FIGURE 1.

Purported model of gut-brain axis in healthy and injured brain. Depicted in figure is the bidirectional exchange between the brain and the gut in both a healthy state and injured state. In normal functioning, the brain’s neuroendocrine control of the gut through the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis via the Vagus Nerve releases molecules such as acetylcholine and corticotropin-releasing hormone (CRH) to modulate enteric functions such as contractility, secretion of digestive enzymes, and immune function. A balanced microbiome with favorable features such as high bacterial diversity and abundance of beneficial taxa of bacteria such as firmicutes and short-chain-fatty-acid (SCFA) producing bacteria, such as Roseburia and Faecalibacterium, will exchange metabolites up the GBA. Gut bacteria produce neurotransmitters, such as serotonin, GABA, and dopamine, and SCFA-producing bacteria release SCFAs, metabolites directly linked to neuronal health and blood-brain-barrier integrity. The gut also is evidenced to modulate brain homeostasis and immune function by its release of macrophages and other white blood cells to aid in immune support. In an injured state, the interplay between the gut-brain is adjusted to meet the energetic changes and inflammation caused by brain injury. After harm is induced by trauma and/or compromised blood supply, the necrotic and injured brain tissue initiates apoptosis and inflammatory pathways that provoke the release of damage associated molecular patterns (DAMPs), cytokines, and other immune cells to trigger the ANS and HPA axis through the vagus nerve as well as sympathetic “stress” neuronal fibers. This injury response by the brain ensues changes to the gut, including microbial composition leading to dysbiosis and the predominance of opportunistic bacteria at the expense of more beneficial taxa, as well as increased gut epithelial barrier permeability. Such changes compromise the integrity of the gut (“leaky gut”), releasing bacteria and its metabolites up the GBA, including lipopolysaccharide (LPS), an endotoxin released from gram-negative bacteria that activates the transmembrane toll-like receptor 4 (TLR4) and initiates an innate immune response that exacerbates neuroinflammation. In addition, immune cells such as macrophages and neutrophils are released from the gut and migrate to the site of injury. While the migration of immune-fighting support can aid in the recovery after brain injury, it often aggravates the brain tissue and leads to delayed parenchymal recovery as well as secondary issues from prolonged inflammation.