Komagataella pastoris KM71H attenuates cognitive deficits and depressive-like behavior by the TLR4/NF-κB signaling pathway in an Aβ 1-40 -induced AD-like mouse model

Komagataella pastoris is a promising probiotic for modulating the microbiota-gut-brain axis, and growing evidence has demonstrated the relevance of this axis in the pathophysiology of neurological and psychiatric disorders, such as Alzheimer disease (AD) and major depressive disorder. This study investigated the ameliorated cognitive impairment and antidepressive-like effect of K. pastoris treatment on an AD-like mouse model induced by amyloid β ₁₋₄₀ peptide (Aβ ₁₋₄₀ ). Behavioral tests revealed that Aβ ₁₋₄₀ administration (400 pmol/mouse, icv) increased immobility time in the tail suspension test, decreased spatial and working memory, and increased the time animals took to reach the chocolate cookies, and these behavioral changes were attenuated by the K. pastoris KM71H treatment (8 log CFU ^− 1 /mouse, ig). Biochemical changes also occurred as the applied protocol decreased reactive species and lipid peroxidation in the hippocampi and small intestine and reduced NRLP3, TLR4, Nfҡb, and IL-1β expression in the small intestine of mice. We believe that the ameliorated cognitive impairment and antidepressant effects of K. pastoris KM71H are due to its antioxidant activity and the modulation of the TLR4/NF-κB pathway, and our findings led us to conclude that K. pastoris KM71H is a promising therapeutic strategy for treating Alzheimer disease and major depressive disorder.