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.