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Extracellular Vesicles from probiotics mediated Walnut green husk polysaccharide alleviates ochratoxin-A-induced cognitive impairment via SCFA and 5-HT mediated microbiota-gut-brain axis

ABSTRACT:

BACKGROUND: Ochratoxin A (OTA) have made it a serious hazard to food safety worldwide that poses a serious health risk to humans. Our previous research showed that Walnut green husk polysaccharides (WGP) can effectively alleviate intestinal inflammation and intestinal microbiota disturbances caused by OTA. The present study further explored whether WGP can prevents OTA-induced cognitive impairments and elucidate its neuroprotective mechanism. Here, we established fecal microbiota transplantation, Lactobacillus johnsonii (L.john) and Akkermansia muciniphila (AKK) colonization, L.john and AKK-derived extracellular vesicles (EVs), as well as 5-HT and short-chain fatty acid (SCFA) supplementation tests to evaluate the role of the intestinal microbiota and its metabolites in WGP in alleviating OTA-induced cognitive impairment.

RESULTS: OTA exposure induced cognitive impairments and inhibition of hippocampal neurogenesis, which was reversed by WGP supplementation. Meanwhile, WGP supplementation significantly reversed OTA-induced gut dysbacteriosis and low abundance of L.john and AKK, high proinflammation factor levels and low neurotransmitter levels in serum, intestine and hippocampus, as well as low SCFA levels in fecal. Antibiotic cocktail treatment eliminates the neuroprotective effect of WGP on OTA-treated mice. In addition, transplantation of the OTA-gut microbiota into normal mice causing similar results to OTA treatment, and these changes were alleviated with the transplantation of OTA+WGP-gut microbiota. Furthermore, colonization with L.john and AKK markedly reversed OTA-induced cognitive impairments and inhibition of hippocampal neurogenesis, as well as increased 5-HT and SCFA levels. EVs derived from L.john and AKK exhibit consistent performance with colonized L.john and AKK, and also have superior abilities in alleviating OTA-induced cognitive impairment and inhibiting hippocampal neurogenesis. Moreover, as a key regulatory factor of microbiota-gut-brain axis, 5-HT and SCFA supplementation significantly alleviated OTA-induced cognitive impairment and inhibition of hippocampal neurogenesis.

CONCLUSIONS: Taken together, this work provides new evidence for microbiota-gut-brain axis involved in the neuroprotective effects of WGP on OTA-induced cognitive dysfunction. L.john, AKK and its derived EVs mediate the ameliorative effects of WGP on OTA-induced cognitive impairment. A feasible mechanism is that WGP increased the content of L.john, AKK and its derived EVs, which improve 5-HT and SCFA production in colon to ameliorate cognitive impairment and enhance hippocampal neurogenesis.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS10673 | MetaboLights | 2024-10-10

REPOSITORIES: MetaboLights

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Project description:Background: The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. The negative impact of poor dietary patterns on brain development and neurological function may be related to gut microbiota disturbance. The role of phlorizin in mitigating glucose and lipid metabolism disorders is well documented. However, the protective effect of phlorizin on diabetes-related cognitive dysfunction is unclear. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. Results: Dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Moreover, integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Conclusions: These results indicate that gut microbiota and their metabolites mediate the ameliorative effect of phlorizin on HFFD-induced cognitive impairment. Therefore, phlorizin can be used as an easy-to-implement nutritional therapy to prevent and alleviate metabolism-related neurodegenerative diseases by targeting the regulation of the microbiome-gut-brain axis.

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Extracellular Vesicles from probiotics mediated Walnut green husk polysaccharide alleviates ochratoxin-A-induced cognitive impairment via SCFA and 5-HT mediated microbiota-gut-brain axis

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