scholarly journals Human and preclinical studies of the host–gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323314
Author(s):  
François Brial ◽  
Julien Chilloux ◽  
Trine Nielsen ◽  
Sara Vieira-Silva ◽  
Gwen Falony ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Human Study ◽  
Experimental Studies ◽  
Saturated Fat ◽  
Metabolic Health ◽  
High Fat ◽  
Chronic Infusion ◽  
Gene Richness ◽  
Fat Diets ◽  
Study Participants

ObjectiveGut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health.DesignIn 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes.ResultsIn the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion.ConclusionOur human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.

scholarly journals Microbiome Determinants and Physiological Effects of the Benzoate-Hippurate Microbial-Host Co-Metabolic Pathway

2019 ◽  
Author(s):  
François Brial ◽  
Julien Chilloux ◽  
Trine Nielsen ◽  
Sara Vieira-Silva ◽  
Gwen Falony ◽  
...  
Keyword(s):  
Cell Mass ◽  
Saturated Fat ◽  
Metabolic Health ◽  
Protective Effects ◽  
Liver Inflammation ◽  
High Fat ◽  
Translational Study ◽  
Depth Analysis ◽  
Gene Richness

ABSTRACTObjectiveGut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate.DesignWe profiled the urine metabolome by 1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes.ResultsIn-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causality in vivo through chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation.ConclusionOur translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.

scholarly journals The association between the maternal diet and the maternal and infant gut microbiome: a systematic review

2020 ◽  
pp. 1-29 ◽  
Author(s):  
Siofra E. Maher ◽  
Eileen C. O’Brien ◽  
Rebecca L. Moore ◽  
David F. Byrne ◽  
Aisling A. Geraghty ◽  
...  
Keyword(s):  
Microbial Diversity ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Maternal Diet ◽  
Rrna Gene ◽  
High Fat ◽  
High Fat Diets ◽  
Culture Independent ◽  
Infant Gut Microbiome ◽  
Fat Diets

Abstract During pregnancy, changes occur to influence the maternal gut microbiome, and potentially the fetal microbiome. Diet has been shown to impact the gut microbiome. Little research has been conducted examining diet during pregnancy with respect to the gut microbiome. To meet inclusion criteria, dietary analyses must have been conducted as part of the primary aim. The primary outcome was the composition of the gut microbiome (infant or maternal), as assessed using culture-independent sequencing techniques. This review identified seven studies for inclusion, five examining the maternal gut microbiome and two examining the fetal gut microbiome. Microbial data were attained through analysis of stool samples by 16S rRNA gene-based microbiota assessment. Studies found an association between the maternal diet and gut microbiome. High-fat diets (% fat of total energy), fat-soluble vitamins (mg/day) and fibre (g/day) were the most significant nutrients associated with the gut microbiota composition of both neonates and mothers. High-fat diets were significantly associated with a reduction in microbial diversity. High-fat diets may reduce microbial diversity, while fibre intake may be positively associated with microbial diversity. The results of this review must be interpreted with caution. The number of studies was low, and the risk of observational bias and heterogeneity across the studies must be considered. However, these results show promise for dietary intervention and microbial manipulation in order to favour an increase of health-associated taxa in the gut of the mother and her offspring.

scholarly journals Liver tumorigenesis is promoted by a high saturated fat diet specifically in male mice and is associated with hepatic expression of the proto-oncogene Agap2 and enrichment of the intestinal microbiome with Coprococcus

2018 ◽  
Vol 40 (2) ◽  
pp. 349-359 ◽  
Author(s):  
Kim B Pedersen ◽  
Casey F Pulliam ◽  
Aarshvi Patel ◽  
Fabio Del Piero ◽  
Tatiane T N Watanabe ◽  
...  
Keyword(s):  
Dietary Fat ◽  
Gut Microbiome ◽  
Liver Tumors ◽  
Saturated Fat ◽  
Tumor Promotion ◽  
Intestinal Microbiome ◽  
Hepatic Expression ◽  
Fat Diets ◽  
Hepatic Transcriptome ◽  
High Degree

Abstract Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, we investigated the role of dietary fat type in tumor promotion by high-fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth.

scholarly journals Effects of Three-Month Administration of High-Saturated Fat Diet and High-Polyunsaturated Fat Diets with Different Linoleic Acid (LA, C18:2n–6) to α-Linolenic Acid (ALA, C18:3n–3) Ratio on the Mouse Liver Proteome

