Alterations in the composition of gut microbiota--known as dysbiosis--has been proposed to contribute to the development of obesity, thereby supporting the potential interest of nutrients targeting ...the gut with beneficial effect for host adiposity. We test the ability of a specific concentrate of water-extractable high molecular weight arabinoxylans (AX) from wheat to modulate both the gut microbiota and lipid metabolism in high-fat (HF) diet-induced obese mice.
Mice were fed either a control diet (CT) or a HF diet, or a HF diet supplemented with AX (10% w/w) during 4 weeks. AX supplementation restored the number of bacteria that were decreased upon HF feeding, i.e. Bacteroides-Prevotella spp. and Roseburia spp. Importantly, AX treatment markedly increased caecal bifidobacteria content, in particular Bifidobacterium animalis lactis. This effect was accompanied by improvement of gut barrier function and by a lower circulating inflammatory marker. Interestingly, rumenic acid (C18:2 c9,t11) was increased in white adipose tissue due to AX treatment, suggesting the influence of gut bacterial metabolism on host tissue. In parallel, AX treatment decreased adipocyte size and HF diet-induced expression of genes mediating differentiation, fatty acid uptake, fatty acid oxidation and inflammation, and decreased a key lipogenic enzyme activity in the subcutaneous adipose tissue. Furthermore, AX treatment significantly decreased HF-induced adiposity, body weight gain, serum and hepatic cholesterol accumulation and insulin resistance. Correlation analysis reveals that Roseburia spp. and Bacteroides/Prevotella levels inversely correlate with these host metabolic parameters.
Supplementation of a concentrate of water-extractable high molecular weight AX in the diet counteracted HF-induced gut dysbiosis together with an improvement of obesity and lipid-lowering effects. We postulate that hypocholesterolemic, anti-inflammatory and anti-obesity effects are related to changes in gut microbiota. These data support a role for wheat AX as interesting nutrients with prebiotic properties related to obesity prevention.
At birth, the human colon is rapidly colonized by gut microbes. Owing to their vast number and their capacity to ferment nutrients and secrete bioactive compounds, these gastrointestinal microbes act ...as an environmental factor that affects the host's physiology and metabolism, particularly in the context of obesity and its related metabolic disorders. Experiments that compared germ-free and colonized mice or analyzed the influence of nutrients that qualitatively change the composition of the gut microbiota (namely prebiotics) showed that gut microbes induce a wide variety of host responses within the intestinal mucosa and thereby control the gut's barrier and endocrine functions. Gut microbes also influence the metabolism of cells in tissues outside of the intestines (in the liver and adipose tissue) and thereby modulate lipid and glucose homeostasis, as well as systemic inflammation, in the host. A number of studies describe characteristic differences between the composition and/or activity of the gut microbiota of lean individuals and those with obesity. Although these data are controversial, they suggest that specific phyla, classes or species of bacteria, or bacterial metabolic activities could be beneficial or detrimental to patients with obesity. The gut microbiota is, therefore, a potential nutritional and pharmacological target in the management of obesity and obesity-related disorders.
Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which ...suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.
Each human intestine harbours not only hundreds of trillions of bacteria but also bacteriophage particles, viruses, fungi and archaea, which constitute a complex and dynamic ecosystem referred to as ...the gut microbiota. An increasing number of data obtained during the last 10 years have indicated changes in gut bacterial composition or function in type 2 diabetic patients. Analysis of this ‘dysbiosis’ enables the detection of alterations in specific bacteria, clusters of bacteria or bacterial functions associated with the occurrence or evolution of type 2 diabetes; these bacteria are predominantly involved in the control of inflammation and energy homeostasis. Our review focuses on two key questions: does gut dysbiosis truly play a role in the occurrence of type 2 diabetes, and will recent discoveries linking the gut microbiota to host health be helpful for the development of novel therapeutic approaches for type 2 diabetes? Here we review how pharmacological, surgical and nutritional interventions for type 2 diabetic patients may impact the gut microbiota. Experimental studies in animals are identifying which bacterial metabolites and components act on host immune homeostasis and glucose metabolism, primarily by targeting intestinal cells involved in endocrine and gut barrier functions. We discuss novel approaches (e.g. probiotics, prebiotics and faecal transfer) and the need for research and adequate intervention studies to evaluate the feasibility and relevance of these new therapies for the management of type 2 diabetes.
