Modulating effects of creatine prevent sex-dependent hippocampal neuroinflammation, neuronal damage, and electrophysiological dysfunction induced by chronic colitis.

Chronic inflammation in inflammatory bowel disease (IBD) disrupts the gut-brain axis, thereby inducing abnormal immune responses in the brain that are increasingly recognized as a source of neurological comorbidities. In the present work, we investigated the structural integrity and electrophysiological function of hippocampal cornu ammonis 1 (CA1) pyramidal neurons in a rat model of ulcerative colitis induced by dextran sulfate sodium administration. Moreover, given the known neuroprotective properties of the nutraceutical creatine, we aimed to determine whether its oral supplementation prevents or mitigates hippocampal alterations caused by chronic colitis. In both, we also examined the sex differences. Our findings reveal that male rats exhibited a greater colitis-induced hippocampal neuroinflammation, while microglial activation does not differ between sexes. Males developed a markedly altered hippocampal phenotype characterized by significant CA1 neuronal damage, reduced intrinsic excitability reflected by increased rheobase, remodeled inward and outward membrane current profiles and upregulation of a key ion channel such as Kv2.1. In contrast, females displayed a substantially milder phenotype, showing conserved neuronal integrity and electrophysiological properties despite molecular changes including increased Cav1.2. This indicates that the magnitude of hippocampal damage correlates with the severity of colitis-induced neuroinflammation, which differs between sexes. Significantly, creatine supplementation was highly effective in both sexes and prevented colitis-induced hippocampal neuroinflammation, microglial activation, neuronal damage, and electrophysiological dysfunction. The supplementation restored hippocampal creatine levels, preserved neuronal integrity, and normalized impaired excitability. This protective action is exerted only on those parameters altered by colitis, suggesting that the seemingly smaller effect of creatine in females is due to their lower initial pathological burden. Our results indicate a pronounced hippocampal vulnerability of males to chronic colitis and establish creatine as a promising, potent neuromodulator to prevent inflammation-driven brain dysfunction.