Gulf War Illness (GWI) is a chronic condition marked by unexplained neurological and gastrointestinal symptoms affecting Gulf War Veterans. They experience cognitive deficits, chronic fatigue, neuroinflammation in combination with gut dysbiosis. It is, therefore, suspected that altered gut-brain signaling plays a prominent role in GWI. Cholecystokinin (CCK) A receptor-containing vagal afferent neurons (VANs) are emerging as important mediators of the gut-brain axis, making them potential targets for understanding GWI pathophysiology. Having validated deafferentation of inflammatory signaling via gut afferents using the CCK-SAP method, we subjected 70 mice to bilateral nodose ganglia (NG) injection with either CCK-SAP or sham treatment (BLANK-SAP). Vagal deafferentation in CCK-SAP mice was verified as reduced number of Cckar-expressing VANs in NG vs Blank-SAP treated mice using RNA in situ hybridization. Each group received either GW agents (GW) or vehicle plus stress (CON/S). Mice were tested on cognitive and exercise behavior tests at approximately post treatment (PT) day 60, 90, and 190. Deficits caused by GW agents on a novel object recognition (NOR) memory test, on which normal VEH/CON mice show enhanced exploration of novel objects (p< 0.05-0.01), could be completely mitigated in treated GW mice (p< 0.05-0.01). Habituation during a 1 hr exploration of an open field arena, observed in VEH/CON (p< 0.05-0.01) but not GW mice, was not improved in GW+CCK-SAP mice. On a passive avoidance test vagal deafferentation appeared to improve associative learning since the average group latency to enter the dark aversive chamber was apparently greater in GW+CCK-SAP vs GW-SAP group (p< 0.1). On a passive wheel running test GW agents reduced overall daily activity indicating reluctance to engage in locomotor activity; vagal deafferentation provided slight normalization. The phenotypic differences in GW mice were supported by enhanced astrogliosis measured in hippocampal CA1 subfield vs CON/S. In contrast, latency to exhaustion on an exercise endurance test revealed an apparent reduction (tire faster) in both GW-SAP and GW-CCK-SAP groups as compared to CON/S. Using Echo MRI at PT193 GW mice displayed reduced fat mass (p=0.06) compared to CON/S, and this was further reduced in GW+CCK-SAP mice (p< 0.001), suggesting an altered metabolic profile produced by combined GW agent exposure and vagal deafferentation. Together, these results provide novel mechanistic information on the role of gut-brain axis in GWI pathophysiology and of potential therapeutic benefit provided by vagal deafferentation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Kozlova et al. (2026) studied this question.