Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models
Xing Ge, … , Yinghua Yu, Xu-Feng Huang
Xing Ge, … , Yinghua Yu, Xu-Feng Huang
Published February 15, 2023
Citation Information: J Clin Invest. 2023;133(4):e154612. https://doi.org/10.1172/JCI154612.
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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 5

QA damage of dopaminergic and glutamatergic neurons is prevented by butyrate in C. elegans.

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QA damage of dopaminergic and glutamatergic neurons is prevented by buty...
Transgenic C. elegans strains, including BZ555 (dat-1p::GFP), EG1285 [unc-47p::GFP+lin-15(+)], and DA1240 [eat-4::GFP+lin-15(+)], were used to visualize dopaminergic, glutamatergic, and GABAergic neurons. Worms were exposed to 20 mM QA and/or 10 mM butyrate for 1 hour at L4 stag and then treated with butyrate (10 mM) for 24 hours. Fluorescence images were taken to measure morphology and fluorescence intensity. (A) Dopamine neurons were visualized by expression of dat-1p::GFP. Red arrow shows the loss of dendrites in 2 pairs of CEP neurons. Scale bars: 50 μm. ADE, anterior deirid neuron. (B) The fluorescence intensity of dopaminergic neurons was significantly different after treatment with QA and/or butyrate. (C) Glutamatergic neurons labeled with eat-4::GFP in the control worm. Red arrows show neuronal loss in ALM and PVD neurons. Scale bars: 200 μm. PLM, posterior lateral microtubule neuron; LUA, lumbar ganglion interneuron. (D) The fluorescence intensity of glutamatergic neurons was significantly different after exposure to QA and/or butyrate. (E) GABAergic neurons were visualized by expression of unc-47::GFP. Scale bars: 200 μm. RMEs, ring motor neuron E; DVE, dorsorectal ventral process E. (F) No change in fluorescence intensity of GABAergic neurons was observed after QA treatment (P = 0.76). Data indicate the mean ± SEM. n = 10 independent experiments performed in triplicate. *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.