Publications
157 results found
Q S Medeiros PH, Ledwaba SE, Bolick DT, et al., 2019, A murine model of diarrhea, growth impairment and metabolic disturbances with Shigella flexneri infection and the role of zinc deficiency, Gut Microbes, Vol: 10, Pages: 615-630, ISSN: 1949-0984
Shigella is one of the major enteric pathogens worldwide. We present a murine model of S. flexneri infection and investigate the role of zinc deficiency (ZD). C57BL/6 mice fed either standard chow (HC) or ZD diets were pretreated with an antibiotic cocktail and received S. flexneri strain 2457T orally. Antibiotic pre-treated ZD mice showed higher S. flexneri colonization than non-treated mice. ZD mice showed persistent colonization for at least 50 days post-infection (pi). S. flexneri-infected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice. S. flexneri preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes. Infection with S. flexneri ΔmxiG (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden. Several biochemical changes related to energy, inflammation and gut-microbial metabolism were observed. Zinc supplementation increased weight gains and reduced intestinal inflammation and stool shedding in ZD infected mice. In conclusion, young antibiotic-treated mice provide a new model of oral S. flexneri infection, with ZD promoting prolonged infection outcomes.
Consortium H, Drake L, Frost G, et al., 2019, Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Publisher: Imperial College London
The HUNGer consortium is comprised of a multi-disciplinary, multi-national consortium of world leading researchers, with expertise in physiology and nutrition, through to clinical research, public health and agriculture in LMIC settings. The HUNGer consortium was awarded the MRC Confidence in Global Nutrition and Health award in 2018.The HUNGer consortium is developing a programme of work that will directly address United Nations Sustainable Development Goal 2 (SDG-2): End hunger, achieve food security and improve nutrition, and promote sustainable agriculture. We believe there are a number of critical unanswered questions regarding the role of the gut in undernutrition, which if answered could significantly improve the effective management and prevention of undernutrition.The following document represents the consensus opinion of the HUNGer consortium concerning the key challenges that currently limit the effective management and prevention of undernutrition and the most promising potential solutions.
Hoyles L, Swann J, 2019, Influence of the Human Gut Microbiome on the Metabolic Phenotype, HANDBOOK OF METABOLIC PHENOTYPING, Editors: Lindon, Nicholson, Holmes, Publisher: ELSEVIER SCIENCE BV, Pages: 535-560, ISBN: 978-0-12-812293-8
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- Citations: 13
Sfyri PP, Yuldasheva NY, Tzimou A, et al., 2018, Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 129, Pages: 504-519, ISSN: 0891-5849
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- Citations: 14
Medlock G, Carey M, McDuffie D, et al., 2018, Inferring metabolic mechanisms of interaction within a defined gut microbiota, Cell Systems, Vol: 7, Pages: 245-257.e6, ISSN: 2405-4712
The diversity and number of species present within microbial communities create the potential for a multitudeof interspecies metabolic interactions. Here, we develop, apply, and experimentally test a framework forinferring metabolic mechanisms associated with interspecies interactions. We perform pairwise growth andmetabolome profiling of co-cultures of strains from a model mouse microbiota. We then apply our framework todissect emergent metabolic behaviors that occur in co-culture. Based on one of the inferences from thisframework, we identify and interrogate an amino acid cross-feeding interaction and validate that the proposedinteraction leads to a growth benefit in vitro. Our results reveal the type and extent of emergent metabolicbehavior in microbial communities composed of gut microbes. We focus on growth-modulating interactions, butthe framework can be applied to interspecies interactions that modulate any phenotype of interest withinmicrobial communities.
Passmore I, Letertre M, Preston M, et al., 2018, Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria, PLoS Pathogens, Vol: 14, ISSN: 1553-7366
Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro.
