Imperial College London

DrIsabelGarcia Perez

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Lecturer in Precision & Systems Medicine
 
 
 
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i.garcia-perez

 
 
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101Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

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Year
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60 results found

Posma JM, Garcia-Perez I, Frost G, Aljuraiban GS, Chan Q, Van Horn L, Daviglus M, Stamler J, Holmes E, Elliott P, Nicholson JKet al., 2021, Nutriome-metabolome relationships provide insights into dietary intake and metabolism (vol 1, pg 426, 2020), NATURE FOOD

Journal article

Barton W, Cronin O, GarciaPerez I, Whiston R, Holmes E, Woods T, Molloy CB, Molloy MG, Shanahan F, Cotter PD, OSullivan Oet al., 2021, The effects of sustained fitness improvement on the gut microbiome: A longitudinal, repeated measures case‐study approach, Translational Sports Medicine, Vol: 4, Pages: 174-192, ISSN: 2573-8488

The athlete gut microbiome differs from that of non‐athletes in its composition and metabolic function. Short‐term fitness improvement in sedentary adults does not replicate the microbiome characteristics of athletes. The objective of this study was to investigate whether sustained fitness improvement leads to pronounced alterations in the gut microbiome. This was achieved using a repeated‐measures, case‐study approach that examined the gut microbiome of two initially unfit volunteers undertaking progressive exercise training over a 6‐month period. Samples were collected every two weeks, and microbiome, metabolome, diet, body composition, and cardiorespiratory fitness data were recorded. Training culminated in both participants completing their respective goals (a marathon or Olympic‐distance triathlon) with improved body composition and fitness parameters. Increases in gut microbiota α‐diversity occurred with sustained training and fluctuations occurred in response to training events (eg, injury, illness, and training peaks). Participants’ BMI reduced during the study and was significantly associated with increased urinary measurements of N‐methyl nicotinate and hippurate, and decreased phenylacetylglutamine. These results suggest that sustained fitness improvements support alterations to gut microbiota and physiologically‐relevant metabolites. This study provides longitudinal analysis of the gut microbiome response to real‐world events during progressive fitness training, including intercurrent illness and injury.

Journal article

Penney N, Barton W, Posma J, Darzi A, Frost G, Cotter P, Holmes E, Shanahan F, O Sullivan O, Garcia Perez Iet al., 2020, Investigating the role of diet and exercise in gut microbe-hostcometabolism, mSystems, Vol: 5, Pages: 1-16, ISSN: 2379-5077

We investigated the individual and combined effects of diet and physical exercise on metabolism and the gut microbiome to establish how these lifestyle factors influence host-microbiome cometabolism. Urinary and fecal samples were collected from athletes and less active controls. Individuals were further classified according to an objective dietary assessment score of adherence to healthy dietary habits according to WHO guidelines, calculated from their proton nuclear magnetic resonance (1H-NMR) urinary profiles. Subsequent models were generated comparing extremes of dietary habits, exercise, and the combined effect of both. Differences in metabolic phenotypes and gut microbiome profiles between the two groups were assessed. Each of the models pertaining to diet healthiness, physical exercise, or a combination of both displayed a metabolic and functional microbial signature, with a significant proportion of the metabolites identified as discriminating between the various pairwise comparisons resulting from gut microbe-host cometabolism. Microbial diversity was associated with a combination of high adherence to healthy dietary habits and exercise and was correlated with a distinct array of microbially derived metabolites, including markers of proteolytic activity. Improved control of dietary confounders, through the use of an objective dietary assessment score, has uncovered further insights into the complex, multifactorial relationship between diet, exercise, the gut microbiome, and metabolism. Furthermore, the observation of higher proteolytic activity associated with higher microbial diversity indicates that increased microbial diversity may confer deleterious as well as beneficial effects on the host.

Journal article

Petropoulou K, Salt LJ, Edwards CH, Warren FJ, Garcia-Perez I, Chambers ES, Alshaalan R, Khatib M, Perez-Moral N, Cross KL, Kellingray L, Stanley R, Koev T, Khimyak YZ, Narbad A, Penney N, Serrano-Contreras JI, Charalambides MN, Miguens Blanco J, Castro Seoane R, McDonald JAK, Marchesi JR, Holmes E, Godsland IF, Morrison DJ, Preston T, Domoney C, Wilde PJ, Frost GSet al., 2020, A natural mutation in Pisum sativum L. (pea) alters starch assembly and improves glucose homeostasis in humans, Nature Food

Journal article

Willis ND, Lloyd AJ, Xie L, Stiegler M, Tailliart K, Garcia-Perez I, Chambers ES, Beckmann M, Draper J, Mathers JCet al., 2020, Design and characterisation of a randomized food intervention that mimics exposure to a typical UK diet to provide urine samples for identification and validation of metabolite biomarkers of food intake, Frontiers in Nutrition, Vol: 7, Pages: 1-16, ISSN: 2296-861X

