Phlorizin ameliorates cognitive and behavioral impairments via the microbiota-gut-brain axis in high-fat and high-fructose diet-induced obese male mice

IF 8.8 2区 医学 Q1 IMMUNOLOGY
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引用次数: 0

Abstract

The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. Phlorizin, a well-studied natural compound found in apples and other plants, is recognized for its bioactive properties, including modulation of glucose and lipid metabolism. Despite its established role in mitigating metabolic disorders, the neuroprotective effects of phlorizin, particularly against diabetes-related cognitive dysfunction, have not been fully elucidated. 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. We found that 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. 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. Therefore, phlorizin shows promise as a potential nutritional therapy for addressing cognitive impairment associated with metabolic disorders. Further research is needed to explore its effectiveness in preventing and alleviating neurodegenerative diseases.

通过微生物群-肠-脑轴改善高脂和高果糖饮食诱导的肥胖雄性小鼠的认知和行为损伤
长期高脂肪、高糖饮食会加剧与 2 型糖尿病(T2DM)相关的认知障碍。氯嗪是一种在苹果和其他植物中发现的天然化合物,其生物活性特性已得到公认,包括调节葡萄糖和脂质代谢。尽管叶绿素在缓解代谢紊乱方面的作用已得到证实,但它对神经的保护作用,尤其是对糖尿病相关认知功能障碍的保护作用,尚未得到充分阐明。因此,本研究旨在探讨膳食补充氯苯甘醚对高脂高果糖饮食(HFFD)诱导的认知功能障碍的影响,并评估微生物群-肠-脑轴的关键作用。我们发现,连续 14 周通过膳食补充氯苯甘醚能有效预防高脂高果饮食小鼠的糖脂代谢紊乱、空间学习障碍和记忆损伤。此外,叶枯素还能改善 HFFD 引起的海马突触可塑性下降、神经炎症和小胶质细胞过度激活。转录组学分析表明,氯嗪对认知障碍的保护作用与海马中神经递质和突触相关基因表达的增加有关。氯嗪治疗缓解了结肠微生物群紊乱,主要表现为肠道微生物群多样性和短链脂肪酸(SCFA)产生菌丰度的增加。经氯雷他定处理后,SCFA、5′-单磷酸肌苷(IMP)和D(-)-beta-羟丁酸(BHB)等微生物代谢物的含量也显著增加。综合多组学分析观察到了氯嗪调节基因、微生物群和代谢物之间的紧密联系。此外,通过抗生素治疗去除肠道微生物群会降低氯嗪对 HFFD 引起的认知障碍的保护作用,这突出了肠道微生物群在介导认知行为中的关键作用。重要的是,仅补充 SCFA 和 BHB 就能模拟氯苯甘醚对认知功能的调节作用。因此,氯苯甘醚有望成为一种潜在的营养疗法,用于治疗与代谢紊乱相关的认知障碍。还需要进一步的研究来探索它在预防和缓解神经退行性疾病方面的有效性。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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