Aleman JO, Bokulich NA, Swann JR, et al., 2018, Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women, Journal of Translational Medicine, Vol: 16, ISSN: 1479-5876
Background:Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity.Methods:We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2–3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by 1H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways.Results:Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metab
DeBoer M, Platts-Mills J, Scharf R, et al., 2018, Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT): a protocol for a randomised factorial, double-blind, placebo- controlled trial of azithromycin, nitazoxanide and nicotinamide, BMJ Open, Vol: 8, ISSN: 2044-6055
Introduction In many developing areas in the world, a high burden of enteric pathogens in early childhood are associated with growth deficits. The tryptophan-kynurenine-niacin pathway has been linked to enteric inflammatory responses to intestinal infections. However, it is not known in these settings whether scheduled antimicrobial intervention to reduce subclinical enteric pathogen carriage or repletion of the tryptophan-kynurenine-niacin pathway improves linear growth and development.Methods and analysis We are conducting a randomised, placebo-controlled, factorial intervention trial in the rural setting of Haydom, Tanzania. We are recruiting 1188 children within the first 14 days of life, who will be randomised in a 2×2 factorial design to administration of antimicrobials (azithromycin and nitazoxanide, randomised together) and nicotinamide. The nicotinamide is administered as a daily oral dose, which for breast-feeding children aged 0–6 months is given to the mother and for children aged 6–18 months is given to the child directly. Azithromycin is given to the child as a single oral dose at months 6, 9, 12 and 15; nitazoxanide is given as a 3-day course at months 12 and 15. Mother/child pairs are followed via monthly in-home visits. The primary outcome is the child’s length-for-age Z-score at 18 months. Secondary outcomes for the child include additional anthropometry measures; stool pathogen burden and bacterial microbiome; systemic and enteric inflammation; blood metabolomics, growth factors, inflammation and nutrition; hydrogen breath assessment to estimate small-intestinal bacterial overgrowth and assessment of cognitive development. Secondary outcomes for the mother include breastmilk content of nicotinamide, other vitamins and amino acids; blood measures of tryptophan-kynurenine-niacin pathway and stool pathogens.Ethics and dissemination This trial has been approved by the Tanzanian National Institute for Medical Research, th
Martin G, Kolida S, Marchesi J, et al., 2018, In vitro modeling of bile acid processing by the human fecal microbiota, Frontiers in Microbiology, Vol: 9, ISSN: 1664-302X
Bile acids, the products of concerted host and gut bacterial metabolism, have important signaling functions within the mammalian metabolic system and a key role in digestion. Given the complexity of the mega-variate bacterial community residing in the gastrointestinal tract, studying associations between individual bacterial genera and bile acid processing remains a challenge. Here, we present a novel in vitro approach to determine the bacterial genera associated with the metabolism of different primary bile acids and their potential to contribute to inter-individual variation in this processing. Anaerobic, pH-controlled batch cultures were inoculated with human fecal microbiota and treated with individual conjugated primary bile acids (500 μg/ml) to serve as the sole substrate for 24 h. Samples were collected throughout the experiment (0, 5, 10, and 24 h) and the bacterial composition was determined by 16S rRNA gene sequencing and the bile acid signatures were characterized using a targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) approach. Data fusion techniques were used to identify statistical bacterial-metabolic linkages. An increase in gut bacteria associated bile acids was observed over 24 h with variation in the rate of bile acid metabolism across the volunteers (n = 7). Correlation analysis identified a significant association between the Gemmiger genus and the deconjugation of glycine conjugated bile acids while the deconjugation of taurocholic acid was associated with bacteria from the Eubacterium and Ruminococcus genera. A positive correlation between Dorea and deoxycholic acid production suggest a potential role for this genus in cholic acid dehydroxylation. A slower deconjugation of taurocholic acid was observed in individuals with a greater abundance of Parasutterella and Akkermansia. This work demonstrates the utility of integrating compositional (metataxonomics) and functional (metabonomics) systems biology approaches
Panic G, Coulibaly JT, Harvey N, et al., 2018, Characterizing the Biochemical Response to Schistosoma mansoni Infection and Treatment with Praziquantel in Preschool and School Aged Children, JOURNAL OF PROTEOME RESEARCH, Vol: 17, Pages: 2028-2033, ISSN: 1535-3893
Giallourou N, Medlock G, Bolick D, et al., 2018, A novel mouse model of Campylobacter jejuni enteropathy and diarrhea, PLoS Pathogens, Vol: 14, Pages: 1-23, ISSN: 1553-7366
Campylobacter infections are among the leading bacterial causes of diarrhea and of ‘environmental enteropathy’ (EE) and growth failure worldwide. However, the lack of an inexpensive small animal model of enteric disease with Campylobacter has been a major limitation for understanding its pathogenesis, interventions or vaccine development. We describe a robust standard mouse model that can exhibit reproducible bloody diarrhea or growth failure, depending on the zinc or protein deficient diet and on antibiotic alteration of normal microbiota prior to infection. Zinc deficiency and the use of antibiotics create a niche for Campylobacter infection to establish by narrowing the metabolic flexibility of these mice for pathogen clearance and by promoting intestinal and systemic inflammation. Several biomarkers and intestinal pathology in this model also mimic those seen in human disease. This model provides a novel tool to test specific hypotheses regarding disease pathogenesis as well as vaccine development that is currently in progress.