Poor dietary choices are major risk factors for obesity and non-communicable diseases, which places an increasing burden on healthcare systems worldwide. To monitor the effectiveness of healthy eating guidelines and strategies, there is a need for objective measures of dietary intake in community settings. Metabolites derived from specific foods present in urine samples can provide objective biomarkers of food intake (BFIs). Whilst the majority of biomarker discovery/validation studies have investigated potential biomarkers for single foods only, this study considered the whole diet by using menus that delivered a wide range of foods in meals that emulated conventional UK eating patterns. Fifty-one healthy participants (range 19–77 years; 57% female) followed a uniquely designed, randomized controlled dietary intervention, and provided spot urine samples suitable for discovery of BFIs within a real-world context. Free-living participants prepared and consumed all foods and drinks in their own homes and were asked to follow the protocols for meal consumption and home urine sample collection. This study also assessed the robustness, and impact on data quality, of a minimally invasive urine collection protocol. Overall the study design was well-accepted by participants and concluded successfully without any drop outs. Compliance for urine collection, adherence to menu plans, and observance of recommended meal timings, was shown to be very high. Metabolome analysis using mass spectrometry coupled with data mining demonstrated that the study protocol was well-suited for BFI discovery and validation. Novel, putative biomarkers for an extended range of foods were identified including legumes, curry, strongly-heated products, and artificially sweetened, low calorie beverages. In conclusion, aspects of this study design would help to overcome several current challenges in the development of BFI technology. One specific attribute was the examination of BFI generalizabil

Journal article

Beckmann M, Wilson T, Zubair H, Lloyd AJ, Lyons L, Phillips H, Tailliart K, Gregory N, Thatcher R, Garcia-Perez I, Frost G, Mathers JC, Draper Jet al., 2020, A standardized strategy for simultaneous quantification of urine metabolites to validate development of a biomarker panel allowing comprehensive assessment of dietary exposure., Molecular Nutrition and Food Research, Vol: 64, Pages: 1-15, ISSN: 1613-4125

SCOPE: Metabolites derived from individual foods found in human biofluids after consumption could provide objective measures of dietary intake. For comprehensive dietary assessment, quantification methods would need to manage the structurally diverse mixture of target metabolites present at a wide concentration range. METHODS & RESULTS: We developed a strategy for selection of candidate dietary exposure biomarkers, providing comprehensive coverage. An analytical method for 62 food biomarkers was validated by extensive analysis of chromatographic and ionization behaviour characteristics using triple quadrupole mass spectrometry. We used urine samples from two food intervention studies: one controlled, inpatient study (n = 19) and the other a free-living study where individuals (n = 15) were provided with food as a series of menu plans. As proof-of-principle, we demonstrated that the biomarker panel could discriminate between menu plans by detecting distinctive changes in the concentration in urine of targeted metabolites. We showed quantitative relationships between four biomarker concentrations in urine and dietary intake. CONCLUSIONS: We have demonstrated design concepts for an analytical strategy allowing simultaneous quantification of a comprehensive panel of chemically-diverse biomarkers of a wide range of commonly-consumed foods. We propose that integration of self-reported dietary recording tools with biomarker approaches will provide more robust assessment of dietary exposure. This article is protected by copyright. All rights reserved.

Journal article

Garcia Perez I, Posma JM, Serrano Contreras JI, Boulange C, Chan Q, Frost G, Stamler J, Elliott P, Lindon J, Holmes E, Nicholson Jet al., 2020, Identifying unknown metabolites using NMR-based metabolic profiling techniques, Nature Protocols, Vol: 15, Pages: 2538-2567, ISSN: 1750-2799

Metabolic profiling of biological samples provides important insights into multiple physiological and pathological processes, but is hindered by a lack of automated annotation and standardised methods for structure elucidation of candidate disease biomarkers. Here, we describe a system for identifying molecular species derived from NMR spectroscopy based metabolic phenotyping studies, with detailed info on sample preparation, data acquisition, and data modelling. We provide eight different modular workflows to be followed in a recommended sequential order according to their level of difficulty. This multi-platform system involves the use of statistical spectroscopic tools such as STOCSY, STORM and RED-STORM to identify other signals in the NMR spectra relating to the same molecule. It also utilizes 2D-NMR spectroscopic analysis, separation and pre-concentration techniques, multiple hyphenated analytical platforms and data extraction from existing databases. The complete system, using all eight workflows, would take up to a month, as it includes multidimensional NMR experiments that require prolonged experiment times. However, easier identification cases using fewer steps would take two or three days. This approach to biomarker discovery is efficient, cost-effective and offers increased chemical space coverage of the metabolome, resulting in faster and more accurate assignment of NMR-generated biomarkers arising from metabolic phenotyping studies. Finally, it requires basic understanding of Matlab in order to perform statistical spectroscopic tools and analytical skills to perform Solid Phase Extraction, LC-fraction collection, LC-NMR-MS and 1D and 2D NMR experiments.

