Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed ...hosts. In healthy individuals the intestinal microbiota have a symbiotic relationship with the host organism and possess important and unique functions, including a metabolic function （i.e. digestion of dietary compounds and xenobiotics, fermentation of undigestible carbohydrates with production of short chain fatty acids）, a mucosal barrier function （i.e. by inhibiting pathogen invasion and strengthening epithelial barrier integrity）, and an immune modula- tory function （i.e. mucosal immune system priming and maintenance of intestinal epithelium homeostasis）. A fine balance regulates the mechanism that allows co- existence of mammals with their commensal bacteria. In IBD this mechanism of immune tolerance is impaired because of several potential causative factors. The gut microbiota composition and activity of IBD patients are abnormal, with a decreased prevalence of dominant members of the human commensal microbiota （i.e. Clostridium IXa and IV groups, Bacteroides, bifldobacteria） and a concomitant increase in detrimental bacteria （i.e. sulphate-reducing bacteria, Escherichia coll. The observed dysbiosis is concomitant with defectiveinnate immunity and bacterial killing （i.e. reduced mucosal defensins and IgA, malfunctioning phagocytosis） and overaggressive adaptive immune response （due to ineffective regulatory T cells and antigen presenting cells）, which are considered the basis of IBD pathogen- esis. However, we still do not know how the interplay between these parameters causes the disease. Studies looking at gut microbial composition, epithelial integrity and mucosal immune markers in genotyped IBD populations are therefore warranted to shed light on this obscure pathogenesis.
Over the last 10–15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new ‘omic’ technologies ...that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.
PURPOSE OF REVIEWThe spread of the Western lifestyle across the globe has led to a pandemic in obesity-related metabolic disease. The Mediterranean diet (MedDiet), Okinawa diet (OkD) and Nordic diet, ...derived from very different regions of the world and culinary traditions, have a large whole plant food component and are associated with reduced disease risk. This review focuses on polyphenol : microbiome interactions as one possible common mechanistic driver linking the protective effects whole plant foods against metabolic disease across healthy dietary patterns irrespective of geography.
RECENT FINDINGSAlthough mechanistic evidence in humans is still scarce, animal studies suggest that polyphenol or polyphenol rich foods induce changes within the gut microbiota and its metabolic output of trimethylamine N-oxide, short-chain fatty acids, bile acids and small phenolic acids. These cross-kingdom signaling molecules regulate mammalian lipid and glucose homeostasis, inflammation and energy storage or thermogenesis, physiological processes determining obesity-related metabolic and cardiovascular disease risk. However, it appears that where in the intestine metabolites are produced, the microbiota communities involved, and interactions between the metabolites themselves, can all influence physiological responses, highlighting the need for a greater understanding of the kinetics and site of production of microbial metabolites within the gut.
SUMMARYInteractions between polyphenols and metabolites produced by the gut microbiota are emerging as a possible unifying protective mechanism underpinning diverse healthy dietary patterns signaling across culinary traditions, across geography and across domains of life.
The quantification of short-chain and medium-chain fatty acids is becoming more and more relevant in fecal and plasma samples due to their biological impact, which has been associated with colon ...rectal cancer and fiber consumption. For these reasons, a fast, cost-effective, and reproducible analytical method is highly required. In this research, a gas chromatography–mass spectrometry method based on full scan and multiple reaction monitoring (MRM) acquisition modes were optimized and validated for the analysis of short-chain and medium-chain fatty acids in three biological samples: human fecal water, fecal fermentation supernatants, and human plasma. Several extraction solvents (acidified water, diethyl ether, dichloromethane, ethyl acetate, and methyl
tert
-butyl ether (MTBE) were further evaluated, demonstrating that the latter was clearly the most suitable solvent with recoveries from 75.4 to 124.4% and coefficient of variations lower than 20%. The applicability of the GC–MS method was tested, for instance, acetic acid was quantified by using samples of plasma and feces from healthy donors at mean values of 66.9 μM and 24.5 mM, respectively. The optimized protocol could successfully find applications within multi-compartment human studies. In parallel, a second pilot experiment on fecal fermentation supernatants indicated that the proposed protocol is suitable to follow the formation of SCFAs during in vitro fermentation by the human gut microbiota. In summary, the present work provided an improved GC–MS method for precise and accurate quantification of SCFAs and MCFAs in human feces and plasma.