Mayneris-Perxachs J, Swann JR, 2018, Metabolic phenotyping of malnutrition during the first 1,000 days of life, European Journal of Nutrition, ISSN: 0044-264X
Giallourou N, Medlock GL, Bolick DT, et al., 2018, A novel mouse model of<i>Campylobacter jejuni</i>enteropathy and diarrhea
<jats:title>Abstract</jats:title><jats:p><jats:italic>Campylobacter</jats:italic>infections are among the leading bacterial causes of diarrhea and of ‘environmental enteropathy’ (EE) and growth failure worldwide. However, the lack of an inexpensive small animal model of enteric disease with<jats:italic>Campylobacter</jats:italic>has been a major limitation for understanding its pathogenesis, interventions or vaccine development. We describe a robust standard mouse model that can exhibit reproducible bloody diarrhea or growth failure, depending on the zinc or protein deficient diet and on antibiotic alteration of normal microbiota prior to infection. Zinc deficiency and the use of antibiotics create a niche for<jats:italic>Campylobacter</jats:italic>infection to establish by narrowing the metabolic flexibility of these mice for pathogen clearance and by promoting intestinal and systemic inflammation. Several biomarkers and intestinal pathology in this model also mimic those seen in human disease. This model provides a novel tool to testing specific hypotheses regarding disease pathogenesis as well as vaccine development that is currently in progress.</jats:p><jats:sec><jats:title>Author Summary</jats:title><jats:p><jats:italic>Campylobacter jejuni</jats:italic>has been identified as one of the leading causes of enteropathy and diarrhea. In developing countries, these repeated enteric infections often result in growth deficits and cognitive impairment. There is a lack of small animal models of<jats:italic>Campylobacter</jats:italic>infection. This is a major hurdle in understanding the pathogenesis of<jats:italic>Campylobacter</jats:italic>infection in order to lead to therapeutic treatments and vaccines. We have developed a highly reproducible mouse model of<jats:italic>Campylobacter</jats:italic>infection that has clinical o
Farras M, Chandwe K, Mayneris-Perxachs J, et al., 2018, Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea, PLoS ONE, Vol: 13, ISSN: 1932-6203
Background:Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia.Methods/Principal findings:We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy.Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013).Conclusions/Significance:Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of
Leng J, Proudman C, Darby A, et al., 2018, Exploration of the faecal microbiota and biomarker discovery in equine grass sickness, Journal of Proteome Research, Vol: 17, Pages: 1120-1128, ISSN: 1535-3893
Equine grass sickness (EGS) is a frequently fatal disease of horses, responsible for the death of 1-2% of the UK horse population annually. The etiology of this disease is currently uncharacterized although there is evidence it is associated with Clostridium botulinum neurotoxin in the gut. Prevention is currently not possible and ileal biopsy diagnosis is invasive. The aim of this study was to characterize the fecal microbiota and biofluid metabolic profiles of EGS horses, to further understand the mechanisms underlying this disease and identify metabolic biomarkers to aid in diagnosis. Urine, plasma and feces were collected from horses with EGS, matched controls (MC), and hospital controls (HC). Sequencing the16S rRNA gene of the fecal bacterial population of the study horses found a severe dysbiosis in EGS horses, with an increase in Bacteroidetes and a decrease in Firmicutes bacteria. Metabolic profiling by 1H nuclear magnetic resonance (NMR) spectroscopy found EGS to be associated with the lower urinary excretion of hippurate and 4-cresyl sulfate and higher excretion of O-acetyl carnitine and trimethylamine-N-oxide (TMAO). The predictive ability of the complete urinary metabolic signature and using the four discriminatory urinary metabolites to classify horses by disease status was assessed using a second (test) set of horses. The urinary metabolome and a combination of the four candidate biomarkers showed promise in aiding the identification of horses with EGS. Characterization of the metabolic shifts associated with EGS offers the potential of a non-invasive test to aid pre-mortem diagnosis.
