Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury
Marie Hanscom, David J. Loane, Terez Shea-Donohue
Marie Hanscom, David J. Loane, Terez Shea-Donohue
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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.

Authors

Marie Hanscom, David J. Loane, Terez Shea-Donohue

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Figure 2

TBI induces significant changes in gut function.

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TBI induces significant changes in gut function. The secondary sequelae ...
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.