Chronic gut inflammation potentiates place aversion in intrinsic and conditioned contexts.

Chronic inflammation in the body evokes behavioural changes that differ from changes following acute inflammation. These include anxio-depressive-like behaviours, which may serve an adaptive function to mitigate increased existential risk when animals are ill or injured. We test here if chronic gut inflammation induced by dextran sodium sulfate (DSS) promotes contextually-specific avoidance in mice. DSS-treated mice and vehicle-treated mice avoided a testing chamber that was previously paired with a mild foot shock relative to an unpaired contextually-distinct chamber. When animals were tested a second time one week later, mice treated with DSS maintained the same level of aversion to the paired context, whereas vehicle-treated mice reduced their aversion. These results suggest that DSS-treated animals had prolonged aversion to a context previously paired with a negative stimulus. In an open field test, DSS-treated mice exhibited increased aversion to the centre of the arena. Centre aversion correlated with the severity of gut inflammation. These results suggest that chronic gut inflammation enhanced aversion to potentially threatening contexts, both intrinsic and learned. DSS-treated mice also exhibited heterogeneous changes in gene transcript expression in neural structures known to play a role in contextual place avoidance. Expression of the proinflammatory cytokine Il1b mRNA was increased in the nucleus accumbens, and expression of the antioxidant regulator Nrf2 was increased in the anterior cingulate cortex. These transcriptional changes co-occur with the observed behavioural phenotypes and support a growing body of evidence indicating that chronic gut inflammation alters the brain to promote anxiety-like phenomena, which may help account for the high comorbidity of anxiety diseases in people with chronic somatic inflammation.