Komagataella phaffii KM71H Attenuates Sleep Deprivation–Induced Anxiety and Cognitive Dysfunction via Neuroimmune–Metabolic and Stress-Related Pathways

Sleep deprivation (SD) disrupts emotional regulation and hippocampal-dependent memory through converging neuroimmune, metabolic, oxidative, and neuroendocrine mechanisms. Psychobiotics have emerged as promising strategies to counteract these alterations by modulating the microbiota–gut–brain axis. Komagataella phaffii KM71H has previously demonstrated antidepressant-like and immunometabolic benefits; however, its effects on SD-induced anxiety and cognitive dysfunction remain unexplored. Here, we investigated whether K. phaffii KM71H attenuates behavioral, biochemical, and molecular alterations induced by SD in mice. Male mice received oral K. phaffii KM71H (1 × 10⁸ CFU) or vehicle for 14 days, and SD was induced using the multiple-platform method. Behavioral performance, oxidative stress markers, corticosterone levels, acetylcholinesterase activity, and the expression of neuroimmune and stress-related genes were evaluated in brain and intestinal tissues. Treatment with K. phaffii KM71H prevented the anxiogenic-like phenotype and rescued spatial working memory without affecting locomotion. The yeast reduced reactive species in all evaluated tissues, lowered plasma corticosterone, and normalized acetylcholinesterase activity. Additionally, K. phaffii KM71H downregulated key inflammatory and immune-related markers -indoleamine 2,3-dioxygenase, interleukin-6, nuclear factor kappa-B, and Toll-like receptor 4, as well as glycogen synthase kinase-3β, a regulator of synaptic plasticity, and the glucocorticoid receptor, a component of the HPA axis. Together, these findings identify K. phaffii KM71H as a psychobiotic candidate capable of mitigating SD-induced neurobehavioral dysfunction through coordinated modulation of neuroimmune–metabolic and stress-related pathways, supporting its translational potential for sleep-related neuropsychiatric conditions.