Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a chronic and progressive disease, and management requires an understanding of both the primary neurological injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The brain-gut axis is composed of bidirectional pathways through which TBI-induced neuroinflammation and neurodegeneration impact gut function. The resulting TBI-induced dysautonomia and systemic inflammation contribute to the secondary GI events, including dysmotility and increased mucosal permeability. These effects shape, and are shaped by, changes in microbiota composition and activation of resident and recruited immune cells. Microbial products and immune cell mediators in turn modulate brain-gut activity. Importantly, secondary enteric inflammatory challenges prolong systemic inflammation and worsen TBI-induced neuropathology and neurobehavioral deficits. The importance of brain-gut communication in maintaining GI homeostasis highlights it as a viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or systemic inflammation offer the most promise.

Figure 1. Innate immune responses in brain and periphery following traumatic brain injury.

(i) Depending on the severity of traumatic brain injury (TBI), the primary mechanical injury consists of meningeal contusion, axonal shearing, and cerebrovascular injury that leads to meningeal and neuronal cell death and activation of microglia and astrocytes. (ii) Neuronal injury and glial activation generate chemokines, cytokines, and reactive oxygen species (ROS) and release of damage-associated molecular patterns (DAMPs), eliciting an inflammatory response. (iii) When exposed to DAMPs, phagocytic microglia clear debris and produce neurotrophic factors. (iv) Chronic stimulation of these pathways induces secondary injury via recruitment of leukocytes, which initially facilitate clearance of tissue debris but then contribute to progression of inflammation and blood-brain barrier (BBB) breakdown. (v) The ensuing cytotoxic edema and impaired BBB function increase intracranial pressure (ICP) and lead to reduced cerebral blood flow (CBF), amplifying hypoxia to disrupt energy supply in the brain. This causes further neuronal loss and a feed-forward cycle of neuroinflammation and neurodegeneration. (vi) These progressive pathological changes lead to neurological dysfunction and deficits in motor, cognitive, and affective function. TBI also alters the autonomic nervous system (ANS), which is hard-wired to monitor and modulate DAMPs, thereby producing extracerebral and peripheral innate immune responses. (vii) Sympathetic ANS activation results in peripheral release of catecholamines (epinephrine/norepinephrine; E/NE), which suppress systemic immune responses. The vagus stimulates splenic T lymphocytes and inhibits proinflammatory responses of macrophages, via the cholinergic antiinflammatory pathway (CAP) that dampens systemic inflammation. (viii) The release of catecholamines and glucocorticoids via the hypothalamic-pituitary-adrenal (HPA) axis modulates systemic immune cell function after TBI. (ix) TBI can also disrupt systemic cellular defense mechanisms.

Figure 2. TBI induces significant changes in gut function.

The secondary sequelae of TBI in the gut include (i) mucosal damage associated with increased permeability and (ii) malabsorption of nutrients and electrolytes. Enhanced mucosal permeability mobilizes gut defenses, which include increased numbers of activated enteric glial cells culminating in (iii) reactive gliosis and generation of products that promote barrier function and epithelial repair. TBI-induced dysautonomia is characterized by sympathetic dominance, which in combination with the (iv) local release of proinflammatory mediators from resident and recruited immune cells inhibits smooth muscle contraction. These early TBI-induced effects on GI motility include (v) gastroparesis leading to food intolerance. Dysmotility also promotes (vi) changes in microbial composition and (vii) microbial products and metabolites. Compromised barrier function facilitates their passage across the mucosa, leading to activation of (vii) vagal and (ix) spinal afferents that are fundamental to (x) gut-brain communication. A secondary gut challenge such as enteric infection or inflammation prolongs the effects of i–xi and contributes to (xi) levels of circulating inflammatory mediators. Long-lasting systemic inflammation, dysautonomia, and dysbiosis contribute to the chronicity of TBI-induced effects on the gut as well as the increased susceptibility of TBI patients to GI disorders. IECs, intestinal epithelial cells; TJ, tight junctions; AJ, adherens junctions; DS, desmosomes; GJ, gap junctions; GC, goblet cells; EEC, enteroendocrine cells; EGC, enteric glial cells; rEGC, reactive EGC; MM, muscularis mucosae; Th1, T helper cells; CM, circular muscle; EN, enteric neurons; LM, longitudinal muscle.

Figure 3. Bidirectional interactions of the brain-gut axis and therapeutic targets.

The brain and gut communicate through direct (neural) and indirect (systemic) bidirectional pathways. The brain influences GI function through the ANS (sympathetic and vagal efferents), systemic circulation (blood vessels and lymph), and HPA axis. Signals from the gut, including nutrients, mechanical stimuli, and microbiota and their products and metabolites (e.g., short-chain fatty acids), modulate brain function via neural (ENS neurons, glial cells, vagal afferents, spinal afferents), immune (resident and recruited immune cells), and endocrine (hormones released by enteroendocrine cells) mechanisms. TBI-induced GI dysfunction or secondary enteric challenges worsen neurological outcomes by activating local and systemic immune responses that increase BBB permeability and infiltration of activated circulating immune cells and exacerbate ongoing astrocyte- and microglia-mediated neuropathology. The cells and pathways involved in these bidirectional signaling pathways provide viable targets for therapeutic intervention in TBI patients, particularly those with GI comorbidities. Treatments that potentially benefit both the brain and the gut in TBI patients include reduction of sympathetic activation or restoration of vagal tone; use of pre-/probiotics or fecal microbial transplant to correct gut dysbiosis; and suppression of local and systemic proinflammatory immune responses through approved immunosuppressors or emerging nanotherapeutics. EEC, enteroendocrine cells; EGC, enteric glial cells; ICC, interstitial cells of Cajal; SMC, smooth muscle cells.