Journal article

Posma JM, Garcia Perez I, Frost G, Aljuraiban G, Chan Q, Van Horn L, Daviglus M, Stamler J, Holmes E, Elliott P, Nicholson Jet al., 2020, Nutriome-metabolome relationships provide insights into dietary intake and metabolism, Nature Food, Vol: 1, Pages: 426-436, ISSN: 2662-1355

Dietary assessment traditionally relies on self-reported data which are often inaccurate and may result in erroneous diet-disease risk associations. We illustrate how urinary metabolic phenotyping can be used as alternative approach for obtaining information on dietary patterns. We used two multi-pass 24-hr dietary recalls, obtained on two occasions on average three weeks apart, paired with two 24-hr urine collections from 1,848 U.S. individuals; 67 nutrients influenced the urinary metabotype measured with ¹H-NMR spectroscopy characterized by 46 structurally identified metabolites. We investigated the stability of each metabolite over time and showed that the urinary metabolic profile is more stable within individuals than reported dietary patterns. The 46 metabolites accurately predicted healthy and unhealthy dietary patterns in a free-living U.S. cohort and replicated in an independent U.K. cohort. We mapped these metabolites into a host-microbial metabolic network to identify key pathways and functions. These data can be used in future studies to evaluate how this set of diet-derived, stable, measurable bioanalytical markers are associated with disease risk. This knowledge may give new insights into biological pathways that characterize the shift from a healthy to unhealthy metabolic phenotype and hence give entry points for prevention and intervention strategies.

Journal article

Garcia Perez I, Posma JM, Chambers E, Mathers J, Draper J, Beckmann M, Nicholson J, Holmes E, Frost Get al., 2020, Dietary metabotype modelling predicts individual responses to dietary interventions, Nature Food, Vol: 1, Pages: 355-364, ISSN: 2662-1355

Habitual consumption of poor quality diets is linked directly to risk factors for many non-communicable disease. This has resulted in the vast majority of countries globally and the World Health Organisation developing policies for healthy eating to reduce the prevalence of non communicable disease in the population. However, there is mounting evidence of variability in individual metabolic responses to any dietary intervention. We have developed a method for applying a pipeline for understanding inter-individual differences in response to diet, based on coupling data from highly-controlled dietary studies with deep metabolic phenotyping. In this feasibility study, we create an individual Dietary Metabotype Score (DMS) that embodies inter-individual variability in dietary response and captures consequent dynamic changes in concentrations of urinary metabolites. We find an inverse relationship between the DMS and blood glucose concentration. There is also a relationship between the DMS and urinary metabolic energy loss. Furthermore we employ a metabolic entropy approach to visualize individual and collective responses to dietary. Potentially, the DMS offers a method to target and to enhance dietary response at an individual level therefore reducing burden of non communicable diseases at a population level.

Journal article

Allegretti JR, Kassam Z, Mullish BH, Chiang A, Carrellas M, Hurtado J, Marchesi JR, McDonald JAK, Pechlivanis A, Barker GF, Miguens Blanco J, Garcia Perez I, Wong WF, Gerardin Y, Silverstein M, Kennedy K, Thompson Cet al., 2020, Effects of fecal microbiota transplantation with oral capsules in obese patients, Clinical Gastroenterology and Hepatology, Vol: 18, Pages: 855-863.e2, ISSN: 1542-3565

Background & AimsStudies in mice have shown that the intestinal microbiota can contribute to obesity via the anorexigenic gut hormone glucagon-like peptide 1 (GLP1) and bile acids, which affect lipid metabolism. We performed a randomized, placebo-controlled pilot study of the effects of fecal microbiota transplantation (FMT) in obese, metabolically uncompromised patients.MethodsWe performed a double-blind study of 22 obese patients (body mass index [BMI] ≥ 35kg/m2) without a diagnosis of diabetes, non-alcoholic steatohepatitis, or metabolic syndrome. Participants were randomly assigned (1:1) to groups that received FMT by capsules (induction dose of 30 capsules at week 4 and maintenance dose of 12 capsules at week 8) or placebo capsules. FMT capsules were derived from a single, lean donor (BMI, 17.5 kg/m2). Patients were followed through week 26; the primary outcome was safety. Stool and serum samples were collected from patients at baseline and at weeks 1, 4, 6, 8 and 12 after administration of the first dose of FMT or placebo and analyzed by 16S RNA gene sequencing. Stool and serum samples were analyzed for metabolomics by liquid chromatography-mass spectrometry. Additional outcomes were change in area under the curve for GLP1 at week 12.ResultsWe observed no significant differences in adverse events between patients who received FMT vs placebo. There was no increase in the area under the curve of GLP1 in either group. Patients who received FMT had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001). Patients who received FMT had a sustained decrease in stool levels of taurocholic acid (P<.05), compared with baseline; bile acid profiles began to more closely resemble those of the donor. We did not observe significant changes in mean BMI at week 12 in either group.ConclusionsIn a placebo-controlled pilot study, we found that FMT capsules (derived from a lean donor) were safe but did not reduce BMI in obese metabol

