Imperial College London

ProfessorGaryFrost

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Nutrition and Dietetics
 
 
 
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Contact

 

+44 (0)20 7594 0959g.frost Website

 
 
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Location

 

Commonwealth BiuldingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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454 results found

Frampton J, Murphy K, Frost G, Chambers Eet al., 2021, Higher dietary fibre intake is associated with increased skeletal muscle mass and strength in adults aged 40 years and older, Journal of Cachexia, Sarcopenia and Muscle, ISSN: 2190-6009

BackgroundSkeletal muscle mass begins to decline from 40 years of age. Limited data suggest that dietary fibre may modify lean body mass, of which, skeletal muscle is the largest and most malleable component. We investigated the relationship between dietary fibre intake, skeletal muscle mass, and associated metabolic and functional parameters in adults aged 40 years and older. MethodsWe analysed cross-sectional data from the US National Health and Nutrition Examination Survey between 2011 and 2018 from adults aged 40 years and older. Covariate-adjusted multiple linear regression analyses were used to evaluate the association between dietary fibre intake and body mass components (body mass, BMI, total lean mass, appendicular lean mass, bone mineral content, total fat, trunk fat; n = 6454), glucose homeostasis (fasting glucose, fasting insulin, HOMA2-IR; n = 5032), and skeletal muscle strength (combined grip strength; n = 5326). Body mass components and skeletal muscle strength were expressed relative to body mass (per kg of body mass [BM]). ResultsHigher intakes of dietary fibre were significantly associated with increased relative total lean mass (β: 0.69 g/kg BM; 95% CI, 0.48 to 0.89 g/kg BM; P<0.001), relative appendicular lean mass (β: 0.34 g/kg BM; 95% CI, 0.23 to 0.45 g/kg BM; P<0.001), relative bone mineral content (β: 0.05 g/kg BM; 95% CI, 0.02 to 0.07 g/kg BM; P<0.001), and relative combined grip strength (β: 0.002 kg/kg BM; 95% CI, 0.001 to 0.003 kg/kg BM; P<0.001).Conversely, higher dietary fibre intakes were significantly associated with a lower body mass (β: -0.20; 95% CI, -0.28 to -0.11 kg; P<0.001), BMI (β: -0.08 kg/m2; 95%CI, -0.10 to -0.05 kg/m2), relative total fat (β: -0.68 g/kg BM; 95% CI, -0.89 to -0.47 g/kg BM; P<0.001), relative trunk fat (β: -0.48 g/kg BM; 95%CI, -0.63 to -0.33 g/kg; P<0.001), fasting glucose (β: -0.01 mmol/L; 95% CI, -0.02 to -0.00 mmol/L; P=0.017), fasting ins

Journal article

Frampton J, Cobbold B, Nozdrin M, Oo HTH, Wilson H, Murphy KG, Frost G, Chambers ESet al., 2021, The effect of a single bout of continuous aerobic exercise on glucose, insulin and glucagon concentrations compared to resting conditions in healthy adults: a systematic review, meta-analysis and meta-regression, Sports Medicine, Vol: 51, Pages: 1949-1966, ISSN: 0112-1642

Background:Elevated glucose and insulin levels are major risk factors in the development of cardiometabolic disease. Aerobic exercise is widely recommended to improve glycaemic control, yet its acute effect on glycaemia and glucoregulatory hormones has not been systematically reviewed and analysed in healthy adults.Objective:To determine the effect of a single bout of continuous aerobic exercise on circulating glucose, insulin, and glucagon concentrations in healthy adults.Methods:CENTRAL, CINAHL, Embase, Global Health, HMIC, Medline, PubMed, PsycINFO, ScienceDirect, Scopus and Web of Science databases were searched from inception to May 2020. Papers were included if they reported a randomised, crossover study measuring glucose and/or insulin and/or glucagon concentrations before and immediately after a single bout of continuous aerobic exercise (≥ 30 min) compared to a time-matched, resting control arm in healthy adults. The risk of bias and quality of evidence were assessed using the Cochrane Risk of Bias Tool and GRADE approach, respectively. Random-effects meta-analyses were performed for glucose, insulin, and glucagon. Sub-group meta-analyses and meta-regression were performed for categorical (metabolic state [postprandial or fasted], exercise mode [cycle ergometer or treadmill]) and continuous (age, body mass index, % males, maximal aerobic capacity, exercise duration, exercise intensity) covariates, respectively.Results42 papers (51 studies) were considered eligible: glucose (45 studies, 391 participants), insulin (38 studies, 377 participants) and glucagon (5 studies, 47 participants). Acute aerobic exercise had no significant effect on glucose concentrations (mean difference: − 0.05 mmol/L; 95% CI, − 0.22 to 0.13 mmol/L; P = 0.589; I2: 91.08%, large heterogeneity; moderate-quality evidence). Acute aerobic exercise significantly decreased insulin concentrations (mean difference: − 18.07 pmol/L; 95% CI, − 30.47

