HIV-1 Tat-induced diarrhea drives a glial inflammatory reaction to the central nervous system associated with a significant cognitive decline.

Acquired immunodeficiency syndrome (AIDS)-associated gastrointestinal and cognitive dysfunctions are complications related to HIV infection that significantly increase the morbidity and mortality1. HIV-1 Trans activating factor protein (Tat), by inducing mucosal damage, may reach the nerve part of the gut, the enteric nervous system (ENS), affecting its functions and resulting in a secretory diarrhea2. Since in the central nervous system (CNS) the glial cells are directly involved in mediating neurotoxic effects induced by HIV-1 Tat3, the possible role played by enteric glial cells (EGCs) to trigger and spread an HIV-1 Tat-induced neuroinflammatory response throughout the “gut-brain” axis was investigated.We tested our hypothesis that enteric glia is involved in HIV-1 Tat-induced diarrhea and cognitive dysfunctions to verify: (I) how the activation of the enteric glia modulates the diarrhea;(ii) if EGC-activation is localized at the intestinal level or it is associated with a signaling to the CNS; (iii) what is the pathway by which HIV-1 Tat signaling propagates from the periphery to the brain; (iv) if these events correlate with cognitive impairment. In eight-weeks-old Wistar male rats, HIV-1 Tat peptide (100 ng/ml) was injected into the lumen of the animal colon at day 1. In a subset of animals, HIV 1-Tat was administered immediately after lidocaine topic application in a single dose (0.03% w/v). In another group of animals, a single dose of bisacodyl (20 mg/Kg) was administrated orally by gavage. Animals were euthanatized at different time points (7, 12, 14 and 21 days) depending upon the scheduled experimental plan, and colon, thoracic and cervical spinal cord and brain were isolated to perform immunofluorescence, in situ hybridization and biochemical/molecular analyses.  Finally, we investigated the memory skills of treated rats by the object recognition test. Our study demonstrates that a single colonic application of HIV-1 Tat induces an acute diarrhea that is at least partially modulated by the activation of glia cells in the submucosal plexus. This local response is able to trigger and activate glia cells in the spinal cord and brain cortex through the expression of Cx43, that results in an inflammatory reaction in the brain and that is associated with a significant cognitive decline in treated rats.