ABSTRACT
The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of ...metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p‐cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision‐cut liver slices prepared from control mice, Kupffer cell (KC)‐depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose‐dependently reduced the LPS‐induced up‐regulation of proinflammatory mediators at both mRNA and protein levels in precision‐cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide‐binding domain and leucine‐rich repeat containing (NLR) family pyrin domain‐containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF‐KB pathway and downstream proinflammatory gene up‐regulation. Indole also prevented LPS‐induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β‐hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.‐B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 32, 6681–6693 (2018). www.fasebj.org
To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction.
...We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe
) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed.
ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe
mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in
and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation.
We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.
In vitro studies have suggested that isolated gut bacteria are able to metabolize PUFA into CLA (conjugated linoleic acids) and CLnA (conjugated linolenic acids). However, the bioavailability of ...fatty acid metabolites produced in vivo by the gut microbes remains to be studied. Therefore, we measured intestinal concentration and plasma accumulation of bacterial metabolites produced from dietary PUFA in mice, first injected with a lipoprotein lipase inhibitor, then force-fed with either sunflower oil (200 µl) rich in n-6 PUFA or linseed oil (200 µl) rich in n-3 PUFA. The greatest production of bacterial metabolites was observed in the caecum and colon, and at a much lesser extent in the jejunum and ileum. In the caecal content, CLA proportions were higher in sunflower oil force-fed mice whereas CLnA proportions were higher in linseed oil force-fed mice. The accumulation of the main metabolites (CLA cis-9,trans-11-18:2 and CLnA cis-9,trans-11,cis-15-18:3) in the caecal tissue was not associated with their increase in the plasma, therefore suggesting that, if endogenously produced CLA and CLnA have any biological role in host metabolism regulation, their effect would be confined at the intestinal level, where the microbiota is abundant.
Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body ...weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases.
We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect.
We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat-fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14(-)(/)(-) mutant mice mimicked the metabolic and inflammatory effects of antibiotics.
This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.
To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.
Genetic (ob/ob) or diet-induced obese ...and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.
In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.
We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.
Scope
Binge consumption of alcohol is an alarming global health problem. Acute ethanol intoxication is characterized by hepatic inflammation and oxidative stress, which could be promoted by gut ...barrier function alterations. In this study, we have tested the hypothesis of the hepatoprotective effect of rhubarb extract in a mouse model of binge drinking and we explored the contribution of the gut microbiota in the related metabolic effects.
Methods and results
Mice were fed a control diet supplemented with or without 0.3% rhubarb extract for 17 days and were necropsied 6 h after an alcohol challenge. Supplementation with rhubarb extract changed the microbial ecosystem (assessed by 16S rDNA pyrosequencing) in favor of Akkermansia muciniphila and Parabacteroides goldsteinii. Furthermore, it improved alcohol‐induced hepatic injury, downregulated key markers of both inflammatory and oxidative stresses in the liver tissue, without affecting significantly steatosis. In the gut, rhubarb supplementation increased crypt depth, tissue weight, and the expression of antimicrobial peptides.
Conclusions
These findings suggest that some bacterial genders involved in gut barrier function, are promoted by phytochemicals present in rhubarb extract, and could therefore be involved in the modulation of the susceptibility to hepatic diseases linked to acute alcohol consumption.
Rhubarb extract induces profound changes in gut microbial composition and down‐regulates acute alcohol‐induced inflammatory and oxidative stresses in the liver of mice. We hypothesize that the increase in specific bacteria by rhubarb extract protects against hepatic damage by reinforcing gut barrier functions. Adapted with permission from Servier MedicalArt (http://creativecommons.org/licenses/by/3.0/legalcode).
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