet, and neurologic outcome will be collected for secondary outcomes. Identifying a
role of stable alterations to the gut microbiome and robust effects of a promising and translatable therapy,
acetate, as a therapeutic target in humans by four highly complementary research centers will establish
disruption of the microbiome-gut-brain axis as a TReND mechanism and provide a foundation for clinical trials.