Journal article

Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J, Maitland K, Frost Get al., 2021, Development of a legume-enriched feed for treatment of severe acute malnutrition [version 1; peer review: 1 approved with reservations], Wellcome Open Research, Vol: 6, ISSN: 2398-502X

Outcomes in children hospitalised with severe acute malnutrition (SAM) remain poor. The current milk-based formulations focus on restoring weight-gain but fail to address modification of the integrity of the gut barrier and may exacerbate malabsorption owing to functional lactase, maltase and sucrase deficiency. We hypothesise that nutritional feeds should be designed to promote bacterial diversity and restore gastrointestinal (GI) barrier function.</ns3:p><ns3:p> <ns3:bold>Methods:</ns3:bold> Our major objective was to develop a lactose-free, fermentable carbohydrate-containing alternative to traditional F75 and F100 formulae for the inpatient treatment of SAM. New target nutritional characteristics were developed and relevant food and infant food specific legislation were reviewed. Suitable certified suppliers of ingredients were identified. Processing and manufacture steps were evaluated and optimised for safety (nutritional, chemical and microbiological), and efficacy at meeting target characteristics (lactose-free, containing resistant starch 0.4-0.5% final product weight).</ns3:p><ns3:p> <ns3:bold>Results:</ns3:bold> A final validated production process was developed and implemented to produce a novel food product for the inpatient treatment of SAM in children in Africa designed to reduce risk of osmotic diarrhoea and support symbiotic gut microbial populations. The final product matched the macronutrient profile of double-concentrated F100, adhered to all relevant legislation regulating infant foods, was lactose free, and contained 0.6% resistant starch. Chickpeas were selected as the source of resistant starch, since they are widely grown and eaten throughout Africa. Micronutrient content could not be matched in this ready-to-use product, so this was replaced at the point of feeding, as was fluid lost through concentration.</ns3:p><ns3:p> <ns3:bold>Conclusions:</ns3:bold> The processes a

Journal article

Wu Y, Posma JM, Holmes E, Chambers E, Frost G, Garcia Perez Iet al., 2021, Odd chain fatty acids are not robust biomarkers for dietary intake of fiber, Molecular Nutrition and Food Research, ISSN: 1613-4125

Prior investigation has suggested a positive association between increased colonic propionate production and circulating odd-chain fatty acids [(OCFAs; pentadecanoic acid (C15:0), heptadecanoic acid (C17:0)]. As the major source of propionate in humans is the microbial fermentation of dietary fiber, OCFAs have been proposed as candidate biomarkers of dietary fiber. The objective of this study is to critically assess the plausibility, robustness, reliability, dose-response, time-response aspects of OCFAs as potential biomarkers of fermentable fibers in two independent studies using a validated analytical method. OCFAs were first assessed in a fiber supplementation study, where 21 participants received 10g dietary fiber supplementation for 7 days with blood samples collected on the final day at a 420 minute study visit. OCFAs were then assessed in a highly controlled inpatient setting, which 19 participants consumed a high fiber (45.1g/day) and a low fiber diet (13.6g/day) for 4 days. Collectively in both studies, dietary intakes of fiber as fiber supplementations or having consumed a high fiber diet did not increase circulating levels of OCFAs. The dose and temporal relations were not observed. Current study has generated new insight on the utility of OCFAs as fiber biomarkers and highlighted the importance of critical assessment of candidate dietary biomarkers before application.