Journal article

Barbas-Bernardos C, Garcia-Perez I, Lorenzo MP, Alonso-Herranz V, Nicholson J, Garcia Aet al., 2020, Development and validation of a high performance liquid chromatography-tandem mass spectrometry method for the absolute analysis of 17 alpha D-amino acids in cooked meals, Journal of Chromatography A, Vol: 1611, Pages: 1-17, ISSN: 0021-9673

In the nutrition field, there is a lack of understanding about the impact that dietary chiral composition may have on health, especially regarding cooked meals. Chiral amino acids (AAs) are naturally present in food and their proportion may vary quite a lot. Besides, the D-amino acids (D-AAs) are present in very low concentration compared to L-AAs, so very sensitive methods are required for their accurate quantitation. Moreover, some of them have been described as indicators of quality and different food processes. In this research, we propose a robust method for the absolute quantitation and enantiomeric ratio of 17 D-AAs in cooked meals. The AAs were extracted from 1 g of the homogenised meal with methanol, derivatised with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester ((S)-NIFE) and analysed by RP-LC-MS/MS. The separation was carried out with an Acquity BEH C18 (100 mm x 2.1 mm, 1.7 µm) column at 70 ºC, with 10 mmol/L ammonium bicarbonate in water as eluent A and acetonitrile as eluent B at a 0.3 mL/min flow rate in gradient elution. The MS operated in positive electrospray ionisation method in multiple reaction monitoring (MRM) mode. Isotopically labelled AAs were used as internal standards for the quantitation. The method was validated for 17 D-AAs in the cooked food samples in terms of specificity, linearity, precision, accuracy, matrix effect and stability. LLOQ are 2.0 ng/mL for most of them. Additionally, linearity was also studied for L-AAs. After optimization and validation, the method was applied to real breakfast, lunch and dinner samples of cooked meals (n = 18) that were part of a diet with a very high concordance with WHO dietary guidelines. Level of concentration of major and minor D-AAs have been described per total daily intake and within each of the three main meals. This method can be used for quality control purposes as well as to investigate the role of chiral composition in food and clinical outcomes.

Journal article

O'Donovan CM, Madigan SM, Garcia-Perez I, Rankin A, O' Sullivan O, Cotter PDet al., 2020, Distinct microbiome composition and metabolome exists across subgroups of elite Irish athletes, Journal of Science and Medicine in Sport, Vol: 23, Pages: 63-68, ISSN: 1440-2440

ObjectivesThe gut microbiome has begun to be characterised in athlete groups, albeit, to date, only across a subset of sports. This study aimed to determine if the gut microbiome and metabolome differed across sports classification groups (SCGs) among elite Irish athletes, many of whom were participating in the 2016 Summer Olympics.MethodsFaecal and urine samples were collected from 37 international level athletes. Faecal samples were prepared for shotgun metagenomic sequencing and faecal and urine samples underwent metabolomic profiling.ResultsDifferences were observed in the composition and functional capacity of the gut microbiome of athletes across SCGs. The microbiomes of athletes participating in sports with a high dynamic component were the most distinct compositionally (greater differences in proportions of species), while those of athletes participating in sports with high dynamic and static components were the most functionally distinct (greater differences in functional potential). Additionally, both microbial (faecal) and human (urine) derived metabolites were found to vary between SCGs. In particular cis-aconitate, succinic acid and lactate, in urine samples, and creatinine, in faeces, were found to be significantly different between groups. These differences were evident despite the absence of significant differences in diet, as determined using food frequency questionnaires, which were translated into nutrient intake values using FETA.ConclusionsDifferences in the gut microbiome and metabolome between groups, in the absence of dietary changes, indicates a role for training load or type as a contributory factor. Further exploration of this hypothesis has the potential to benefit athletes, aspiring athletes and the general public.

Journal article

Kundu P, Lee HU, Garcia-Perez I, Tay EXY, Kim H, Faylon LE, Martin KA, Purbojati R, Drautz-Moses DI, Ghosh S, Nicholson JK, Schuster S, Holmes E, Pettersson Set al., 2019, Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice., Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.

Journal article

Wilson T, Garcia-Perez I, Posma JM, Lloyd AJ, Chambers ES, Tailliart K, Zubair H, Beckmann M, Mathers JC, Holmes E, Frost G, Draper Jet al., 2019, Spot and cumulative urine samples are suitable replacements for 24-hour urine collections for objective measures of dietary exposure in adults using metabolite biomarkers, Journal of Nutrition, Vol: 149, Pages: 1692-1700, ISSN: 0022-3166