Shortt C, Hasselwander O, Meynier A, et al., 2018, Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients, European Journal of Nutrition, Vol: 57, Pages: 25-49, ISSN: 0044-264X
PurposeThere is considerable interest in the effects of the intestinal microbiota (IM) composition, its activities in relation with the metabolism of dietary substrates and the impact these effects may have in the development and prevention of certain non-communicable diseases. It is acknowledged that a complex interdependence exists between the IM and the mammalian host and that the IM possesses a far greater diversity of genes and repertoire of metabolic and enzymatic capabilities than their hosts. However, full knowledge of the metabolic activities and interactions of the IM and the functional redundancy that may exist are lacking. Thus, the current review aims to assess recent literature relating to the role played by the IM in the absorption and metabolism of key nutrients and non-nutrients.MethodsA systematic review (PROSPERO registration: CRD42015019087) was carried out focussing on energy and the following candidate dietary substrates: protein, carbohydrate, fat, fibre, resistant starch (RS), and polyphenols to further understand the effect of the IM on the dietary substrates and the resulting by-products and host impacts. Particular attention was paid to the characterisation of the IM which are predominantly implicated in each case, changes in metabolites, and indirect markers and any potential impacts on the host.ResultsStudies show that the IM plays a key role in the metabolism of the substrates studied. However, with the exception of studies focusing on fibre and polyphenols, there have been relatively few recent human studies specifically evaluating microbial metabolism. In addition, comparison of the effects of the IM across studies was difficult due to lack of specific analysis/description of the bacteria involved. Considerable animal-derived data exist, but experience suggests that care must be taken when extrapolating these results to humans. Nevertheless, it appears that the IM plays a role in energy homeostasis and that protein microbial breakdown
Rowland I, Gibson GR, Heinken A, et al., 2018, Gut microbiota functions: metabolism of nutrients and other food components, European Journal of Nutrition, Vol: 57, Pages: 1-24, ISSN: 1436-6215
The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays.