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1678
Author(s):  
Kamila P. Liput ◽  
Adam Lepczyński ◽  
Agata Nawrocka ◽  
Ewa Poławska ◽  
Magdalena Ogłuszka ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Linolenic Acid ◽  
Mouse Liver ◽  
Saturated Fat ◽  
Standard Diet ◽  
High Fat ◽  
Two Dimensional Gel Electrophoresis ◽  
Altered Expression ◽  
High Fat Diets ◽  
Fat Diets

The aim of the study was to evaluate the effect of different types of high-fat diets (HFDs) on the proteomic profile of mouse liver. The analysis included four dietary groups of mice fed a standard diet (STD group), a high-fat diet rich in SFAs (SFA group), and high-fat diets dominated by PUFAs with linoleic acid (LA, C18:2n–6) to α-linolenic acid (ALA, C18:3n–3) ratios of 14:1 (14:1 group) and 5:1 (5:1 group). After three months of diets, liver proteins were resolved by two-dimensional gel electrophoresis (2DE) using 17 cm non-linear 3–10 pH gradient strips. Protein spots with different expression were identified by MALDI-TOF/TOF. The expression of 13 liver proteins was changed in the SFA group compared to the STD group (↓: ALB, APOA1, IVD, MAT1A, OAT and PHB; ↑: ALDH1L1, UniProtKB—Q91V76, GALK1, GPD1, HMGCS2, KHK and TKFC). Eleven proteins with altered expression were recorded in the 14:1 group compared to the SFA group (↓: ARG1, FTL1, GPD1, HGD, HMGCS2 and MAT1A; ↑: APOA1, CA3, GLO1, HDHD3 and IVD). The expression of 11 proteins was altered in the 5:1 group compared to the SFA group (↓: ATP5F1B, FTL1, GALK1, HGD, HSPA9, HSPD1, PC and TKFC; ↑: ACAT2, CA3 and GSTP1). High-PUFA diets significantly affected the expression of proteins involved in, e.g., carbohydrate metabolism, and had varying effects on plasma total cholesterol and glucose levels. The outcomes of this study revealed crucial liver proteins affected by different high-fat diets.

Maternal and postweaning high-fat diets disturb hippocampal gene expression, learning, and memory function

2014 ◽  
Vol 306 (8) ◽  
pp. R527-R537 ◽  
Author(s):  
Kathleen C. Page ◽  
Elizabeth K. Jones ◽  
Endla K. Anday
Keyword(s):  
Gene Expression ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Memory Function ◽  
Saturated Fat ◽  
Spatial Learning And Memory ◽  
Adult Males ◽  
High Fat ◽  
High Fat Diets ◽  
Fat Diets

We tested the hypothesis that excess saturated fat consumption during pregnancy, lactation, and/or postweaning alters the expression of genes mediating hippocampal synaptic efficacy and impairs spatial learning and memory in adulthood. Dams were fed control chow or a diet high in saturated fat before mating, during pregnancy, and into lactation. Offspring were weaned to either standard chow or a diet high in saturated fat. The Morris Water Maze was used to evaluate spatial learning and memory. Open field testing was used to evaluate motor activity. Hippocampal gene expression in adult males was measured using RT-PCR and ELISA. Offspring from high fat-fed dams took longer, swam farther, and faster to try and find the hidden platform during the 5-day learning period. Control offspring consuming standard chow spent the most time in memory quadrant during the probe test. Offspring from high fat-fed dams consuming excess saturated fat spent the least. The levels of mRNA and protein for brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein were significantly decreased by maternal diet effects. Nerve growth factor mRNA and protein levels were significantly reduced in response to both maternal and postweaning high-fat diets. Expression levels for the N-methyl-d-aspartate receptor (NMDA) receptor subunit NR2B as well as synaptophysin were significantly decreased in response to both maternal and postweaning diets. Synaptotagmin was significantly increased in offspring from high fat-fed dams. These data support the hypothesis that exposure to excess saturated fat during hippocampal development is associated with complex patterns of gene expression and deficits in learning and memory.

scholarly journals The Effect of High Fat Diet on Cerebrovascular Health and Pathology: A Species Comparative Review

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3406
Author(s):  
Benjamin Zimmerman ◽  
Payel Kundu ◽  
William D. Rooney ◽  
Jacob Raber
Keyword(s):  
Animal Models ◽  
High Fat Diet ◽  
Animal Studies ◽  
Vascular Dysfunction ◽  
Saturated Fat ◽  
Laboratory Animals ◽  
High Fat ◽  
Vascular Effects ◽  
Comparative Review ◽  
Fat Diets