BACKGROUND: Measurement of multiple food intake exposure biomarkers in urine may offer an objective method for monitoring diet. The potential of spot and cumulative urine samples that have reduced burden on participants as replacements for 24-h urine collections has not been evaluated. OBJECTIVE: The aim of this study was to determine the utility of spot and cumulative urine samples for classifying the metabolic profiles of people according to dietary intake when compared with 24-h urine collections in a controlled dietary intervention study. METHODS: Nineteen healthy individuals (10 male, 9 female, aged 21-65 y, BMI 20-35 kg/m2) each consumed 4 distinctly different diets, each for 1 wk. Spot urine samples were collected ∼2 h post meals on 3 intervention days/wk. Cumulative urine samples were collected daily over 3 separate temporal periods. A 24-h urine collection was created by combining the 3 cumulative urine samples. Urine samples were analyzed with metabolite fingerprinting by both high-resolution flow infusion electrospray mass spectrometry (FIE-HRMS) and proton nuclear magnetic resonance spectroscopy (1H-NMR). Concentrations of dietary intake biomarkers were measured with liquid chromatography triple quadrupole mass spectrometry and by integration of 1H-NMR data. RESULTS: Cross-validation modeling with 1H-NMR and FIE-HRMS data demonstrated the power of spot and cumulative urine samples in predicting dietary patterns in 24-h urine collections. Particularly, there was no significant loss of information when post-dinner (PD) spot or overnight cumulative samples were substituted for 24-h urine collections (classification accuracies of 0.891 and 0.938, respectively). Quantitative analysis of urine samples also demonstrated the relation between PD spot samples and 24-h urines for dietary exposure biomarkers. CONCLUSIONS: We conclude that PD spot urine samples are suitable replacements for 24-h urine collections. Alternatively, cumulative samples collected overn

Journal article

Allegretti JR, Mullish B, Hurtado J, Carrellas M, Marcus J, Phelps E, Pettee W, Marchesi J, McDonald JAK, Barker G, Blanco JM, Perez IG, Kelly CR, Grinspan A, Fischer Met al., 2019, Short chain fatty acid profiles are altered by fecal microbiota transplantation for the treatment of inflammatory bowel disease and recurrent clostridioides difficile infection, American Journal of Gastroenterology, Vol: 114, Pages: S484-S485, ISSN: 0002-9270

Journal article

Lahiri S, Kim H, Garcia-Perez I, Reza MM, Martin KA, Kundu P, Cox LM, Selkrig J, Posma JM, Zhang H, Padmanabhan P, Moret C, Gulyás B, Blaser MJ, Auwerx J, Holmes E, Nicholson J, Wahli W, Pettersson Set al., 2019, The gut microbiota influences skeletal muscle mass and function in mice, Science Translational Medicine, Vol: 11, ISSN: 1946-6234

The functional interactions between the gut microbiota and the host are important for host physiology, homeostasis, and sustained health. We compared the skeletal muscle of germ-free mice that lacked a gut microbiota to the skeletal muscle of pathogen-free mice that had a gut microbiota. Compared to pathogen-free mouse skeletal muscle, germ-free mouse skeletal muscle showed atrophy, decreased expression of insulin-like growth factor 1, and reduced transcription of genes associated with skeletal muscle growth and mitochondrial function. Nuclear magnetic resonance spectrometry analysis of skeletal muscle, liver, and serum from germ-free mice revealed multiple changes in the amounts of amino acids, including glycine and alanine, compared to pathogen-free mice. Germ-free mice also showed reduced serum choline, the precursor of acetylcholine, the key neurotransmitter that signals between muscle and nerve at neuromuscular junctions. Reduced expression of genes encoding Rapsyn and Lrp4, two proteins important for neuromuscular junction assembly and function, was also observed in skeletal muscle from germ-free mice compared to pathogen-free mice. Transplanting the gut microbiota from pathogen-free mice into germ-free mice resulted in an increase in skeletal muscle mass, a reduction in muscle atrophy markers, improved oxidative metabolic capacity of the muscle, and elevated expression of the neuromuscular junction assembly genes <jats:italic>Rapsyn</jats:italic> and <jats:italic>Lrp4</jats:italic>. Treating germ-free mice with short-chain fatty acids (microbial metabolites) partly reversed skeletal muscle impairments. Our results suggest a role for the gut microbiota in regulating skeletal muscle mass and function in mice.</jats:p>

Journal article

Ek A, Nystrom CD, Chirita-Emandi A, Tur JA, Nordin K, Bouzas C, Argelich E, Alfredo Martinez J, Frost G, Garcia-Perez I, Saez M, Paul C, Lof M, Nowicka Pet al., 2019, A randomized controlled trial for overweight and obesity in preschoolers: the More and Less Europe study- an intervention within the STOP project, BMC Public Health, Vol: 19, Pages: 1-13, ISSN: 1471-2458