Medlock GL, Carey M, McDuffie D, et al., 2018, Metabolic mechanisms of interaction within a defined gut microbiota, Publisher: bioRxiv
Metabolic interactions among species are ubiquitous in nature, and the fitness costs and benefits they impose often reinforce and stabilize them over time. These interactions are of particular importance in the human gut, where they have functions ranging from enhancing digestion to preventing (or exacerbating) infections. The diversity and sheer number of species present lead to the potential for a multitude of metabolic interactions among species to occur. However, identifying the mechanism and consequences of metabolic interactions between even two species is incredibly challenging. Here, we develop, apply, and experimentally test a framework for identifying potential metabolic mechanisms associated with interspecies interactions. We perform pairwise growth and metabolome profiling of co-cultures of strains from the altered Schaedler flora (ASF), a defined murine microbiota. We then apply our novel framework, which we call the Constant Yield Expectation (ConYE) model, to dissect emergent metabolic behaviors that occur in co-culture. Using the ConYE model, we identify and interrogate an amino acid cross-feeding interaction that is likely to confer a growth benefit to one ASF strain (Clostridium sp. ASF356) in co-culture with another strain (Parabacteroides goldsteinii ASF519). We experimentally validate that the proposed interaction leads to a growth benefit for this strain via media supplementation experiments. Our results reveal the type and extent of emergent metabolic behavior in microbial communities and demonstrate how metabolomic data can be used to identify potential metabolic interactions between organisms such as gut microbes. Our in vitro characterization of the ASF strains and interactions between them also enhances our ability to interpret and design experiments that utilize ASF-colonized animals. We anticipate that this work will improve the tractability of studies utilizing mice colonized with the ASF. Here, we focus on growth-modulating interaction
Costabile A, Buttarazzi I, Kolida S, et al., 2017, An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults, PLoS ONE, Vol: 12, ISSN: 1932-6203
Coronary heart disease (CHD) is one of the major causes of death and disability in industrialised countries, with elevated blood cholesterol an established risk factor. Total plasma cholesterol reduction in populations suffering from primary hypercholesterolemia may lower CHD incidence. This study investigated the cholesterol reducing capacity of Lactobacillus plantarum ECGC 13110402, a strain selected for its high bile salt hydrolase activity, in 49 normal to mildly hypercholesterolaemic adults. Primary efficacy outcomes included effect on blood lipids (total cholesterol (TC), low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) and triacylgycerides (TAG), inflammatory biomarkers and occurrence/severity of gastrointestinal side effects to establish safety and tolerance of the intervention. Secondary outcomes included blood pressure, immune biomarkers, gut microbiota characterisation and metabonome changes. The study was run in a parallel, double blind, placebo controlled, randomised design in which the active group ingested 2x109 CFU encapsulated Lactobacillus plantarum ECGC 13110402 twice daily. Daily ingestion of the active treatment resulted in a statistically significant reduction in LDL-C in volunteers with baseline TC<5mM during the 0–12 week period (13.9%, P = 0.030), a significant reduction in TC in volunteers with baseline TC≥6mM in the 0–6 week period (37.6%, P = 0.045), a significant decrease in TAG (53.9% P = 0.030) and an increase in HDL-C (14.7%, P = 0.007) in the over 60 years population in the 6–12 week period. A statistically significant reduction in systolic blood pressure was also observed across the active study group in the 6-12-week period (6.6%, P = 0.003). No impact on gastrointestinal function and side effects was observed during the study. Similar to blood and urine metabonomic analyses, faecal metagenomics did not reveal significant changes upon active or placebo intake. The results of this study sug
Bartelt LA, Bolick DT, Mayneris-Perxachs J, et al., 2017, Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli, PLoS Pathogens, Vol: 13, ISSN: 1553-7366
Diverse enteropathogen exposures associate with childhood malnutrition. To elucidatemechanistic pathways whereby enteric microbes interact during malnutrition, we used proteindeficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusingon common enteropathogens in malnourished children, Giardia lamblia and enteroaggregativeEscherichia coli (EAEC), we provide new insights into intersecting pathogen-specificmechanisms that enhance malnutrition. We show for the first time that during protein malnutrition,the intestinal microbiota permits persistent Giardia colonization and simultaneouslycontributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardiainfectedmice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardiainfections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis duringgrowth impairment, whereas host nicotinamide utilization adaptations that correspond withgrowth recovery increase. EAEC promotes intestinal inflammation and markers of myeloidcell activation. During co-infection, intestinal inflammatory signaling and cellular recruitmentresponses to EAEC are preserved together with a Giardia-mediated diminishment in myeloidcell activation. Conversely, EAEC extinguishes markers of host energy expenditureregulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integratingimmunologic and metabolic profiles during co-pathogen infection and malnutrition, wedevelop a working mechanistic model of how cumulative diet-induced and pathogen-triggeredmicrobial perturbations result in an increasingly wasted host.