Journal article

Cai M, Dou B, Pugh J, Lett A, Frost Get al., 2021, The impact of starchy food structure on postprandial glycemic response and appetite: a systematic review with meta-analysis of randomized crossover trials, American Journal of Clinical Nutrition, Vol: 114, Pages: 472-487, ISSN: 0002-9165

BackgroundStarchy foods can have a profound effect on metabolism. The structural properties of starchy foods can affect their digestibility and postprandial metabolic responses, which in the long term may be associated with the risk of type 2 diabetes and obesity.ObjectivesThis systematic review sought to evaluate the clinical evidence regarding the impact of the microstructures within starchy foods on postprandial glucose and insulin responses alongside appetite regulation.MethodsA systematic search was performed in the PUBMED, Ovid Medicine, EMBASE, and Google Scholar databases for data published up to 18 January 2021. Data were extracted by 3 independent reviewers from randomized crossover trials (RCTs) that investigated the effect of microstructural factors on postprandial glucose, insulin, appetite-regulating hormone responses, and subjective satiety scores in healthy participants.ResultsWe identified 745 potential articles, and 25 RCTs (n = 369 participants) met our inclusion criteria: 6 evaluated the amylose-to-amylopectin ratio, 6 evaluated the degree of starch gelatinization, 2 evaluated the degree of starch retrogradation, 1 studied starch–protein interactions, and 12 investigated cell and tissue structures. Meta-analyses showed that significant reductions in postprandial glucose and insulin levels was caused by starch with a high amylose content [standardized mean difference (SMD) = −0.64 mmol/L*min (95% CI: −0.83 to −0.46) and SMD = −0.81 pmol/L*min (95% CI: −1.07 to −0.55), respectively], less-gelatinized starch [SMD = −0.54 mmol/L*min (95% CI: −0.75 to −0.34) and SMD = −0.48 pmol/L*min (95% CI: −0.75 to −0.21), respectively], retrograded starch (for glucose incremental AUC; SMD = −0.46 pmol/L*min; 95% CI: −0.80 to −0.12), and intact and large particles [SMD = −0.43 mmol/L*min (95% CI: −0.58 to −0.28) and SMD = −0.63 pmol/L*min (95% CI

Journal article

Connon R, George EC, Olupot-Olupot P, Kiguli S, Chagaluka G, Alaroker F, Opoka RO, Mpoya A, Walsh K, Engoru C, Nteziyaremye J, Mallewa M, Kennedy N, Nakuya M, Namayanja C, Nabawanuka E, Sennyondo T, Amorut D, Williams Musika C, Bates I, Boele van Hensbroek M, Evans JA, Uyoga S, Williams TN, Frost G, Gibb DM, Maitland K, Walker AS, TRACT trial groupet al., 2021, Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data, BMC Public Health, Vol: 21, ISSN: 1471-2458

BACKGROUND: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. METHODS: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. RESULTS: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63-3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19-1.74), p < 0.001); history of transfusion (1.48(1.13-1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21-1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47-0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47-0.76), p < 0.001); younger-age (1.07 (1.03-1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46-0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross

Journal article

Thompson A, Bourke C, Robertson R, Shivakumar N, Edwards C, Preston T, Holmes E, Paul K, Gary F, Douglas Met al., 2021, Understanding the role of the gut in undernutrition: what can technology tell us?, Gut, Vol: 70, Pages: 1580-1594, ISSN: 0017-5749

Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)—a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability—is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.

Journal article

Griffin J, Albaloul AH, Kopytek A, Elliott P, Frost Get al., 2021, Effect of ultraprocessed food intake on cardiometabolic risk is mediated by diet quality: a cross-sectional study, BMJ Nutrition, Prevention & Health, Vol: 4, Pages: 174-180, ISSN: 2516-5542