BackgroundChildhood overweight and obesity is a serious public health issue with an increase being observed in preschool-aged children. Treating childhood obesity is difficult and few countries use standardized treatments. Therefore, there is a need to find effective approaches that are feasible for both health care providers and families. Thus, the overall aim of this study is to assess the acceptance and effectiveness of a parent support program (the More and Less, ML) for the management of overweight and obesity followed by a mobile health (mHealth) program (the MINISTOP application) in a socially diverse population of families.Methods/designA two-arm, parallel design randomized controlled trial in 300 2-to 6-year-old children with overweight and obesity from Romania, Spain and Sweden (n = 100 from each). Following baseline assessments children are randomized into the intervention or control group in a 1:1 ratio. The intervention, the ML program, consists of 10-weekly group sessions which focus on evidence-based parenting practices, followed by the previously validated MINISTOP application for 6-months to support healthy eating and physical activity behaviors. The primary outcome is change in body mass index (BMI) z-score after 9-months and secondary outcomes include: waist circumference, eating behavior (Child Eating Behavior Questionnaire), parenting behavior (Comprehensive Feeding Practices Questionnaire), physical activity (ActiGraph wGT3x-BT), dietary patterns (based on metabolic markers from urine and 24 h dietary recalls), epigenetic and gut hormones (fasting blood samples), and the overall acceptance of the overweight and obesity management in young children (semi-structured interviews). Outcomes are measured at baseline and after: 10-weeks (only BMI z-score, waist circumference), 9-months (all outcomes), 15- and 21-months (all outcomes except physical activity, dietary patterns, epigenetics and gut hormones) post-baseline.DiscussionT

Journal article

Chambers E, Byrne C, Morrison D, Murphy K, Preston T, Tedford MC, Garcia Perez I, Fountana S, Serrano Contreras J, Holmes E, Roberts J, Reynolds C, Boyton R, Altmann D, McDonald J, Marchesi J, Akbar A, Riddell N, Wallis G, Frost Get al., 2019, Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial, Gut, Vol: 68, Pages: 1430-1438, ISSN: 0017-5749

Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses.Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.

Journal article

Lloyd AJ, Willis ND, Wilson T, Zubair H, Xie L, Chambers E, Garcia-Perez I, Tailliart K, Beckmann M, Mathers JC, Draper Jet al., 2019, Developing a food exposure and urine sampling strategy for dietary exposure biomarker validation in free-living individuals, Molecular Nutrition and Food Research, Vol: 63, Pages: 1-9, ISSN: 1613-4125

SCOPE: Dietary choices modulate the risk of chronic diseases and improving diet is a central component of public health strategies. Food-derived metabolites present in urine could provide objective biomarkers of dietary exposure. To assist biomarker validation we aimed to develop a food intervention strategy mimicking a typical annual diet over a short period of time and assessed urine sampling protocols potentially suitable for future deployment of biomarker technology in free-living populations. METHODS AND RESULTS: Six different menu plans representing comprehensively a typical UK annual diet that were split into two dietary experimental periods. Free-living adult participants (n = 15 and n = 36, respectively) were provided with all their food, as a series of menu plans, over a period of 3 consecutive days. Multiple spot urine samples were collected and stored at home. CONCLUSION: We established a successful food exposure strategy following a conventional UK eating pattern, which was suitable for biomarker validation in free-living individuals. The urine sampling procedure was acceptable for volunteers and delivered samples suitable for biomarker quantification. Our study design provides scope for validation of existing biomarker candidates and potentially for discovery of new biomarker-leads and should help inform the future deployment of biomarker technology for habitual dietary exposure measurement.

Journal article

Lloyd AJ, Willis ND, Wilson T, Zubair H, Chambers E, Garcia-Perez I, Xie L, Tailliart K, Beckmann M, Mathers JC, Draper Jet al., 2019, Addressing the pitfalls when designing intervention studies to discover and validate biomarkers of habitual dietary intake, Metabolomics, Vol: 15, ISSN: 1573-3882

IntroductionDietary exposure monitoring within populations is reliant on self-reported measures such as Food Frequency Questionnaires and diet diaries. These methods often contain inaccurate information due to participant misreporting, non-compliance and bias. Urinary metabolites derived from individual foods could provide additional objective indicators of dietary exposure. For biomarker approaches to have utility it is essential that they cover a wide-range of commonly consumed foods and the methodology works in a real-world environment.ObjectivesTo test that the methodology works in a real-world environment and to consider the impact of the major sources of likely variance; particularly complex meals, different food formulations, processing and cooking methods, as well as the dynamics of biomarker duration in the body.MethodsWe designed and tested a dietary exposure biomarker discovery and validation strategy based on a food intervention study involving free-living individuals preparing meals and collecting urine samples at home. Two experimental periods were built around three consecutive day menu plans where all foods and drinks were provided (n = 15 and n = 36).ResultsThe experimental design was validated by confirming known consumption biomarkers in urinary samples after the first menu plan. We tested biomarker performance with different food formulations and processing methods involving meat, wholegrain, fruits and vegetables.ConclusionIt was demonstrated that spot urine samples, together with robust dietary biomarkers, despite major sources of variance, could be used successfully for dietary exposure monitoring in large epidemiological studies.

