Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Yanckello, Lucille M.; Hoffman, Jared D.; Chang, Ya‐Hsuan; Lin, Penghui; Nehra, Geetika; Chlipala, George E.; McCulloch, Scott; Hammond, Tyler C.; Yackzan, Andrew T.; Lane, Andrew N.; Green, Stefan J.; Hartz, Anika M.S.; Lin, Ai-Ling

doi:10.1080/1028415x.2021.1889452

Cited by 14 publications

(15 citation statements)

References 45 publications

(52 reference statements)

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“…Genotype differences may be pronounced during early disease, but the disease course causes both genotypes to exhibit a similar biochemical profile as the disease progresses and neurons are lost. These genotype differences should be further explored to determine whether precision interventions, like the consumption of inulin or the administration of rapamycin, could be implemented for ε4 carriers [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, alterations of bile acid production have been observed in AD patients due to gut microbiome imbalances, suggesting another mechanism by which AD patients may benefit from therapeutic strategies aiming to restore normal brain metabolism like the ketogenic diet [ 59 , 60 ]. Another animal study showed that by modulating the gut microbiome with a prebiotic diet, mice with the human APOE ε4 gene had enhanced systemic metabolism and reduced neuroinflammatory gene expression, another hallmark of AD pathology [ 51 , 61 ]. Collectively, modulating metabolic function and the gut microbiome may profoundly impact reducing the risk of AD.…”

Section: Discussionmentioning

confidence: 99%

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Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer’s Disease

Hammond

Xing

Yanckello

et al. 2021

Journal of Cellular Immunology

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Alzheimer's disease (AD) is the most common form of dementia with hallmarks of β-amyloid (Aβ) plaques, tau tangles, and neurodegeneration. Studies have shown that neurodegeneration components, especially brain metabolic deficits, are more predictable for AD severity than Aβ and tau. However, detailed knowledge of the biochemical composition of AD brain tissue vs. normal brain tissue remains unclear. In this study, we performed a metabolomics analysis on the brain tissue of 158 community-based older adults in the University of Kentucky AD Research Center brain bank to characterize the biochemical profiles of brains with and without AD based on white/gray matter type, apolipoprotein E genotype (ε3 vs ε4 variants), and disease stage (early vs late) as all these factors influence metabolic processes. We also used machine learning to rank the top metabolites separating controls and AD in gray and white matter. Compared with control samples, we found that glutamate and creatine metabolism were more critical for predicting AD in the gray matter, while glycine, fatty acid, pyrimidine, tricarboxylic acid (TCA) cycle, and phosphatidylcholine metabolism were more critical in the white matter. In ε4 carriers, metabolites associated with the TCA cycle and oxidative phosphorylation were prominent in advanced stages compared to the early stages. In ε3 carriers, metabolites related to oxidative DNA damage, changes in inhibitory neurotransmitters, and disruptions of neuronal membranes were prominent in advanced stages compared to the early stages. In early disease, ε4 carriers had metabolites related to poor kidney function and altered neuronal sterol metabolism compared to ε3 carriers, but there were few differences between genotypes in late disease. Our results indicate that metabolism plays a pivotal role in differentiating APOE-and stage-dependent changes in AD and may facilitate precision lifestyle and dietary interventions to mitigate AD risk in the early stages, especially for ε4 carriers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer’s Disease

Hammond

Xing

Yanckello

et al. 2021

Journal of Cellular Immunology

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“…Second, we determined if prebiotic inulin could mitigate injury-induced dysbiosis and restore CBF and WMI by modulating gut microbiome from 3 months post injury (mpi) to 5 mpi. We chose inulin because it consists of non-digestible carbohydrates that can stimulate the growth of bacteria that produce SCFAs [ 14 , 15 ] and enhance neuroprotection [ 16 , 17 ]. We expect the outcomes from the study will advance our knowledge on dysbiosis after CHI from acute to chronic phases, and the potential of dietary intervention for facilitating CHI recovery.…”

