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Microbial-derived metabolites are the intermediate or end products of bacterial digestion. They are one of the most important molecules for the gut to connect with the brain. Depending on the levels of specific metabolites produced in the host, it can exert beneficial or detrimental effects on the brain and have been linked to several neurodegenerative and neuropsychiatric disorders. However, the underlying mechanisms remain largely unexplored. Insight into these mechanisms could reveal new pathways or targets, resulting in novel treatment approaches targeting neurodegenerative diseases. We have reviewed selected metabolites, including short-chain fatty acids, aromatic amino acids, trimethylamine-N-oxide,  urolithin A, anthocyanins, equols, imidazole, and propionate to highlight their mechanism of action, underlying role in maintaining intestinal homeostasis and regulating neuro-immunoendocrine function. Further discussed on  how altered metabolite levels can influence the gut–brain axis could lead to new prevention strategies or novel treatment approaches to neural disorders.

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population carrying grim outcomes. Their genesis is often multifactorial, with a history of early exposure to xenobiotics like pesticides or diagnostic exposure to ionizing radiation. A holistic molecular insight into their mechanistic induction is still unclear upon single or combinatorial exposure to different toxicants. In the present study, one-month-old C57/BL-6J male mice were treated orally with malathion (MAL) (50mg/kg body wt. for 14 days) and/or a single whole-body radiation (IR) (0.5 Gy) on the 8th day. Post-treatment, behavioral assays were conducted to assess exploratory behavior, memory, and learning. Following sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Differential expression analysis, Gene ontology, and pathway enrichment revealed several common and uniquely altered genes, biological processes, and pathways related to neurodegeneration, synaptic transmission and plasticity, neuronal survival, proliferation, and regulation of neuronal death. Increased astrogliosis was observed in the IR and co-exposure groups, with significant neuronal cell death and reduction in the expression of NeuN in all three groups. Sholl analysis and dendritic arborization/ spine density study revealed decreased total apical neuronal path length and dendritic spine density in all three groups. Decreased levels of antioxidant enzymes GST and GSH and acetylcholinesterase enzyme activity were also detected. However, there were no changes in exploratory behavior or learning and memory. Thus, explicating the molecular mechanisms behind MAL and IR can provide novel insights into the genesis of environmental factor-driven neurodegenerative pathogenesis.

Pelvic radiotherapy is the endorsed course of treatment for pelvic malignancies, which frequently cover pelvic primary tumor lesions as well as non-cancerous lymphatic drainage sites in the pelvic area. As a result, pelvic irradiation may indiscriminately cause harm to healthy tissues and organs in the pelvic area in individuals undergoing treatment. Some studies suggest that gut microbial dysbiosis can be correlated with the incidence of radiation-induced toxicities in cancer patients. Since, the consequences were earlier thought to be solely due to the targeted or non-targeted effect of radiation, the role of gut microbiota in the non-targeted effects of radiation and the mechanistic role of the gut-brain axis in the pelvic irradiation scenario is not well explored. Hence, the current study was carried out to explore implication of gut dysbiosis in behavioral and neuronal changes induced by pelvic irradiation. 3-4-month-old Sprague Dawley rats were given a single dose of 6 Gy pelvic irradiation. Fecal samples of control and treated mice were collected at different timepoints to assess microbial abundance and diversity using 16S rRNA-based metagenomic sequencing. Behavioral analysis, histological analysis of intestine, brain and gene expression analysis of brain hippocampus was performed to ascertain the indirect impact of microbial dysbiosis on cognition. Following pelvic irradiation, significant microbial dysbiosis and behavioral alterations were observed with distinct changes in the microbial diversity and a significant decline in the locomotor effect and anxiety level at each time point following radiation. Histological analysis revealed a significant reduction in villus distortion as well as a significant decrease in neuronal cells, matured neurons, and an increase in reactive astrocytes, suggesting that pelvic irradiation promotes neuroinflammation. Gene expression analysis revealed a significant reduction in neural plasticity. Altogether, this study demonstrated that gut dysbiosis caused by pelvic irradiation alters behavior, intestinal morphology, integrity, and brain neuronal maturation, as well as lowers the levels of neural plasticity expression. Current study provides evidence for the influence of gut dysbiosis on pelvic irradiation induced cognitive impairment in a rat model.

Neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, are major global health concerns and are linked to xenobiotic exposure. The rampant use of pesticides and increased number of radiological examinations can lead to neuronal alterations in the brain through oxidative stress and DNA damage. Understanding the impact of co-exposure to these agents can help identify interaction effects, enhance risk assessment, address vulnerable populations, and uncover long-term cumulative impacts that remain largely unknown. Therefore, in the current study, we aimed to explore the isolated and combined effects of low-dose radiation and malathion in the mouse brain. Mice were administered malathion (50 mg/kg) orally for 14 days, and a single whole-body low-dose radiation (0.5 Gy) on the 8th day. Five months post-exposure, behavioural, histological, enzymatic, and metabolomic analyses were carried out. Increased neuroinflammation and impaired neuronal maturation were observed in all treated groups, with neuronal death observed exclusively in the radiation group and persistent oxidative damage and acetylcholinesterase inhibition were identified in the malathion group. Additionally, the co-exposure group exhibited synergistic reductions in alpha-linoleic acid and linoleic acid metabolism, phosphatidylcholine biosynthesis, phospholipid biosynthesis, and sphingolipid metabolism within the hippocampus. Increased anxiety and reduced exploration were most pronounced in the co-exposure group, followed by the radiation group. This study provides insights into the effects of co-exposure to neurotoxicants such as low-dose radiation and malathion, revealing synergetic neuronal damage and dysregulated amino acid and lipid metabolism in the mouse hippocampus, and identifies metabolomic signatures enabling biomarker discovery and carries potential implications for the progression of neurodegeneration due to delayed systemic effects.

Recent years have witnessed a drastic upsurge in neurological disorders, with sporadic cases contributing more than ever to their cause. Radiation exposure through diagnostic or therapeutic routes often results in neurological injuries indicative of neurodegenerative pathogenesis. Nevertheless, the impact of low doses of radiation on the brain remains a subject of extensive discussion, as research findings have presented conflicting evidence regarding potential harm and benefits. In the present study, C57/BL mice were exposed to a whole-body single dose of 0.5 Gy X-ray. Fourteen days after treatment, the animals were euthanized, and the hippocampus was isolated and processed for metabolomic analysis. Statistical and bioinformatic analysis revealed 115 metabolites altered in the radiation-exposed group, while pathway enrichment analysis unveiled alterations in tyrosine, phenylalanine, aminoacyl-tRNA metabolism, arginine biosynthesis, glutathione, arginine, proline metabolism, etc. Furthermore, a multiomics interaction network of the genes and the metabolites was constructed to gather an overview of their interaction with the neighboring genes and metabolites in different pathways. These metabolic pathways correlate with synthesizing neurotransmitters such as dopamine and neurodegenerative diseases such as Alzheimer's, Parkinson's, and dementia. The present study findings unveiled metabolomic level regulation of low-dose radiation-induced neurotoxicity and its implication in the pathogenesis of neurological disorders.Competing Interest StatementThe authors have declared no competing interest.