Swann JR, Garcia-Perez I, Braniste V, et al., 2017, Application of 1H NMR spectroscopy to the metabolic phenotyping of rodent brain extracts: a metabonomic study of gut microbial influence on host brain metabolism, Journal of Pharmaceutical and Biomedical Analysis, Vol: 143, Pages: 141-146, ISSN: 1873-264X
H NMR Spectroscopy has been applied to determine the neurochemical profiles of brain extracts from the frontal cortex and hippocampal regions of germ free and normal mice and rats. The results revealed a number of differences between germ free (GF) and conventional (CV) rats or specific pathogen-free (SPF) mice with microbiome-associated metabolic variation found to be both species- and region-dependent. In the mouse, the GF frontal cortex contained lower amounts of creatine, N-acetyl-aspartate (NAA), glycerophosphocholine and lactate, but greater amounts of choline compared to that of specific pathogen free (SPF) mice. In the hippocampus, the GF mice had greater creatine, NAA, lactate and taurine content compared to those of the SPF animals, but lower relative quantities of succinate and an unidentified lipid-related component. The GF rat frontal cortex contained higher relative quantities of lactate, creatine and NAA compared to the CV animals whilst the GF hippocampus was characterized by higher taurine and phosphocholine concentrations and lower quantities of NAA, N-acetylaspartylglutamate and choline compared to the CV animals. Of note is that, in both rat and mouse brain extracts, concentrations of hippocampal taurine were found to be greater in the absence of an established microbiome. The results provide further evidence that brain biochemistry can be influenced by gut microbial status, specifically metabolites involved in energy metabolism demonstrating biochemical dialogue between the microbiome and brain.
Bolick DT, Mayneris-Perxachs J, Medlock GL, et al., 2017, Increased urinary trimethylamine N-oxide (TMAO) following Cryptosporidium infection and protein malnutrition independent of microbiome effects, Journal of Infectious Diseases, Vol: 216, Pages: 64-71, ISSN: 1537-6613
Cryptosporidium infections have been associated with growth stunting, even in the absence of diarrhea. Having previously detailed the effects of protein deficiency on both microbiome and metabolome in this model, we now describe the specific gut microbial and biochemical effects of Cryptosporidium infection. Protein-deficient mice were infected with Cryptosporidium parvum oocysts for 6–13 days and compared with uninfected controls. Following infection, there was an increase in the urinary excretion of choline- and amino-acid-derived metabolites. Conversely, infection reduced the excretion of the microbial–host cometabolite (3-hydroxyphenyl)propionate-sulfate and disrupted metabolites involved in the tricarboxylic acid (TCA) cycle. Correlation analysis of microbial and biochemical profiles resulted in associations between various microbiota members and TCA cycle metabolites, as well as some microbial-specific degradation products. However, no correlation was observed between the majority of the infection-associated metabolites and the fecal bacteria, suggesting that these biochemical perturbations are independent of concurrent changes in the relative abundance of members of the microbiota. We conclude that cryptosporidial infection in protein-deficient mice can mimic some metabolic changes seen in malnourished children and may help elucidate our understanding of long-term metabolic consequences of early childhood enteric infections.
Hicks LC, Powles ST, Swann JR, et al., 2017, EFFECTS OF TIME ON URINARY METABOLIC SIGNATURES IN INFLAMMATORY BOWEL DISEASE, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S611-S612, ISSN: 0016-5085
Massot-Cladera M, Mayneris-Perxachs J, Costabile A, et al., 2017, Association between urinary metabolic profile and the intestinal effects of cocoa in rats, British Journal of Nutrition, Vol: 117, Pages: 623-634, ISSN: 0007-1145
The aim of this study was to elucidate the relationship between the urinary metabolic fingerprint and the effects of cocoa and cocoa fibre on body weight, hormone metabolism, intestinal immunity and microbiota composition. To this effect, Wistar rats were fed, for 3 weeks, a diet containing 10 % cocoa (C10) or two other diets with same the proportion of fibres: one based on cocoa fibre (CF) and another containing inulin as a reference (REF) diet. The rats’ 24 h urine samples were analysed by an untargeted 1H NMR spectroscopy-based metabonomic approach. Concentrations of faecal IgA and plasma metabolic hormones were also quantified. The C10 diet decreased the intestinal IgA, plasma glucagon-like peptide-1 and glucagon concentrations and increased ghrelin levels compared with those in the REF group. Clear differences were observed between the metabolic profiles from the C10 group and those from the CF group. Urine metabolites derived from cocoa correlated with the cocoa effects on body weight, immunity and the gut microbiota. Overall, cocoa intake alters the host and bacterial metabolism concerning energy and amino acid pathways, leading to a metabolic signature that can be used as a marker for consumption. This metabolic profile correlates with body weight, metabolic hormones, intestinal immunity and microbiota composition.
