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 2

Cortical volume and neuronal morphology are changed in individuals with obesity and obese mice.

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Cortical volume and neuronal morphology are changed in individuals with ...
(A) Statistical maps show regions (blue) with reduced GMV in individuals in the obese group as captured by 3D-T1 axial and sagittal slice imaging (MNI T1 template available in MRIcron software). The MRI study included 19 individuals with obesity and 21 age- and sex-matched, nonobese controls. (B) Representative reconstructions of Golgi-Cox–stained neurons in the frontal cortex of obese and control mice. (C) The total neurite length per cell was decreased in the frontal cortex of obese mice. (D) The number of neurite branches was decreased in the frontal cortex of obese mice. (E) Neurite morphology was profiled by Sholl analysis. (F and G) The sum intersection (F) and maximum number of intersections (G) were calculated by Sholl analysis. (H) Synaptic spines were stained with Golgi silver. Blue arrows show mushroom spines. Red arrows show thin spines. (I) Spine density, as determined by the number of spines per 10 μm. (J–L) Ratio of mushroom-like spines (J), thin spines (K), and stubby spines (L). Data indicate the mean ± SEM. n = 4 mice/group for Golgi staining. **P < 0.01 and ***P < 0.001 versus the control group, by 2-tailed Student’s t test.