Objective: To examine the effect of the consumption of ultraprocessed food on diet quality, and cardiometabolic risk (CMR) in an occupational cohort.Design: Cross-sectional.Setting: Occupational cohort.Participants: 53 163 British police force employees enrolled (2004–2012) into the Airwave Health Monitoring Study. A total of 28 forces across the UK agreed to participate. 9009 participants with available 7-day diet record data and complete co-variate data are reported in this study.Main outcome measures: A CMR and Dietary Approaches to Stop Hypertension score were treated as continuous variables and used to generate measures of cardiometabolic health and diet quality. Secondary outcome measures include percentage of energy from fat, saturated fat, carbohydrate, protein and non-milk extrinsic sugars (NMES) and fibre grams per 1000 kcal of energy intake.Results: In this cohort, 58.3%±11.6 of total energy intake was derived from ultraprocessed (NOVA 4) foods. Ultraprocessed food intake was negatively correlated with diet quality (r=−0.32, p<0.001), fibre (r=−0.20, p<0.001) and protein (r = −0.40, p<0.001) and positively correlated with fat (r=0.18, p<0.001), saturated fat (r=0.14, p<0.001) and nmes (r=0.10, p<0.001) intake . Multivariable analysis suggests a positive association between ultraprocessed food (NOVA 4) consumption and CMR. However, this main effect was no longer observed after adjustment for diet quality (p=0.209). Findings from mediation analysis indicate that the effect of ultraprocessed food (NOVA 4) intake on CMR is mediated by diet quality (p<0.001).Conclusions: Ultraprocessed food consumption is associated with a deterioration in diet quality and positively associated with CMR, although this association is mediated by and dependent on the quality of the diet. The negative impact of ultraprocessed food consumption on diet quality needs to be addressed and controlled studies are needed to fully compre

Journal article

Song P, Gupta A, Goon IY, Hasan M, Mahmood S, Pradeepa R, Siddiqui S, Frost GS, Kusuma D, Miraldo M, Sassi F, Wareham NJ, Ahmed S, Anjana RM, Brage S, Forouhi NG, Jha S, Kasturiratne A, Katulanda P, Khawaja KI, Loh M, Mridha MK, Wickremasinghe AR, Kooner JS, Chambers JCet al., 2021, Data resource profile: Understanding the patterns and determinants of health in South Asians—the South Asia Biobank, International Journal of Epidemiology, Vol: 50, Pages: 717-718e, ISSN: 0300-5771

Journal article

Cherta-Murillo A, Frost GS, 2021, The association of mycoprotein-based foods consumption with diet quality, energy intake and non-communicable diseases' risk in the UK adult population using the National Diet and Nutrition Survey (NDNS) years 2008/09-2016/17: A cross-sectional study., The British Journal of Nutrition: an international journal of nutritional science, Pages: 1-26, ISSN: 0007-1145

Mycoprotein is a fungal-based ingredient rich in fibre and protein used in meat-replacement foods sold under the name of Quorn in 17 countries. Fibre and protein positively regulate glycaemia, lipidaemia, energy intake which are non-communicable diseases' (NCDs) markers. We performed a cross-sectional study to investigate the association of mycoprotein intake with diet quality, nutrient, energy intake and NCDs risk within UK free-living adults from the National Diet and Nutrition Survey (NDNS) from years 2008/09-2016/17. Dietary approaches to stop hypertension (DASH) and healthy diet index (HDI) were calculated to estimate diet quality. Comparison between mycoprotein consumers (>1% kcal) and non-consumers, and associations between consumers and nutrient intakes, NCDs' risk markers and diet quality were investigated using a survey-adjusted general linear model adjusted for sex, age, body mass index (BMI), ethnicity, socio-economic, smoking status, region of residency, total energy, energy density, HDI and non-mycoprotein fibre intake. 5507 adults were included, of which 3.44% were mycoprotein consumers and had a higher intake of dietary fibre (+22.18%,p<0.001), DASH score (+23.33%) and HDI (+8.89%) (p<0.001, both) and lower BMI (-4.77%,p=0.00) vs. non-consumers. There was an association (p=0.00) between mycoprotein consumers and diet quality scores (+0.19 and +0.26), high fibre (+3.17g), total and food energy (+3.09 and +0.22 kcal), but low energy density intakes (-0.08 kcal/g,p=0.04). Consumers were negatively associated with fasting blood glucose (-0.31 mmol/L,p=0.00), and glycated haemoglobin A1c (HbA1c) (-0.15%,p=0.01). In conclusion, mycoprotein intake is associated with lower glycaemic markers and energy density intake, and high fibre, energy intake and diet quality scores.