Li JV, Swann J, Marchesi JR, 2017, Biology of the Microbiome 2: Metabolic Role, Gastroenterology Clinics of North America, Vol: 46, Pages: 37-47, ISSN: 0889-8553
The human microbiome is a new frontier in biology and one that is helping to define what it is to be human. Recently, we have begun to understand that the “communication” between the host and its microbiome is via a metabolic superhighway. By interrogating and understanding the molecules involved we may start to know who the main players are, and how we can modulate them and the mechanisms of health and disease.
Grimaldi R, Cela D, Swann JR, et al., 2016, In vitro fermentation of B-GOS: impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children, FEMS Microbiology Ecology, Vol: 93, ISSN: 0168-6496
Children with autism spectrum disorders (ASD) often suffer gastrointestinal problems consistent with imbalances in the gut microbial population. Treatment with antibiotics or pro/prebiotics has been postulated to regulate microbiota and improve gut symptoms, but there is a lack of evidence for such approaches, especially for prebiotics. This study assessed the influence of a prebiotic galactooligosaccharide (B-GOS) on gut microbial ecology and metabolic function using faecal samples from autistic and non-autistic children in an in vitro gut model system. Bacteriology was analysed using flow cytometry combined with fluorescence in situ hybridization and metabolic activity by HPLC and 1H-NMR. Consistent with previous studies, the microbiota of children with ASD contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared with non-autistic children. B-GOS administration significantly increased bifidobacterial populations in each compartment of the models, both with autistic and non-autistic-derived samples, and lactobacilli in the final vessel of non-autistic models. In addition, changes in other bacterial population have been seen in particular for Clostridium, Rosburia, Bacteroides, Atopobium, Faecalibacterium prausnitzii, Sutterella spp. and Veillonellaceae. Furthermore, the addition of B-GOS to the models significantly altered short-chain fatty acid production in both groups, and increased ethanol and lactate in autistic children.
Biggs MB, Medlock GL, Moutinho TJ, et al., 2016, Systems-level metabolism of the Altered Schaedler Flora, a complete gut microbiota, ISME Journal, Vol: 11, Pages: 426-438, ISSN: 1751-7362
The Altered Schaedler Flora (ASF) is a model microbial community with both in vivo and in vitro relevance. Here we provide the first characterization of the ASF community in vitro, independent of a murine host. We compared the functional genetic content of the ASF to wild murine metagenomes and found that the ASF functionally represents wild microbiomes better than random consortia of similar taxonomic composition. We developed a chemically-defined medium that supported growth of seven of the eight ASF members. To elucidate the metabolic capabilities of these ASF species—including potential for interactions such as cross feeding—we performed a spent media screen and analyzed the results through dynamic growth measurements and non-targeted metabolic profiling. We found that cross-feeding is relatively rare (32 of 3 570 possible cases), but is enriched between Clostridium ASF356 and Parabacteroides ASF519. We identified many cases of emergent metabolism (856 of 3 570 possible cases). These data will inform efforts to understand ASF dynamics and spatial distribution in vivo, to design pre- and probiotics that modulate relative abundances of ASF members, and will be essential for validating computational models of ASF metabolism. Well-characterized, experimentally tractable microbial communities enable research that can translate into more effective microbiome-targeted therapies to improve human health.