In both humans and animal models, consumption of a high-saturated-fat diet has been linked to vascular dysfunction and cognitive impairments. Laboratory animals provide excellent models for more invasive high-fat-diet-related research. However, the physiological differences between humans and common animal models in terms of how they react metabolically to high-fat diets need to be considered. Here, we review the factors that may affect the translatability of mechanistic research in animal models, paying special attention to the effects of a high-fat diet on vascular outcomes. We draw attention to the dissociation between metabolic syndrome and dyslipidemia in rodents, unlike the state in humans, where the two commonly occur. We also discuss the differential vulnerability between species to the metabolic and vascular effects of macronutrients in the diet. Findings from animal studies are better interpreted as modeling specific aspects of dysfunction. We conclude that the differences between species provide an opportunity to explore why some species are protected from the detrimental aspects of high-fat-diet-induced dysfunction, and to translate these findings into benefits for human health.

scholarly journals Quercetin Ameliorates Insulin Resistance and Restores Gut Microbiome in Mice on High-Fat Diets

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1251
Author(s):  
Yuqing Tan ◽  
Christina C. Tam ◽  
Matt Rolston ◽  
Priscila Alves ◽  
Ling Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiome ◽  
Liver Lipid ◽  
High Fat ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Expression Of Genes ◽  
High Fat Diets ◽  
Health Promoting ◽  
Fat Diets

Quercetin is a flavonoid that has been shown to have health-promoting capacities due to its potent antioxidant activity. However, the effect of chronic intake of quercetin on the gut microbiome and diabetes-related biomarkers remains unclear. Male C57BL/6J mice were fed HF or HF supplemented with 0.05% quercetin (HFQ) for 6 weeks. Diabetes-related biomarkers in blood were determined in mice fed high-fat (HF) diets supplemented with quercetin. Mice fed the HFQ diet gained less body, liver, and adipose weight, while liver lipid and blood glucose levels were also lowered. Diabetes-related plasma biomarkers insulin, leptin, resistin, and glucagon were significantly reduced by quercetin supplementation. In feces, quercetin supplementation significantly increased the relative abundance of Akkermansia and decreased the Firmicutes/Bacteroidetes ratio. The expression of genes Srebf1, Ppara, Cyp51, Scd1, and Fasn was downregulated by quercetin supplementation. These results indicated that diabetes biomarkers are associated with early metabolic changes accompanying obesity, and quercetin may ameliorate insulin resistance.

scholarly journals High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2119
Author(s):  
David Dao ◽  
Bingqing Xie ◽  
Urooba Nadeem ◽  
Jason Xiao ◽  
Asad Movahedan ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Enrichment Analysis ◽  
Retinal Disease ◽  
Vessel Diameter ◽  
Age Related Macular Degeneration ◽  
High Fat ◽  
Inhibitor Activity ◽  
Age Related ◽  
Fat Diets ◽  
Transcriptomic Changes

The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.

High-fat diets: healthy or unhealthy?

2007 ◽  
Vol 113 (10) ◽  
pp. 397-399 ◽  
Author(s):  
Marie C. Guldstrand ◽  
Caroline L. Simberg
Keyword(s):  
Saturated Fat ◽  
Normal Weight ◽  
Caloric Content ◽  
Monounsaturated Fat ◽  
Dietary Recommendations ◽  
High Fat ◽  
Treatment And Prevention ◽  
Low Carbohydrate ◽  
High Fat Diets ◽  
Fat Diets

In the current dietary recommendations for the treatment and prevention of Type 2 diabetes and its related complications, there is flexibility in the proportion of energy derived from monounsaturated fat and carbohydrate as a replacement for saturated fat. Over the last few years, several population studies have shown that subjects eating a lot of refined grains and processed foods have a much larger increase in waist circumference than those following a diet higher in monounsaturated fat, protein and carbohydrates rich in fibre and whole grain. In the present issue of Clinical Science, Sinitskaya and co-workers have demonstrated that, in normal-weight rodents categorized into groups of high-fat and medium-carbohydrate [53%/30% of energy as fat/carbohydrate; 19.66 kJ/g (4.7 kcal/g)], high-fat and low-carbohydrate [67%/9% of energy as fat/carbohydrate; 21.76 kJ/g (5.2 kcal/g)] and high-fat and carbohydrate-free [75%/0% of energy as fat/carbohydrate; 24.69 kJ/g (5.9 kcal/g)] diets, the high-fat diets containing carbohydrates were both obesogenic and diabetogenic, whereas the very-high-fat and carbohydrate-free diet was not obesogenic but led to insulin resistance and higher risk of cardiovascular disease. This finding may indicate that high-fat diets could easily give rise to an unhealthy diet when combined with carbohydrates, highlighting the significance of macronutrient composition, rather than caloric content, in high-fat diets.

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