Modeling of the luminal butyrate concentration to design an oral formulation capable of achieving a pharmaceutical response

Korsten, Sandra Gabriële Patricia Johanna; Smits, Evelien A. W.; Garssen, Johan; Vromans, Herman

doi:10.1016/j.phanu.2019.100166

Cited by 9 publications

(12 citation statements)

References 20 publications

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“…NaB inhibits NRF2 ‐ARE luciferase activity at the NaB concentration ranges from 4 to 10 mM (Figure 1b) while lower NaB concentration (<2 mM) slightly increased the luciferase activities but not significant (these low concentrations are easily achievable in in vivo situation, including human). [ 53 ] In addition, RT‐PCR revealed NaB significantly decreased the mRNA expression levels of NRF2 and NRF2 ‐target genes including NQO1 , HO1 , Peroxiredoxin‐1( PRDX1 ), Thioredoxin 1 ( TXN1 ), and Thioredoxin 2 ( TXN2 ), while increased the NRF2 negative regulator KEAP1 mRNA levels compared to control (Figure 1c,d). The protein levels measured by Western Blot were further validated showing that NaB decreased NRF2, NOQ1, and HO1, while increased KEAP1 protein expression (Figure 1e).…”

Section: Resultsmentioning

confidence: 96%

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

Wang

Shannar

et al. 2022

Molecular Nutrition Food Res

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Scope: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. Methods and results: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. Conclusion: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.

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Section: Resultsmentioning

confidence: 96%

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

Wang

Shannar

et al. 2022

Molecular Nutrition Food Res

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“…At present, oral butyrate is commonly used as a supplement but has low bioavailability and most butyrate producing bacteria are anaerobic which limits the production capacity of this metabolite. Studies are being done to evaluate butyrate concentration in the small intestine in order to develop oral formulations that maintain pharmacologically active butyrate concentrations [ 77 ]. Collectively, several studies point towards an important role of SCFAs in cholesterol levels.…”

Section: Gut Bacterial Metabolites and Cholesterol Metabolismmentioning

confidence: 99%

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

Vourakis

Mayer

Rousseau

2021

IJMS

112

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Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.

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“…We can use these results to develop clinical applications and regulate the inflammation with controlled changes in intestinal butyrate concentration. Although the reported butyrate concentrations in the literature are in both the micromolar range ,− and the millimolar range, ,, we selected the micromolar range of butyrate, since experimental data for biodistribution of butyrate in that range is available. , Our current model is scalable to study the effect of the millimolar range of butyrate.…”

Section: Resultsmentioning

confidence: 99%

“…Neumann et al developed a dynamical model to investigate the robust bistability of anti-inflammatory butyrate and pro-inflammatory bacterial lipopolysaccharides in gut epithelial cells . The model of Korsten et al showed that orally administered butyrate is capable of achieving pharmaceutical responses in the small intestine through immediate and sustained release . Here, we develop a mathematical model to investigate the interaction between butyrate and immune cells in the gut–bone axis and how the interaction of the gut and bone can contribute to changing trabecular bone volume.…”

Section: Introductionmentioning

confidence: 99%

“…40 The model of Korsten et al showed that orally administered butyrate is capable of achieving pharmaceutical responses in the small intestine through immediate and sustained release. 41 Here, we develop a mathematical model to investigate the interaction between butyrate and immune cells in the gut−bone axis and how the interaction of the gut and bone can contribute to changing trabecular bone volume. In addition to these immune-mediated indirect effects of butyrate, we also conduct an in silico experiment to determine possible mechanisms for direct impacts of butyrate on bone metabolism.…”

Section: ■ Introductionmentioning

confidence: 99%

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Mathematical Modeling of the Gut–Bone Axis and Implications of Butyrate Treatment on Osteoimmunology

Islam

Cook

et al. 2021

Ind. Eng. Chem. Res.

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Butyrate, a short-chain fatty acid produced by the gut microbiota, has pivotal roles in the regulation of the immune system. Recent studies have revealed that butyrate increases the differentiation of peripheral regulatory T cells in the gut−bone axis and promotes osteoblasts' bone forming activity. However, the mechanism of the therapeutic benefit of butyrate in bone remodeling remains incompletely understood. Here, we develop a multicompartment mathematical model to quantitatively predict the contribution of butyrate on the expansion of regulatory T cells in the gut, blood, and bone compartments. We investigate the interplay between regulatory T cell-derived TGF-β and CD8+ T cell-derived Wnt-10b with changes in gut butyrate concentration. In addition, we connect our model to a detailed model of bone metabolism to study the impacts of butyrate and Wnt-10b on trabecular bone volume. Our results indicate both direct and indirect immune-mediated impacts of butyrate on bone metabolism.

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Modeling of the luminal butyrate concentration to design an oral formulation capable of achieving a pharmaceutical response

Cited by 9 publications

References 20 publications

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

Mathematical Modeling of the Gut–Bone Axis and Implications of Butyrate Treatment on Osteoimmunology

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