Mayneris-Perxachs J, Bolick DT, Leng J, et al., 2016, Protein- and zinc-deficient diets modulate the murine microbiome and metabolic phenotype, American Journal of Clinical Nutrition, Vol: 104, Pages: 1253-1262, ISSN: 1938-3207
Background: Environmental enteropathy, linked to undernutrition and chronic infections, affects the physical and mental growth of children in developing areas worldwide. Key to understanding how these factors combine to shape developmental outcomes is first understanding the effects of nutritional deficiencies on the mammalian system, including the effect on the gut microbiota.Objective: We dissect the nutritional components of environmental enteropathy by analyzing the specific metabolic and gut microbiota changes that occur in weaned mouse models of zinc or protein deficiency as compared to well-nourished controls. Design: Using a 1H NMR spectroscopy-based metabolic profiling approach with matching 16S microbiota analyses, the metabolic consequences and specific effects on the fecal microbiota of protein and zinc deficiency were probed independently in a murine model.Results: We find considerable shifts within the intestinal microbiota 14-24d post-weaning in mice maintained on a normal diet (including increases in Proteobacteria and striking decreases in Bacterioidetes). While the zinc deficient microbiota were comparable to the age-matched well-nourished profile, the protein-restricted microbiota remained closer in composition to the weaned enterotype with retention of Bacteroidetes. Striking increases in Verrucomicrobia (predominantly Akkermansia muciniphila) were observed in both well-nourished and protein-deficient mice 14d post-weaning. We find that protein malnutrition impairs growth and has major metabolic consequences (much more than zinc deficiency) that include altered energy, polyamine and purine/pyrimidine metabolism. Consistent with major changes in the gut microbiota, reductions in microbial proteolysis and increases in microbial dietary choline processing were observed.
Guerrant RL, Leite AM, Pinkerton R, et al., 2016, Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in Northeast Brazil, PLOS One, Vol: 11, ISSN: 1932-6203
Critical to the design and assessment of interventions for enteropathy and itsdevelopmental consequences in children living in impoverished conditions arenon-invasive biomarkers that can detect intestinal damage and predict its effectson growth and development. We therefore assessed fecal, urinary and systemicbiomarkers of enteropathy and growth predictors in 375 6-26 month-old childrenwith varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301of these children returned for followup anthropometry after 2-6m. Biomarkersthat correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin(if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption);and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggestingimpaired defenses). In contrast, subsequent growth was predicted in those withhigher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP andSAA (showing intestinal barrier disruption and inflammation). Better growth waspredicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin inpredicting subsequent growth impairment.Biomarkers clustered into markers of 1) functional intestinal barrier disruption andtranslocation, 2) structural intestinal barrier disruption and inflammation and 3)systemic inflammation. Principle components pathway analyses also showedthat L/M with %L, I-FABP and MPO associate with impaired growth, while also(like MPO) associating with a systemic inflammation cluster of kynurenine, LBP,sCD14, SAA and K/T. Systemic evidence of LPS translocation associated withstunting, while markers of barrier disruption or repair (A1AT and Reg1 with lowzonulin) associated with fecal MPO and neopterin.We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPStranslocation and of intestinal and systemic inflammation can help elucidate howwe recognize, understand, and ass
Omairi S, Matsakas A, Degens H, et al., 2016, Enhanced exercise and regenerative capacity in a mouse model that violates size constraints of oxidative muscle fibres, eLife, Vol: 5, ISSN: 2050-084X
A central tenet of skeletal muscle biology is the existence of an inverse relationship between the oxidative fibre capacity and its size. However, robustness of this relationship is unknown. We show that superimposition of Estrogen-related receptor gamma (Errγ) on the myostatin (Mtn) mouse null background (Mtn-/-/ErrγTg/+) results in hypertrophic muscle with a high oxidative capacity thus violating the inverse relationship between fibre size and oxidative capacity. We also examined the canonical view that oxidative muscle phenotype positively correlate with Satellite cell number, the resident stem cells of skeletal muscle. Surprisingly, hypertrophic fibres from Mtn-/-/ErrγTg/+ mouse showed satellite cell deficit which unexpectedly did not affect muscle regeneration. These observations 1) challenge the concept of a constraint between fibre size and oxidative capacity and 2) indicate the important role of the microcirculation in the regenerative capacity of a muscle even when satellite cell numbers are reduced.
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