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<p>Alzheimer’s disease (AD) is a complex neurodegenerative disorder associated with changes in inflammation, oxidative stress, and gut microbiota composition. Butyrolactone I (BTL-I), a fungal metabolite, has shown anti-inflammatory, microbiota regulating, and memory-improving potentials in previous in vitro and AlCl<sub>3</sub>-induced zebrafish studies. However, its effects of memory-improving and gutbrain axis regulating on Aβ-induced mammalian AD models have not been explored. In this study, intragastric administrated BTL-I ameliorated cognitive deficits related to recognition and spatial memory impaired by Aβ<sub>1–42</sub> intracerebroventricular injection in mice. BTL-I maintained gut microbiota balance by increasing the abundance of <i>Blautia</i>, Muribaculaceae, <i>Bacteroides</i>, <i>Akkermansia</i>, etc., and decreasing CAG-352, Clostridia UCG-014, different Lachnospiraceae groups, etc., and Firmicutes/Bacteroidota ratio and elevated the levels of short-chain fatty acids. Additionally, it alleviated intestinal oxidative stress, inflammatory responses, and pathological damage. Furthermore, BTL-I reversed Aβ{en1–42}-induced activation of microglia and astrocytes in the hippocampus and inhibited the elevated oxidative stress and proinflammatory cytokines in both plasma and brain. The correlation analysis between the regulated taxa and biomarkers supports the role of gut microbiota in adjusting inflammation, oxidative stress, and memory. In conclusion, BTL-I may serve as a valuable drug lead for treating Alzheimer’s disease by systematically inhibiting microbiota imbalance, inflammation, and oxidative stress along the gut-brain axis.</p>

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Marine fungal metabolite butyrolactone I improves Aβ1–42-induced cognitive impairment in mice via gut-brain axial microbiota remodeling, anti-inflammation, and antioxidation

  • 期刊论文

  • 发表日期：

    2025年6月10日

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  • Fuyan Yang,
  • Longjian Zhou,
  • Jiahang Deng,
  • Yuan Wang,
  • Zhiyou Yang,
  • Yongping Zhang,
  • Yayue Liu,
  • Yi Zhang

摘要

Alzheimer’s disease (AD) is a complex neurodegenerative disorder associated with changes in inflammation, oxidative stress, and gut microbiota composition. Butyrolactone I (BTL-I), a fungal metabolite, has shown anti-inflammatory, microbiota regulating, and memory-improving potentials in previous in vitro and AlCl3-induced zebrafish studies. However, its effects of memory-improving and gutbrain axis regulating on Aβ-induced mammalian AD models have not been explored. In this study, intragastric administrated BTL-I ameliorated cognitive deficits related to recognition and spatial memory impaired by Aβ1–42 intracerebroventricular injection in mice. BTL-I maintained gut microbiota balance by increasing the abundance of Blautia, Muribaculaceae, Bacteroides, Akkermansia, etc., and decreasing CAG-352, Clostridia UCG-014, different Lachnospiraceae groups, etc., and Firmicutes/Bacteroidota ratio and elevated the levels of short-chain fatty acids. Additionally, it alleviated intestinal oxidative stress, inflammatory responses, and pathological damage. Furthermore, BTL-I reversed Aβ{en1–42}-induced activation of microglia and astrocytes in the hippocampus and inhibited the elevated oxidative stress and proinflammatory cytokines in both plasma and brain. The correlation analysis between the regulated taxa and biomarkers supports the role of gut microbiota in adjusting inflammation, oxidative stress, and memory. In conclusion, BTL-I may serve as a valuable drug lead for treating Alzheimer’s disease by systematically inhibiting microbiota imbalance, inflammation, and oxidative stress along the gut-brain axis.