Is Manganese the Root Cause of Human Mental Disorders?

Mental health disorders are increasing globally and emerging as a leading public health challenge. The etiology of mental disorders is traditionally attributed to a complex interplay of genetic predispositions and social behaviors. Here, we challenge this view and propose that environmental contamination -- specifically, exposure to manganese (Mn) -- is a critical, yet overlooked, driver for the occurrence of mental disorders. Mn is widely used in various aspects of our lives, such as Mn steel for urbanization, agricultural fertilizer, electronic vehicle batteries, and mobile phone. Through laboratory experiments, we demonstrated that Mn exposure slightly enhanced the bacterial stress sensitivity, evidenced by altered gene expression in two-component systems and their Mn(II) oxidation function. Therefore, we hypothesized that cosmopolitan environmental Mn could increase the stress sensitivity of urban airborne microbiomes. Through comparative analysis of downloaded airborne microbiome datasets from eight cities, we found that urbanization levels show a significant positive correlation with the stress sensitivity of airborne microbiomes. Given that airborne particles can enter the human body and potentially impact health, we hypothesized that increased stress sensitivity in airborne microbiomes may influence the human gut microbiome, thereby contributing to mental disorders. To test this, we analyzed two publicly available metagenomic datasets of human gut microbiomes from both mental disorder patients and healthy controls. However, limited differences in stress sensitivity were observed between the groups, partly due to the lack of RNA-seq data for more precise functional profiling. Based on these findings, we propose a pathway linking environmental Mn exposure to increased stress sensitivity in the airborne microbiome, potentially inducing mental disorders.