Dietary lysine deficiency impairs hippocampal-related functions and neurogenesis in rats

Background and Objectives Hippocampal neurogenesis enhances cognitive abilities and can be influenced by various dietary factors. Lysine, an essential amino acid, modulates neuronal activity and synaptic function; however, the impact of dietary lysine deficiency on neurogenesis remains unclear. This study investigated the effects of moderate and severe lysine deficiency on cognitive function, hippocampal neurogenesis, and gut microbiota composition in rats.Methods Adolescent male Sprague–Dawley rats were assigned to three groups for four weeks: sham (adequate lysine), moderate (30%) lysine deficiency, or severe (60%) lysine deficiency. Body composition, body weight, and food intake were monitored weekly. Bromodeoxyuridine was administered at different time points to assess the proliferation and maturation phases of neurogenesis. Fecal samples were collected at the end of the study, and microbiota composition was characterized by 16S rRNA gene sequencing targeting the V3–V4 regions.Results Body composition parameters were significantly impaired in the 60% lysine-deficient groups. Behavioral assessments showed that severe lysine deficiency was associated with altered anxiety-like and cognitive-related behaviors. Neurogenesis assessment revealed that both moderate and severe lysine deficiency reduced hippocampal neural stem cell proliferation, whereas differentiation was impaired only under severe deficiency. At the microbiota level, the 60% lysine-deficient group also showed the most pronounced alterations in gut microbial community composition, including reduced Lactobacillus species.Conclusion Severe lysine deficiency was associated with impaired hippocampal neurogenesis, altered behavior, and gut microbiota composition, suggesting a potential gut-brain axis involvement, although causality remains to be established.