Journal article

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, Vol: 2, Pages: 541-542

Journal article

Habboub N, Manousou P, Forlano R, Mullish BH, Frost G, Challis B, Thursz MR, Dumas M-Eet al., 2021, Metabolic Profiling of NASH Patients and Healthy Controls to Investigate the Transferability of a Healthy Metabolome Using Faecal Microbiota Transplantation, Metabolomics 2021

Conference paper

de la Hunty A, Buttriss J, Draper J, Roche H, Levey G, Florescu A, Penfold N, Frost Get al., 2021, UK Nutrition Research Partnership (NRP) workshop: Forum on advancing dietary intake assessment, NUTRITION BULLETIN, Vol: 46, Pages: 228-237, ISSN: 1471-9827

Journal article

Calder N, Walsh K, Olupot-Olupot P, Ssenyondo T, Muhindo R, Brignardello J, Wang X, McKay E, Morrison D, Holmes E, Frost G, Maitland Ket al., 2021, Modifying gut integrity and microbiome in children with severe acute malnutrition using LEgume-Based Feeds [MIMBLE]: A pilot trial, Cell Reports Medicine, Vol: 2, Pages: 1-17, ISSN: 2666-3791

Case fatality among African children with severe acute malnutrition remains high. We report a 3-arm pilot trial in 58 Ugandan children, comparing feeds targeting disordered gastrointestinal function containing cowpea (CpF, n = 20) or inulin (InF, n = 20) with conventional feeds (ConF, n = 18). Baseline measurements of gut permeability (lactulose:mannitol ratio 1.19 ± SD 2.00), inflammation (fecal calprotectin 539.0 μg/g, interquartile range [IQR] 904.8), and satiety (plasma polypeptide YY 62.6 pmol/l, IQR 110.3) confirm gastrointestinal dysfunction. By day 28, no differences are observable in proportion achieving weight gain >5 g/kg/day (87%, 92%, 86%; p > 0.05), mortality (16%, 30%, 17%; p > 0.05), or edema resolution (83%, 54%, 91%; p > 0.05) among CpF, InF, and ConF. Decreased fecal bacterial richness from day 1 (abundance-based coverage estimator [ACE] 53.2) to day 7 (ACE 40.8) is observed only in ConF (p = 0.025). Bifidobacterium relative abundance increases from day 7 (5.8% ± 8.6%) to day 28 (10.9% ± 8.7%) in CpF (corrected p = 1.000). Legume-enriched feeds support aspects of gut function and the microbiome. Trial registration PACTR201805003381361.

Journal article

Gressier M, Frost G, 2021, Minor changes in fibre intake in the UK population between 2008/2009 and 2016/2017, EUROPEAN JOURNAL OF CLINICAL NUTRITION, ISSN: 0954-3007

Journal article

Lawrence V, Hickson M, Weekes CE, Julian A, Frost G, Murphy Jet al., 2021, A UK survey of nutritional care pathways for patients with COVID-19 prior to and post-hospital stay, JOURNAL OF HUMAN NUTRITION AND DIETETICS, Vol: 34, Pages: 660-669, ISSN: 0952-3871

Journal article

Gressier M, Sassi F, Frost G, 2021, Contribution of reformulation, product renewal, and changes in consumer behavior to the reduction of salt intakes in the UK population between 2008/2009 and 2016/2017, The American Journal of Clinical Nutrition, ISSN: 0002-9165

BackgroundThe UK salt reduction program started in 2003, consisting of education campaigns to raise awareness about the risks associated with a high-salt diet and of a reformulation strategy for food manufacturers. This program is often cited as an example of a successful public health program.ObjectivesThis study aimed to assess: 1) the impacts of changes in food composition and changes in consumer behavior on sodium intakes; and 2) whether changes were similar across socioeconomic groups.MethodsFood intakes for the UK population were derived from food diaries in the UK National Diet and Nutrition Survey for 2008/09 (year 1; n = 1334) and 2016/17 (year 9; n = 995). Year-specific sodium densities of foods were used to calculate the average sodium density of all food and beverage consumed. Changes in sodium density between the 2 years were explained by changes in food composition (change in sodium density of products) and/or changes in behavior (type and quantity of food consumed) using a decomposition approach.ResultsThe program was linked to a 16% (95% CI: −21% to −12%) decrease in sodium intake between years 1 and 9, while the sodium density of foods consumed decreased by 17% (95% CI: −21% to −12%). This decrease was largely driven by reformulation (−12.0 mg/100 g). Changes in food choices reinforced the effects of the program, but had a smaller impact (−1.6 mg/100 g). These effects were similar across socioeconomic groups, whether stratified by education or income, with a consistent effect of reformulation across groups and no differences between groups in behavioral responses to the program.ConclusionsA multi-component sodium reduction strategy deployed in the United Kingdom starting in 2003 corresponded to an important reduction in sodium intakes for the population. This reduction was mostly driven by changes in the food environment (reformulated food products to reduce the sodium density of foods) and, to a smaller extent, b

