Neurodegenerative diseases are characterized by neuronal impairment and loss of function, and with the major shared histopathological hallmarks of misfolding and aggregation of specific proteins inside or outside cells. Some genetic and environmental factors contribute to the promotion of the development and progression of neurodegenerative diseases. Currently, there are no effective treatments for neurodegenerative diseases. It has been revealed that bidirectional communication exists between the brain and the gut. The gut microbiota is a changeable and experience-dependent ecosystem and can be modified by genetic and environmental factors. The gut microbiota provides potential therapeutic targets that can be regulated as new interventions for neurodegenerative diseases. In this review, we discuss genetic and environmental risk factors for neurodegenerative diseases, summarize the communication among the components of the microbiota-gut-brain axis, and discuss the treatment strategy of fecal microbiota transplantation (FMT). FMT is a promising treatment for neurodegenerative diseases, and restoration of the gut microbiota to a premorbid state is a novel goal for prevention and treatment strategies.

Environmental exposure to elevated manganese (Mn) levels is significantly associated with neurocognitive deficits, attracting widespread attention, yet its underlying mechanisms remain incompletely defined. Ferroptosis is recognized as a crucial contributor to cognitive impairments. Our study demonstrates that Mn exposure activates the cGAS-STING pathway, mediating reactive oxygen species (ROS) generation and subsequently inducing apoptosis and ferroptosis. Mechanistically, Mn-induced cGAS-STING activation promotes oxidative stress, characterized by increased ROS and malondialdehyde (MDA) production, alongside diminished glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Furthermore, this activated pathway triggers apoptosis by mediating ROS-dependent alterations in Bax/Bcl-2 expression and Cytochrome C (Cyt C) release from mitochondria. In addition, excessive activation of the cGAS-STING pathway drives ROS accumulation, which impairs iron homeostasis and induces ferroptosis by regulating the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), and acyl-CoA synthetase long-chain family member 4 (ACSL4). Critically, inhibition of either the cGAS-STING pathway or ROS significantly ameliorated Mn-induced oxidative stress, apoptosis, and ferroptosis. Overall, these findings establish that cGAS-STING pathway activation mediates ROS production, leading to apoptosis and ferroptosis, as an essential mechanism of Mn neurotoxicity. Consequently, targeting the cGAS-STING pathway or ROS represents a promising therapeutic strategy for mitigating Mn neurotoxicity.

Neurotoxicity can cause a range of symptoms and disorders in humans, including neurodegenerative diseases, neurodevelopmental disorders, nerve conduction abnormalities, neuroinflammation, autoimmune disorders, and cognitive deficits. The cyclic guanosine-adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway and NF-κB pathway are two important signaling pathways involved in the innate immune response. The cGAS-STING pathway is activated by the recognition of intracellular DNA, which triggers the production of type I interferons and pro-inflammatory cytokines, such as tumor necrosis factor, IL-1β, and IL-6. These cytokines play a role in oxidative stress and mitochondrial dysfunction in neurons. The NF-κB pathway is activated by various stimuli, such as bacterial lipopolysaccharide, viral particle components, and neurotoxins. NF-κB activation may lead to the production of pro-inflammatory cytokines, which promote neuroinflammation and cause neuronal damage. A potential interaction exists between the cGAS-STING and NF-κB pathways, and NF-κB activation blocks STING degradation by inhibiting microtubule-mediated STING transport. This review examines the progress of research on the roles of these pathways in neurotoxicity and their interrelationships. Understanding the mechanisms of these pathways will provide valuable therapeutic insights for preventing and controlling neurotoxicity.

Heavy metal pollution has become a global health challenge. Exposure to heavy metals represents a major health risk. Manganese (Mn) is an essential trace element but also an environmental pollutant. Mn exposure can induce neurotoxicity and lead to neurodegenerative disease. Inflammation and Tau hyperphosphorylation are prominent hallmarks of neurodegenerative diseases induced by Mn exposure. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway can induce powerful innate immune defense programmes and has emerged as a key mediator of inflammation. In recent years, Mn²⁺ has been found to be the second activator of the cGAS-STING pathway in addition to double-stranded DNA (dsDNA). NLRP3 activation is upstream of Tau pathology, and NLRP3 activation induces Tau hyperphosphorylation and aggregation. Mn exposure-induced neurotoxicity may be associated with excessive activation of the cGAS-STING signaling pathway, leading to inflammation. The cGAS-STING/NLRP3 axis may be a promising option for revealing the mechanisms of neurotoxicity of Mn exposure in the future.

Among all types of pollution, heavy metals are considered the greatest threat to human health, and heavy metals are associated with an increased risk of cardiovascular disease, coronary heart disease and neurodegenerative disorders. Manganese (Mn) exposure is well reported to exert neurotoxicity and various neurodegenerative disorders, but the mechanisms are not clear. The gut microbiota plays a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities. The changes in chemical signaling, metabolism and gut microbiota associated with Mn exposure have provided deeper insight into the neurotoxic mechanism of Mn. We observed that Mn exposure increases host manganic bioaccumulation, and β-amyloid (Aβ), receptor-interacting protein kinase 3 (RIP3) and caspase-3 production in the brain, and causes hippocampal degeneration and necrosis. Mn exposure led to decreased gut bacterial richness, especially for Prevotellaceae, Fusobacteriaceae and Lactobacillaceae. In addition, Mn exposure altered the metabolism of tryptamine, taurodeoxycholic acid, β-hydroxypyruvic acid and urocanic acid. Meanwhile, we found correlations between the abundance of certain bacterial species and the level of tryptamine, taurodeoxycholic acid, β-hydroxypyruvic acid and urocanic acid. Fecal microbiome transplantation from normal rats could alleviate the neurotoxicity of Mn exposure by shaping the gut microbiota. Our findings highlight the role of gut dysbiosis-promoted neurotoxicity in Mn exposure and suggest a novel therapeutic strategy of remodeling the gut microbiota.