Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models
Xing Ge, Mingxuan Zheng, Minmin Hu, Xiaoli Fang, Deqin Geng, Sha Liu, Li Wang, Jun Zhang, Li Guan, Peng Zheng, Yuanyi Xie, Wei Pan, Menglu Zhou, Limian Zhou, Renxian Tang, Kuiyang Zheng, Yinghua Yu, Xu-Feng Huang
Xing Ge, Mingxuan Zheng, Minmin Hu, Xiaoli Fang, Deqin Geng, Sha Liu, Li Wang, Jun Zhang, Li Guan, Peng Zheng, Yuanyi Xie, Wei Pan, Menglu Zhou, Limian Zhou, Renxian Tang, Kuiyang Zheng, Yinghua Yu, Xu-Feng Huang
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Research Article Aging Metabolism

Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models

Abstract

Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimer’s disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spine’s intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.

Authors

Xing Ge, Mingxuan Zheng, Minmin Hu, Xiaoli Fang, Deqin Geng, Sha Liu, Li Wang, Jun Zhang, Li Guan, Peng Zheng, Yuanyi Xie, Wei Pan, Menglu Zhou, Limian Zhou, Renxian Tang, Kuiyang Zheng, Yinghua Yu, Xu-Feng Huang

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Figure 7

QA reduction of BDNF expression is prevented by butyrate in epigenetically enhanced SH-SY5Y cells.

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QA reduction of BDNF expression is prevented by butyrate in epigenetical...
(A and B) Butyrate reversed QA-reduced BDNF expression in SH-SY5Y cells. (C and D) MK-801 reversed QA-reduced BDNF expression in SH-SY5Y cells. (E and F) QA decreased the phosphorylation of CREB at serine 133. (G) Dose-response curve for butyrate in the inhibition of HDAC2 enzymatic activity. (H) Relative HDAC2 activity of SH-SY5Y cells after treatment with butyrate for 24 hours. (I) Butyrate increased the acetylation of histone H3 in SH-SY5Y cells with or without QA exposure. (J and K) Butyrate increased the acetylation of histone H3 at lysine 18 (H3K18ac) in SH-SY5Y cells with or without QA exposure, as determined by Western blotting. Data indicate the mean ± SEM. *P < 0.05 and **P < 0.01 versus the control group; #P < 0.05 and ##P < 0.01 versus the QA group, by 1-way ANOVA with Tukey’s multiple-comparison test. (L–O) ChIP analysis showed that butyrate increased the levels of Bdnf promoters in the PII region binding to H3ac (L) and H3K18ac (M) and in the PIV region binding to H3ac (N) and H3K18ac (O). ***P < 0.001, by Student’s t test.