Journal article

Capece D, D'Andrea D, Begalli F, Goracci L, Tornatore L, Alexander JL, Di Veroli A, Leow S-C, Vaiyapuri TS, Ellis JK, Verzella D, Bennett J, Savino L, Ma Y, McKenzie JS, Doria ML, Mason SE, Chng KR, Keun HC, Frost G, Tergaonkar V, Broniowska K, Stunkel W, Takats Z, Kinross JM, Cruciani G, Franzoso Get al., 2021, Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma., Journal of Clinical Investigation, ISSN: 0021-9738

The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Journal article

Miras AD, Kamocka A, Tan T, Pérez-Pevida B, Chahal H, Moorthy K, Purkayastha S, Patel A, Umpleby AM, Frost G, Bloom SR, Ahmed AR, Rubino Fet al., 2021, Long limb compared with standard limb Roux-en-Y gastric bypass for type 2 diabetes and obesity: the LONG LIMB RCT, Efficacy and Mechanism Evaluation, Vol: 8, ISSN: 2050-4365

BackgroundRoux-en-Y gastric bypass is recognised as a standard of care in the treatment of diabetes mellitus and obesity. However, the optimal length of the Roux-en-Y gastric bypass limbs remains controversial, with substantial variation in practice. Specifically, a longer biliopancreatic limb length of 150 cm (‘long limb’) has been hypothesised to be better for the treatment of diabetes mellitus because it increases the postprandial secretion of gut hormones, such as glucagon-like peptide 1, and increases insulin sensitivity, compared with the Roux-en-Y gastric bypass utilising a standard biliopancreatic limb length of 50 cm (‘standard limb’).ObjectiveTo evaluate the mechanisms, clinical efficacy and safety of long limb versus the standard limb Roux-en-Y gastric bypass in patients undergoing metabolic surgery for obesity and diabetes mellitus.DesignA double-blind, mechanistic randomised controlled trial was conducted to evaluate the mechanisms, clinical efficacy and safety of the two interventions.SettingImperial College London, King’s College London and their associated NHS trusts.ParticipantsPatients with obesity and type 2 diabetes mellitus who were eligible for metabolic surgery.InterventionsParticipants were randomly assigned (1 : 1) to 150-cm (long limb) or 50-cm (standard limb) biliopancreatic limb Roux-en-Y gastric bypass with a fixed alimentary limb of 100 cm. The participants underwent meal tolerance tests to measure glucose excursions, glucagon-like peptide 1 and insulin secretion, and hyperinsulinaemic–euglycaemic clamps with stable isotopes to measure insulin sensitivity preoperatively, at 2 weeks after the surgery and at matched 20% total body weight loss. Clinical follow-up continued up to 1 year.Main outcome measuresPrimary – postprandial peak of active glucagon-like peptide 1 concentration at 2 weeks after intervention. Secondary – fasting and postprandial glucose an

Journal article

Bizzotto R, Jennison C, Jones AG, Kurbasic A, Tura A, Kennedy G, Bell JD, Thomas EL, Frost G, Eriksen R, Koivula RW, Brage S, Kaye J, Hattersley AT, Heggie A, McEvoy D, 't Hart LM, Beulens JW, Elders P, Musholt PB, Ridderstrale M, Hansen TH, Allin KH, Hansen T, Vestergaard H, Lundgaard AT, Thomsen HS, De Masi F, Tsirigos KD, Brunak S, Vinuela A, Mahajan A, McDonald TJ, Kokkola T, Forgie IM, Giordano GN, Pavo I, Ruetten H, Dermitzakis E, McCarthy MI, Pedersen O, Schwenk JM, Adamski J, Franks PW, Walker M, Pearson ER, Mari Aet al., 2021, Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study, DIABETES CARE, Vol: 44, Pages: 511-518, ISSN: 0149-5992