Journal article

Churchward MA, Michaud ER, Blanco JM, Garcia-Perez I, Mullish BH, Marchesi J, Xu H, Kao DH, Todd Ket al., 2019, Sa1924 – Effect of short chain fatty acids on gut-brain axis using a microglial cell model, Gastroenterology, Vol: 156, Pages: S-455-S-455, ISSN: 0016-5085

Journal article

Byrne C, Chambers E, Brignardello J, Garcia-Perez I, Holmes E, Gareth W, Tom P, Catriona T, Douglas M, Gary S Fet al., 2019, Effects of inulin propionate ester incorporated into palatable food products on appetite and resting energy expenditure: a randomised crossover study, Nutrients, Vol: 11, ISSN: 2072-6643

Supplementation with inulin-propionate ester (IPE), which delivers propionate to the colon, suppresses ad libitum energy intake and stimulates the release of satiety hormones acutely in humans, and prevents weight gain. In order to determine whether IPE remains effective when incorporated into food products (FP), IPE needs to be added to a widely accepted food system. A bread roll and fruit smoothie were produced. Twenty-one healthy overweight and obese humans participated. Participants attended an acclimatisation visit and a control visit where they consumed un-supplemented food products (FP). Participants then consumed supplemented-FP, containing 10 g/d inulin or IPE for six days followed by a post-supplementation visit in a randomised crossover design. On study visits, supplemented-FP were consumed for the seventh time and ad libitum energy intake was assessed 420 min later. Blood samples were collected to assess hormones and metabolites. Resting energy expenditure (REE) was measured using indirect calorimetry. Taste and appearance ratings were similar between FP. Ad libitum energy intake was significantly different between treatments, due to a decreased intake following IPE-FP. These observations were not related to changes in blood hormones and metabolites. There was an increase in REE following IPE-FP. However, this effect was lost after correcting for changes in fat free mass. Our results suggest that IPE suppresses appetite and may alter REE following its incorporation into palatable food products.

Journal article

Byrne CS, Preston T, Brignardello J, Garcia-Perez I, Holmes E, Frost GS, Morrison DJet al., 2018, The effect of L-rhamnose on gastrointestinal transit rates, short chain fatty acids and appetite regulation, Summer Meeting, Publisher: Cambridge University Press, Pages: E155-E155, ISSN: 0029-6651

Conference paper

Byrne C, Preston T, Brignardello J, Garcia-Perez I, Holmes E, Frost G, Morrison Det al., 2018, The effect of L-rhamnose on intestinal transit time, short chain fatty acids and appetite regulation: a pilot human study using combined 13CO2 / H2 breath tests, Journal of Breath Research, Vol: 12, ISSN: 1752-7155

Background: The appetite-regulating effects of non-digestible carbohydrates (NDC) have in part previously been attributed to their effects on intestinal transit rates as well as microbial production of short chain fatty acids (SCFA). Increased colonic production of the SCFA propionate has been shown to reduce energy intake and stimulate gut hormone secretion acutely in humans. Objective: We investigated the effect of the propiogenic NDC, L-rhamnose, on gastrointestinal transit times using a combined 13CO2/H2 breath test. We hypothesised that L-rhamnose would increase plasma propionate leading to a reduction in appetite, independent of changes in gastrointestinal transit times.Design: We used a dual 13C-octanoic acid/lactose 13C-ureide breath test combined with breath H2 to measure intestinal transit times following the consumption of 25g/d L-rhamnose, compared with inulin and cellulose, in 10 healthy humans in a randomised cross-over design pilot study. Gastric emptying (GE) and oro-caecal transit times (OCTT) were derived from the breath 13C data and compared with breath H2. Plasma SCFA and peptide YY (PYY) were also measured alongside subjective measures of appetite. Results: L-rhamnose significantly slowed GE rates (by 19.5min) but there was no difference in OCTT between treatments. However, breath H2 indicated fermentation of L-rhamnose before it reached the caecum. OCTT was highly correlated with breath H2 for inulin but not for L-rhamnose or cellulose. L-rhamnose consumption significantly increased plasma propionate and PYY but did not significantly reduce subjective appetite measures. Conclusions: The NDCs tested had a minimal effect on intestinal transit time. Our data suggest that L-rhamnose is partially fermented in the small intestine and that breath H2 reflects the site of gastrointestinal fermentation and is only a reliable marker of OCTT for certain NDCs (e.g. inulin). Future studies should focus on investigating the appetite-suppressing potential of L

Journal article

Cronin O, Barton W, Skuse P, Penney NC, Garcia-Perez I, Murphy EF, Woods T, Nugent H, Fanning A, Melgar S, Falvey EC, Holmes E, Cotter PD, O'Sullivan O, Molloy MG, Shanahan Fet al., 2018, A prospective metagenomic and metabolomic analysis of the impact of exercise and/or whey protein supplementation on the gut microbiome of sedentary adults, mSystems, Vol: 3, ISSN: 2379-5077

