A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity

Patkar, Omkar L.; Mohamed, Abdalla Z.; Narayanan, Ashwin; Mardon, Karine; Cowin, Gary; Bhalla, Rajiv; Stimson, D.; Kassiou, Michael; Beecher, Kate; Belmer, Arnauld; Cooper, Ignatius Alvarez; Morgan, Michael; Hume, David; Irvine, Katharine M.; Bartlett, Selena E.; Nasrallah, Fatima A.; Cumming, Paul

doi:10.1038/s41598-021-90817-z

Cited by 24 publications

(24 citation statements)

References 48 publications

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“…Research showed that consumption of 11% sucrose solution for 4 weeks did not increase neuroinflammation in rats [ 74 ], while a prolonged high sucrose intake (5% sucrose solution) for 12 weeks provoked systemic and neuroinflammation in rats [ 75 ]. In addition, Hsu’s study showed that high sucrose intake for 4 weeks moderately impaired hippocampal-dependent spatial learning and memory in adolescent rats [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Shi

et al. 2021

Microbiome

119

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Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Shi

et al. 2021

Microbiome

119

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“…To calculate IBA1 + cell body size, maximum intensity projections (MIPs) were opened in Fiji v1.5 and the free drawing tool was used to measure the area of positive cells with a visible nucleus (20 cells per animal). For microglial arborisation, images were analysed as previously described ( Patkar et al, 2021b ).…”

Section: Methodsmentioning

confidence: 99%

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

et al. 2022

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Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/− mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

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“…This idea was strengthened when studies using the type 1 diabetes model, which does not include an HFD, also showed increased microglial hypertrophy, astrocytic activation and proliferation, and increased proinflammatory gene expression in the hypothalamus [77,85,86]. Further, a recent study showed an increase in the microglial density in the hypothalamus of the binge sucrose rats [87]. Apart from the different hyperglycemic mice models, the direct administration of glucose into the mouse third ventricle has shown a significant increase in the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity in the hypothalamus [20].…”

Section: B Hyperglycemiamentioning

confidence: 99%

Hypothalamic inflammation in metabolic disorders and aging

Bhusal

Rahman

Suk

2021

Cell. Mol. Life Sci.

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The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

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A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity

Cited by 24 publications

References 48 publications

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

Hypothalamic inflammation in metabolic disorders and aging

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