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.
Purpose Radiotherapy is a critical component of cancer treatment, along with surgery and chemotherapy. Approximately, 90% of cancer patients undergoing pelvic radiotherapy show gastrointestinal (GI) toxicity, including bloody diarrhea, and gastritis, most of which are associated with gut dysbiosis. In addition to the direct effect of radiation on the brain, pelvic irradiation can alter the gut microbiome, leading to inflammation and breakdown of the gut–blood barrier. This allows toxins and bacteria to enter the bloodstream and reach the brain. Probiotics have been proven to prevent GI toxicity by producing short-chain fatty acids and exopolysaccharides beneficial for protecting mucosal integrity and oxidative stress reduction in the intestine and also shown to be beneficial in brain health. Microbiota plays a significant role in maintaining gut and brain health, so it is important to study whether bacterial supplementation will help in maintaining the gut and brain structure after radiation exposure. Methods In the present study, male C57BL/6 mice were divided into control, radiation, probiotics, and probiotics + radiation groups. On the 7th day, animals in the radiation and probiotics + radiation groups received a single dose of 4 Gy to whole-body. Posttreatment, mice were sacrificed, and the intestine and brain tissues were excised for histological analysis to assess GI and neuronal damage. Results Radiation-induced damage to the villi height and mucosal thickness was mitigated by the probiotic treatment significantly (p < 0.01). Further, radiation-induced pyknotic cell numbers in the DG, CA2, and CA3 areas were substantially reduced with bacterial supplementation (p < 0.001). Similarly, probiotics reduced neuronal inflammation induced by radiation in the cortex, CA2, and DG region (p < 0.01). Altogether, the probiotics treatment helps mitigate radiation-induced intestinal and neuronal damage. Conclusion In conclusion, the probiotic formulation could attenuate the number of pyknotic cells in the hippocampal brain region and decrease neuroinflammation by reducing the number of microglial cells.
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. Keywords: Malathion, low-dose radiation, organophosphates, hippocampus, co-exposure, behavior, transcriptome
Background: 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. Materials & Methods: 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. Results: 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 villous 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. Conclusion: Current study provides evidence for the influence of gut dysbiosis on pelvic irradiation induced cognitive impairment in a rat model.
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