Journal article

Miras A, Kamocka A, Pérez-Pevida B, Purkayastha S, Moorthy K, Patel A, Chahal H, Frost G, Bassett P, Castagnetto-Gissey L, Coppin L, Jackson N, Umpleby M, Bloom S, Tan T, Ahmed A, Rubino Fet al., 2021, The effect of standard versus longer intestinal bypass on GLP-1 regulation and glucose metabolism in patients with type 2 diabetes undergoing roux-en-Y gastric bypass. The long-limb study, Diabetes Care, Vol: 44, Pages: 1-9, ISSN: 0149-5992

ObjectiveRoux-en-Y gastric bypass (RYGB) characteristically enhances post-prandial levels of Glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesised that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the post-prandial peak in GLP-1, translating into higher insulin secretion and thus additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass.Research Design and MethodsFifty-three patients with type 2 diabetes and obesity were randomised to either ‘standard limb’ RYGB (50cm biliopancreatic limb) or ‘long limb’ RYGB (150cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycaemic hyperinsulinaemic clamps at baseline, 2 weeks and at 20% weight loss after surgery.ResultsBoth groups exhibited enhancement in post-prandial GLP-1 secretion and improvements in glycaemia compared to baseline. There were no significant differences in post-prandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. ConclusionThe findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

Journal article

Gressier M, Swinburn B, Frost G, Segal A, Sassi Fet al., 2021, What is the impact of food reformulation on individual’s behaviour, nutrient intakes and health status? A systematic review of empirical evidence, Obesity Reviews, Vol: 22, Pages: 1-23, ISSN: 1467-7881

Food reformulation aimed at improving the nutritional properties of food products has long been viewed as a promising public health strategy to tackle poor nutrition and obesity. This paper presents a review of the empirical evidence (i.e. modelling studies were excluded) on the impact of food reformulation on food choices, nutrient intakes and health status, based on a systematic search of Medline, Embase, Global Health, and sources of grey literature. Fifty-nine studies (in 35 papers) were included in the review. Most studies examined food choices (n=27) and dietary intakes (n=26). The nutrients most frequently studied were sodium (n=32) and trans-fatty acids (TFA, n=13). Reformulated products were generally accepted and purchased by consumers, which led to improved nutrient intakes in 73% of studies. We also conducted two meta-analyses showing, respectively, a -0.57g/day [95%CI -0.89, -0.25] reduction in salt intake, and an effect size for TFA intake reduction of -1.2, 95% [CI -1.79, -0.61]. Only six studies examined effects on health outcomes, with studies on TFA reformulation showing overall improvement in cardiovascular risk factors. For other nutrients, it remains unclear whether observed improvements in food choices or nutrient intakes may have led to an improvement in health outcomes.

Journal article

Ashok AH, Myers J, Frost G, Turton S, Gunn RN, Passchier J, Colasanti A, Marques TR, Nutt D, Lingford-Hughes A, Howes OD, Rabiner EAet al., 2021, Acute acetate administration increases endogenous opioid levels in the human brain: A [C-11]carfentanil molecular imaging study, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 606-610, ISSN: 0269-8811

Journal article

Brignardello J, Fountana S, Posma JM, Chambers ES, Nicholson JK, Wist J, Frost G, Garcia-Perez I, Holmes Eet al., 2021, Characterization of diet-dependent temporal changes in circulating short-chain fatty acid concentrations: A randomized crossover dietary trial, The American Journal of Clinical Nutrition, ISSN: 0002-9165

