Clostridioides difficile Infection in Aged Mice Decreases Memory Function, Which Can Be Protected with...

Adults aged >65 face a higher risk of both Clostridioides difficile infection (CDI) and dementia. CDI in the elderly may exacerbate functional and cognitive impairments. Current CDI treatment options are limited. Alanyl-glutamine (AQ) is a dipeptide shown to decrease C. difficile toxin effects in vitro and in vivo.

We tested the potential benefits of AQ on the clinical outcomes and cognitive impairment in the aged mouse model of CDI treated at various timings of AQ and vancomycin treatment.

C57BL/6 retired breeder (9 mo) and aged (18 mo) mice were treated with AQ-supplemented water as a 2-wk pretreatment or continuously. The mice underwent a standard CDI protocol (VPI10463) and were treated, or not, with vancomycin. Disease severity was tracked for 14 d, then novel object recognition (NOR) tests for acute memory were performed. Hippocampal tissues were assayed for molecular markers.

NOR testing confirmed CDI-induced cognitive impairment (P = 0.0352). AQ pretreatment had mild neuroprotective effects during CDI. Mice treated with vancomycin and continuous AQ had better clinical scores and better memory performance than vancomycin controls (P = 0.0286). Continuous AQ treatment, when used alone or paired with vancomycin, offered protection against CDI-induced cognitive impairment. The mechanism of CDI-induced memory impairment remains unclear, but infected mice had elevated synaptobrevin-2 (P = 0.0396) and neural cell adhesion molecule (P = 0.008) compared with uninfected controls on day 14 post infection.

Our findings suggest that neuroinflammation and memory loss occur during CDI, which may be ameliorated by AQ supplementation. AQ supplementation may have both neurological and intestinal protective effects during CDI treatment.