The human gut microbiota has been identified as a possible novel CVD risk factor. This review aims to summarise recent insights connecting human gut microbiome activities with CVD and how such ...activities may be modulated by diet. Aberrant gut microbiota profiles have been associated with obesity, type 1 and type 2 diabetes and non-alcoholic fatty liver disease. Transfer of microbiota from obese animals induces metabolic disease and obesity in germ-free animals. Conversely, transfer of pathogen-free microbiota from lean healthy human donors to patients with metabolic disease can increase insulin sensitivity. Not only are aberrant microbiota profiles associated with metabolic disease, but the flux of metabolites derived from gut microbial metabolism of choline, phosphatidylcholine and l-carnitine has been shown to contribute directly to CVD pathology, providing one explanation for increased disease risk of eating too much red meat. Diet, especially high intake of fermentable fibres and plant polyphenols, appears to regulate microbial activities within the gut, supporting regulatory guidelines encouraging increased consumption of whole-plant foods (fruit, vegetables and whole-grain cereals), and providing the scientific rationale for the design of efficacious prebiotics. Similarly, recent human studies with carefully selected probiotic strains show that ingestion of viable microorganisms with the ability to hydrolyse bile salts can lower blood cholesterol, a recognised risk factor in CVD. Taken together such observations raise the intriguing possibility that gut microbiome modulation by whole-plant foods, probiotics and prebiotics may be at the base of healthy eating pyramids advised by regulatory agencies across the globe. In conclusion, dietary strategies which modulate the gut microbiota or their metabolic activities are emerging as efficacious tools for reducing CVD risk and indicate that indeed, the way to a healthy heart may be through a healthy gut microbiota.
Apples are rich in bioactive polyphenols and fiber. Evidence suggests that consumption of apples or their bioactive components is associated with beneficial effects on lipid metabolism and other ...markers of cardiovascular disease (CVD). However, adequately powered randomized controlled trials are necessary to confirm these data and explore the mechanisms.
We aimed to determine the effects of apple consumption on circulating lipids, vascular function, and other CVD risk markers.
The trial was a randomized, controlled, crossover, intervention study. Healthy mildly hypercholesterolemic volunteers (23 women, 17 men), with a mean ± SD BMI 25.3 ± 3.7 kg/m2 and age 51 ± 11 y, consumed 2 apples/d Renetta Canada, rich in proanthocyanidins (PAs) or a sugar- and energy-matched apple control beverage (CB) for 8 wk each, separated by a 4-wk washout period. Fasted blood was collected before and after each treatment. Serum lipids, glucose, insulin, bile acids, and endothelial and inflammation biomarkers were measured, in addition to microvascular reactivity, using laser Doppler imaging with iontophoresis, and arterial stiffness, using pulse wave analysis.
Whole apple (WA) consumption decreased serum total (WA: 5.89 mmol/L; CB: 6.11 mmol/L; P = 0.006) and LDL cholesterol (WA: 3.72 mmol/L; CB: 3.86 mmol/L; P = 0.031), triacylglycerol (WA: 1.17 mmol/L; CB: 1.30 mmol/L; P = 0.021), and intercellular cell adhesion molecule-1 (WA: 153.9 ng/mL; CB: 159.4 ng/mL; P = 0.028), and increased serum uric acid (WA: 341.4 μmol/L; CB: 330 μmol/L; P = 0.020) compared with the CB. The response to endothelium-dependent microvascular vasodilation was greater after the apples WA: 853 perfusion units (PU), CB: 760 PU; P = 0.037 than after the CB. Apples had no effect on blood pressure or other CVD markers.
These data support beneficial hypocholesterolemic and vascular effects of the daily consumption of PA-rich apples by mildly hypercholesterolemic individuals. This trial was registered at clinicaltrials.gov as NCT01988389.
Sustainability of aquaculture is tied to the origin of feed ingredients. In search of sustainable fish meal-free formulations for rainbow trout, we evaluated the effect of Hermetia illucens meal (H) ...and poultry by-product meal (P), singly (10, 30, and 60% of either H or P) or in combination (10% H + 50% P, H10P50), as partial replacement of vegetable protein (VM) on gut microbiota (GM), inflammatory, and immune biomarkers. Fish fed the mixture H10P50 had the best growth performance. H, P, and especially the combination H10P50 partially restored α-diversity that was negatively affected by VM. Diets did not differ in the Firmicutes:Proteobacteria ratio, although the relative abundance of Gammaproteobacteria was reduced in H and was higher in P and in the fishmeal control. H had higher relative abundance of chitin-degrading Actinomyces and Bacillus, Dorea, and Enterococcus. Actinomyces was also higher in H feed, suggesting feed-chain microbiome transmission. P increased the relative abundance of protein degraders Paeniclostridium and Bacteroidales. IL-1β, IL-10, TGF-β, COX-2, and TCR-β gene expression in the midgut and head kidney and plasma lipopolysaccharide (LPS) revealed that the diets did not compromise the gut barrier function or induce inflammation. H, P, and H10P50 therefore appear valid protein sources in fishmeal-free aquafeeds.
Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of ...neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1-3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent-offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (
,
,
,
,
,
,
, and
. We found four de novo disruptive variants of four novel candidate ASD/ID genes:
,
,
,
. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.
Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Patrice D. Cani 1 2 ,
Jacques Amar 3 ,
Miguel Angel Iglesias 1 ,
Marjorie Poggi 4 ,
Claude Knauf 1 ,
Delphine Bastelica 4 ,
Audrey M. ...Neyrinck 2 ,
Francesca Fava 5 ,
Kieran M. Tuohy 5 ,
Chantal Chabo 1 ,
Aurélie Waget 1 ,
Evelyne Delmée 2 ,
Béatrice Cousin 6 ,
Thierry Sulpice 7 ,
Bernard Chamontin 3 ,
Jean Ferrières 3 ,
Jean-François Tanti 8 ,
Glenn R. Gibson 5 ,
Louis Casteilla 6 ,
Nathalie M. Delzenne 2 ,
Marie Christine Alessi 4 and
Rémy Burcelin 1
1 Institute of Molecular Medicine, I2MR Toulouse, France
2 Unité Pharmacokinetics, Metabolism, Nutrition, and Toxicology-73/69, Université catholique de Louvain, Brussels, Belgium
3 Institut National de la Santé et de la Recherche Médicale (INSERM) 558, Toulouse, France
4 INSERM U 626, Marseille, France
5 Food Microbial Sciences Unit, Department of Food Biosciences, University of Reading, Reading, U.K
6 Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
7 Physiogenex S.A.S., Labège Innopole, France
8 INSERM U 568, Nice, France
Address correspondence and reprint requests to Rémy Burcelin, I2MR U858, IFR 31, Hôpital Rangueil, BP 84225, Toulouse 31432
Cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr
Abstract
Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking
an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide
(LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively,
on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times,
a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing
microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion
of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar
extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride
content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14
mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates
that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that
the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration
could be a potent strategy for the control of metabolic diseases.
IKK, inhibitor of κB kinase
IL, interleukin
LPS, lipopolysaccharide
PAI, plasminogen activator inhibitor
TLR4, toll-like receptor 4
TNF, tumor necrosis factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db06-1491.
P.D.C., J.A., and M.A.I. contributed equally to this article.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted April 13, 2007.
Received October 24, 2006.
DIABETES
Obesity is now considered a major public health concern globally as it predisposes to a number of chronic human diseases. Most developed countries have experienced a dramatic and significant rise in ...obesity since the 1980s, with obesity apparently accompanying, hand in hand, the adoption of "Western"-style diets and low-energy expenditure lifestyles around the world. Recent studies report an aberrant gut microbiota in obese subjects and that gut microbial metabolic activities, especially carbohydrate fermentation and bile acid metabolism, can impact on a number of mammalian physiological functions linked to obesity. The aim of this review is to present the evidence for a characteristic "obese-type" gut microbiota and to discuss studies linking microbial metabolic activities with mammalian regulation of lipid and glucose metabolism, thermogenesis, satiety, and chronic systemic inflammation. We focus in particular on short-chain fatty acids (SCFA) produced upon fiber fermentation in the colon. Although SCFA are reported to be elevated in the feces of obese individuals, they are also, in contradiction, identified as key metabolic regulators of the physiological checks and controls mammals rely upon to regulate energy metabolism. Most studies suggest that the gut microbiota differs in composition between lean and obese individuals and that diet, especially the high-fat low-fiber Western-style diet, dramatically impacts on the gut microbiota. There is currently no consensus as to whether the gut microbiota plays a causative role in obesity or is modulated in response to the obese state itself or the diet in obesity. Further studies, especially on the regulatory role of SCFA in human energy homeostasis, are needed to clarify the physiological consequences of an "obese-style" microbiota and any putative dietary modulation of associated disease risk.
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