Immunization with Mycobacterium vaccae NCTC 11659, a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, prevents hippocampal inflammation and anxiety-like behavior in rats consuming a high-fat, high-sugar, Western-style diet
Stress-related psychiatric disorders, such as anxiety, mood disorders, and Post-traumatic stress disorder (PTSD), represent a global health burden, affecting 560 million individuals worldwide. Obesity is a risk factor for neuropsychiatric disorders, often driven by Western diets (WD) which promote chronic low-grade immunometabolic inflammation. WD disrupts gut microbial ecology and sensitizes central immune pathways, favoring glial activation and microglial priming even without overt increases in proinflammatory cytokines. WD is also associated with anxiety-related behaviors. Mycobacterium vaccae NCTC 11659, an immunoregulatory saprophytic environmental bacterium has been shown to promote stress resilience and attenuate neuroinflammatory responses. Here, we investigated whether subcutaneous immunization with heat-killed M. vaccae could protect against WD-induced alterations in microbiome-gut-brain axis signaling. Male Wistar rats were fed control diet (CD) or WD for 9 weeks and treated with vehicle or M. vaccae. Microbiome profiling, gene expression analyses in the hippocampus, hypothalamus, and frontal cortex, and behavioral assessments were performed. M. vaccae prevented WD-induced increases in hippocampal biomarkers of microglial priming and astrocyte activation, while attenuating anxiety-related behaviors. These protective effects were observed despite gut dysbiosis, visceral adiposity, and obesity. Together, these findings suggest that M. vaccae promotes resilience and mitigates diet-induced neurobehavioral dysfunction through modulation of the immune-brain-behavior axis.