Section: Introductionmentioning

confidence: 99%

Inulin Supplementation Mitigates Gut Dysbiosis and Brain Impairment Induced by Mild Traumatic Brain Injury during Chronic Phase

Yanckello

Fanelli

McCulloch

et al. 2022

Journal of Cellular Immunology

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Mild traumatic brain injury (mTBI) has been shown to acutely alter the gut microbiome diversity and composition, known as dysbiosis, which can further exacerbate metabolic and vascular changes in the brain in both humans and rodents. However, it remains unknown how mTBI affects the gut microbiome in the chronic phase recovery (past one week post injury). It is also unknown if injury recovery can be improved by mitigating dysbiosis. The goal of the study is to fill the knowledge gap. First, we aim to understand how mTBI alters the gut microbiome through the chronic period of recovery (3 months post injury). In addition, as the gut microbiome can be modulated by diet, we also investigated if prebiotic inulin, a fermentable fiber that promotes growth of beneficial bacteria and metabolites, would mitigate dysbiosis, improve systemic metabolism, and protect brain structural and vascular integrity when administered after 3 months post closed head injury (CHI). We found that CHI given to male mice at 4 months of age induced gut dysbiosis which peaked at 1.5 months post injury, reduced cerebral blood flow (CBF) and altered brain white matter integrity. Interestingly, we also found that Sham mice had transient dysbiosis, which peaked 24 hours after injury and then normalized. After 8 weeks of inulin feeding, CHI mice had increased abundance of beneficial/anti-inflammatory bacteria, reduced abundance of pathogenic bacteria, enriched levels of short-chain fatty acids, and restored CBF in both hippocampi and left thalamus, compared to the CHI-control fed and Sham groups. Using machine learning, we further identified top bacterial species that separate Sham and CHI mice with and without the diet. Our results indicate that there is an injury- and time-dependent dysbiosis between CHI and Sham mice; inulin is effective to mitigate dysbiosis and improve brain injury recovery in the CHI mice. As there are currently no effective treatments for mTBI, the study may have profound implications for developing therapeutics or preventive interventions in the future.

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“…There were differences in the levels of brain metabolites associated with oxidative stress and the expression of claudin-1 and claudin-5 BBB tight junctions. 110 Gut−Kidney Axis. The composition of the intestinal microbiota of patients with chronic kidney disease (CKD) and the mechanism by which the imbalance of the intestinal flora promotes the progression of CKD have been studied to determine possible treatment goals and improve the survival rate of patients with CKD.…”

Section: Journal Ofmentioning

confidence: 99%

Sources, Processing-Related Transformation, and Gut Axis Regulation of Conventional and Potential Prebiotics

Cheng

Kong

Xia

et al. 2022

J. Agric. Food Chem.

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One strategy to achieve a balanced intestinal microbiota is to introduce prebiotics. Some substances present in the diet, such as soybean extracts, koji glycosylceramides, grape extracts, tea polyphenols, and seaweed extracts, can be considered as potential prebiotics, because they can selectively stimulate the proliferation of beneficial bacteria in the intestine. However, the discovery of novel prebiotics also involves advances in screening methods and the use of thermal and non-thermal processing techniques to modify and enhance the properties of beneficial organisms. The health benefits of prebiotics are also reflected by their participation in regulating the microbiota in different gut axes. In the present review, we introduced the field of prebiotics, focusing on potential prebiotic substances, the process of screening potential prebiotics, the transformation of prebiotics by food-processing technologies, and the roles of prebiotics on gut axis regulation, which, it is hoped, will promote the discovery and utilization of novel prebiotics.

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Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Cited by 14 publications

References 45 publications

Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer’s Disease

Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer’s Disease

Inulin Supplementation Mitigates Gut Dysbiosis and Brain Impairment Induced by Mild Traumatic Brain Injury during Chronic Phase

Sources, Processing-Related Transformation, and Gut Axis Regulation of Conventional and Potential Prebiotics

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