Many components of modern living exert influence on the resident intestinal microbiota of humans with resultant impact on host health. For example, exercise-associated changes in the diversity, composition, and functional profiles of microbial populations in the gut have been described in cross-sectional studies of habitual athletes. However, this relationship is also affected by changes in diet, such as changes in dietary and supplementary protein consumption, that coincide with exercise. To determine whether increasing physical activity and/or increased protein intake modulates gut microbial composition and function, we prospectively challenged healthy but sedentary adults with a short-term exercise regime, with and without concurrent daily whey protein consumption. Metagenomics- and metabolomics-based assessments demonstrated modest changes in gut microbial composition and function following increases in physical activity. Significant changes in the diversity of the gut virome were evident in participants receiving daily whey protein supplementation. Results indicate that improved body composition with exercise is not dependent on major changes in the diversity of microbial populations in the gut. The diverse microbial characteristics previously observed in long-term habitual athletes may be a later response to exercise and fitness improvement. IMPORTANCE The gut microbiota of humans is a critical component of functional development and subsequent health. It is important to understand the lifestyle and dietary factors that affect the gut microbiome and what impact these factors may have. Animal studies suggest that exercise can directly affect the gut microbiota, and elite athletes demonstrate unique beneficial and diverse gut microbiome characteristics. These characteristics are associated with levels of protein consumption and levels of physical activity. The results of this study show that increasing the fitness levels of physically inactive humans leads to mo

Journal article

Barton W, Penney NC, Cronin O, Garcia-Perez I, Molloy MG, Holmes E, Shanahan F, Cotter PD, O'Sullivan Oet al., 2018, The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level, Gut, Vol: 67, Pages: 625-633, ISSN: 0017-5749

OBJECTIVE: It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state. DESIGN: Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively). RESULTS: Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups. CONCLUSIONS: Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet-exercise-gut microbiota paradigm.

Journal article

Posma JM, Garcia Perez I, Ebbels TMD, Lindon JC, Stamler J, Elliott P, Holmes E, Nicholson Jet al., 2018, Optimized phenotypic biomarker discovery and confounder elimination via covariate-adjusted projection to latent structures from metabolic spectroscopy data, Journal of Proteome Research, Vol: 17, Pages: 1586-1595, ISSN: 1535-3893

Metabolism is altered by genetics, diet, disease status, environment and many other factors. Modelling either one of these is often done without considering the effects of the other covariates. Attributing differences in metabolic profile to one of these factors needs to be done while controlling for the metabolic influence of the rest. We describe here a data analysis framework and novel confounder-adjustment algorithm for multivariate analysis of metabolic profiling data. Using simulated data we show that similar numbers of true associations and significantly less false positives are found compared to other commonly used methods. Covariate-Adjusted Projections to Latent Structures (CA-PLS) is exemplified here using a large-scale metabolic phenotyping study of two Chinese populations at different risks for cardiovascular disease. Using CA-PLS we find that some previously reported differences are actually associated with external factors and discover a number of previously unreported biomarkers linked to different metabolic pathways. CA-PLS can be applied to any multivariate data where confounding may be an issue and the confounder-adjustment procedure is translatable to other multivariate regression techniques.

Journal article

Garcia Perez I, Posma JM, Gibson R, Chambers ES, Nicholson JK, Holmes E, Frost Get al., 2017, Modernizing dietary assessment, IUNS 21st ICN International Congress of Nutrition, Publisher: Karger Publishers, Pages: 286-287, ISSN: 1421-9697

Conference paper

Swann JR, Garcia-Perez I, Braniste V, Wilson I, Sidaway JE, Nicholson JK, Pettersson S, Holmes Eet 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.

Journal article

Garcia Perez I, Posma JM, Gibson R, Chambers ES, Hansen TH, Vestergaard H, Hansen T, Beckmann M, Pedersen O, Elliott P, Stamler J, Nicholson JK, Draper J, Mathers JC, Holmes E, Frost Get al., 2017, Objective assessment of dietary patterns using metabolic phenotyping: a randomized, controlled, crossover trial, The Lancet Diabetes & Endocrinology, Vol: 5, Pages: 184-195, ISSN: 2213-8587

Background: The burden of non-communicable diseases, such as obesity, diabetes, coronary heart disease and cancer, can be reduced by the consumption of healthy diets. Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, many of them influenced by food intake. We aim to classify people according to dietary behaviour and enhance dietary reporting using metabolic profiling of urine.Methods: To develop metabolite models from 19 healthy volunteers who attended a clinical research unit for four day periods on four occasions. We used the World Health Organisation’s healthy eating guidelines (increase fruits, vegetables, wholegrains, dietary fibre and decrease fats, sugars, and salt) to develop four dietary interventions lasting for four days each that ranged from a diet associated with a low to high risk of developing non-communicable disease. Urine samples were measured by 1H-NMR spectroscopy. This study is registered as an International Standard Randomized Controlled Trial, number ISRCTN 43087333. INTERMAP U.K. (n=225) and a healthy-eating Danish cohort (n=66) were used as free-living validation datasets.Findings: There was clear separation between the urinary metabolite profiles of the four diets. We also demonstrated significant stepwise differences in metabolite levels between the lowest and highest metabolic risk diets and developed metabolite models for each diet. Application of the derived metabolite models to independent cohorts confirmed the association between urinary metabolic and dietary profiles in INTERMAP (P<0•001) and the Danish cohort (P<0•001).Interpretation: Urinary metabolite models, developed in a highly controlled environment, can classify groups of free-living people into consumers of dietary profiles associated with lower or higher non-communicable disease risk based on multivariate m

Journal article

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