Background: Production of Short-chain fatty acids (SCFAs) from food is a complex and dynamic saccharolytic fermentation process mediated by both human and gut microbial factors. SCFA production and knowledge of the relationship between SCFA profiles and dietary patterns is lacking. Objective: Temporal changes in SCFA levels in response to two contrasting diets were investigated using a novel GC-MS method.Design: Samples were obtained from a randomized, controlled, crossover trial designed to characterize the metabolic response to four diets. Participants (n=19) undertook these diets during an inpatient stay (of 72-h). Serum samples were collected 2-h after breakfast (AB), lunch (AL) and dinner (AD) on day 3 and a fasting sample (FA) was obtained on day 4. 24-h urine samples were collected on day 3. In this sub-study, samples from the two extreme diets representing a diet with high adherence to WHO healthy eating recommendations and a typical Western diet were analyzed using a bespoke GC-MS method developed to detect and quantify 10 SCFAs and precursors in serum and urine samples. Results: Considerable inter-individual variation in serum SCFA concentrations was observed across all time points and temporal fluctuations were observed for both diets. Although the sample collection timing exerted a greater magnitude of effect on circulating SCFA concentrations, the unhealthy diet was associated with a lower concentration of acetic acid (FA: coefficient=-17.0; standard error (SE)=5.8; p-trend=0.00615), 2-methylbutyric acid (AL: coefficient=-0.1; SE=0.028; p-trend=4.13x10-4 and AD: coefficient =-0.1; SE:=0.028; p-trend=2.28x10-3) and 2-hydroxybutyric acid (FA: coefficient=-15.8; standard error=5.11; p-trend: 4.09x10-3). In contrast lactic acid was significantly higher in the unhealthy diet (AL: coefficient=750.2; standard error=315.2; p-trend=0.024 and AD: coefficient=1219.3; standard error=322.6; p-trend: 8.28x10-4). Conclusion: The GC-MS method allowed robust mapping of

Journal article

Skamniotis CG, Edwards CH, Bakalis S, Frost G, Charalambides MNet al., 2020, Eulerian-Lagrangian finite element modelling of food flow-fracture in the stomach to engineer digestion, Innovative Food Science & Emerging Technologies, Vol: 66, ISSN: 1466-8564

Highly processed foods tend to form weak structures which breakdown rapidly in the gastrointestinal (GI) tract, often causing negative effects on human metabolism and health. Developing healthier foods has been limited by the lack of understanding of how foods are digested. Through computational modelling we reveal mechanical gastric food breakdown phenomena and relate food mechanical properties with performance during critical initial digestion stages. Our model relies strictly on a viscoplastic-damage constitutive law, calibrated via rheological experiments on an artificial biscuit bolus and validated by simulating cutting tests. Simulations suggest that bolus separation during bolus backward extrusion and/or indentation by peristaltic waves, and, bolus agglomeration due to hydrostatic compression near the pylorus, are two competing phenomena that can influence the bolus free surface to volume ratio. This showcases the importance of including mechanical aspects of breakdown when designing foods for controlled chemo-mechanical breakdown and associated nutrient release rates.

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

Koivula RW, Atabaki-Pasdar N, Giordano GN, White T, Adamski J, Bell JD, Beulens J, Brage S, Brunak S, De Masi F, Dermitzakis ET, Forgie IM, Frost G, Hansen T, Hansen TH, Hattersley A, Kokkola T, Kurbasic A, Laakso M, Mari A, McDonald TJ, Pedersen O, Rutters F, Schwenk JM, Teare HJA, Thomas EL, Vinuela A, Mahajan A, McCarthy MI, Ruetten H, Walker M, Pearson E, Pavo I, Franks PWet al., 2020, The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study (vol 63, pg 744, 2020), DIABETOLOGIA, Vol: 64, Pages: 260-261, ISSN: 0012-186X

Journal article

Mars RAT, Yang Y, Ward T, Houtti M, Priya S, Lekatz HR, Tang X, Sun Z, Kalari KR, Korem T, Bhattarai Y, Zheng T, Bar N, Frost G, Johnson AJ, van Treuren W, Han S, Ordog T, Grover M, Sonnenburg J, D'Amato M, Camilleri M, Elinav E, Segal E, Blekhman R, Farrugia G, Swann JR, Knights D, Kashyap PCet al., 2020, Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome (vol 182, pg 1460, 2020), Cell, Vol: 183, Pages: 1137-1140, ISSN: 0092-8674

Journal article

Bar N, Korem T, Weissbrod O, Zeevi D, Rothschild D, Leviatan S, Kosower N, Lotan-Pompan M, Weinberger A, Le Roy CI, Menni C, Visconti A, Falchi M, Spector TD, Adamski J, Franks PW, Pedersen O, Segal Eet al., 2020, A reference map of potential determinants for the human serum metabolome, NATURE, Vol: 588, Pages: 135-140, ISSN: 0028-0836

Journal article

Rahman MS, Haskard DO, Frost G, Vorkas P, Woollard KJet al., 2020, Acute dietary saturated fat intake suppresses human monocyte subset inflammatory and chemokine responses, Publisher: OXFORD UNIV PRESS, Pages: 3622-3622, ISSN: 0195-668X

Conference paper

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