The TNFSF12/TWEAK Modulates Colonic Inflammatory Fibroblast Differentiation and Promotes Fibroblast-Monocyte Interactions.

Fibroblasts acquire a proinflammatory phenotype in inflammatory bowel disease, but the factors driving this process and how fibroblasts contribute to mucosal immune responses are incompletely understood. TNF superfamily member 12 (TNFSF12, or TNF-like weak inducer of apoptosis [TWEAK]) has gained interest as a mediator of chronic inflammation. In this study, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP-1 and primary monocytes. Recombinant human TWEAK induced the expression of cytokines, chemokines, and immune receptors in primary colonic fibroblasts. The TWEAK upregulated transcriptome shared 29% homology with a previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblast markers and adhesion molecules (podoplanin [PDPN], ICAM-1, and VCAM-1) and secretion of IL-6, CCL2, and CXCL10. In coculture, fibroblasts induced monocyte adhesion and secretion of CXCL1 and IL-8, and they promoted a CD14high/ICAM-1high phenotype in THP-1 cells, which was enhanced when fibroblasts were prestimulated with TWEAK. Primary monocytes in coculture with TWEAK-treated fibroblasts had altered surface expression of CD16 and triggering receptor expressed on myeloid cells-1 (TREM-1) as well as increased CXCL1 and CXCL10 secretion. Conversely, inhibition of the noncanonical NF-κB pathway on colonic fibroblasts with a NF-κB-inducing kinase small molecule inhibitor impaired their ability to induce a CD14high phenotype on monocytes. Our results indicate that TWEAK promotes an inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

Obesity, Dietary Fats, and Gastrointestinal Cancer Risk-Potential Mechanisms Relating to Lipid Metabolism and Inflammation.

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers.

Perspective: Peer Evaluation of Recommendations for CONSORT Guidelines for Randomized Controlled Trials in Nutrition.

Creating effective dietary guidance requires a rigorous evidence base that is predominantly developed from robust clinical trials or large-scale cohort studies, with the quality of the data available depending on the completeness and accuracy of their reporting. An international group of academics from 14 institutions in 12 different countries and on 5 continents, working on behalf of the Federation of European Nutrition Societies within its "Improving Standards in the Science of Nutrition" initiative, reviewed the Consolidated Standards of Reporting Trials (CONSORT) statement checklist as it pertains to nutrition trials. This perspective piece documents the procedure followed to gain input and consensus on the checklist previously published by this group, including its presentation and interrogation at the International Union of Nutritional Sciences International Congress of Nutrition 2022 (IUNS-ICN 22), inputs from a survey of journal editors, and its piloting on 8 nutrition trials of diverse designs. Overall, the initiative has been met with considerable enthusiasm. At IUNS-ICN 22, refinements to our proposal were elicited through a World Café method discussion with participating nutrition scientists. The contributing journal editors provided valuable insights, and the discussion led to the development of a potential tool specific to assess adherence to the proposed nutrition extension checklist. The piloting of the proposed checklist provided evidence from real-life studies that reporting of nutrition trials can be improved. This initiative aims to stimulate further discussion and development of a CONSORT-nutrition-specific extension.

Cell-Penetrating Milk-Derived Peptides with a Non-Inflammatory Profile.

Milk-derived peptides are known to confer anti-inflammatory effects. We hypothesised that milk-derived cell-penetrating peptides might modulate inflammation in useful ways. Using computational techniques, we identified and synthesised peptides from the milk protein Alpha-S1-casein that were predicted to be cell-penetrating using a machine learning predictor. We modified the interpretation of the prediction results to consider the effects of histidine. Peptides were then selected for testing to determine their cell penetrability and anti-inflammatory effects using HeLa cells and J774.2 mouse macrophage cell lines. The selected peptides all showed cell penetrating behaviour, as judged using confocal microscopy of fluorescently labelled peptides. None of the peptides had an effect on either the NF-κB transcription factor or TNFα and IL-1ß secretion. Thus, the identified milk-derived sequences have the ability to be internalised into the cell without affecting cell homeostatic mechanisms such as NF-κB activation. These peptides are worthy of further investigation for other potential bioactivities or as a naturally derived carrier to promote the cellular internalisation of other active peptides.

Precision nutrition for targeting pathophysiology of cardiometabolic phenotypes.

Obesity is a heterogenous disease accompanied by a broad spectrum of cardiometabolic risk profiles. Traditional paradigms for dietary weight management do not address biological heterogeneity between individuals and have catastrophically failed to combat the global pandemic of obesity-related diseases. Nutritional strategies that extend beyond basic weight management to instead target patient-specific pathophysiology are warranted. In this narrative review, we provide an overview of the tissue-level pathophysiological processes that drive patient heterogeneity to shape distinct cardiometabolic phenotypes in obesity. Specifically, we discuss how divergent physiology and postprandial phenotypes can reveal key metabolic defects within adipose, liver, or skeletal muscle, as well as the integrative involvement of the gut microbiome and the innate immune system. Finally, we highlight potential precision nutritional approaches to target these pathways and discuss recent translational evidence concerning the efficacy of such tailored dietary interventions for different obesity phenotypes, to optimise cardiometabolic benefits.

Nutrition strategies to counteract sarcopenia: a focus on protein, LC n-3 PUFA and precision nutrition.

Diminished skeletal muscle strength and size, termed sarcopenia, contributes substantially to physical disability, falls, dependence and reduced quality of life among older people. Physical activity and nutrition are the cornerstones of sarcopenia prevention and treatment. The optimal daily protein intake required to preserve muscle mass and function among older adults is a topic of intense scientific debate. Older adults require protein intakes about 67 % higher than their younger counterparts to maximally stimulate postprandial muscle protein synthesis rates. In addition, evidence suggests a possible benefit of increasing protein intake above the population reference intake (0⋅83 g/kg/d) on lean mass and, when combined with exercise training, muscle strength. In addition to protein quantity, protein quality, the pattern of protein intake over the day and specific amino acids (i.e. leucine) represent key considerations. Long-chain n-3 PUFA (LC n-3 PUFA) supplementation has been shown to enhance muscle protein synthesis rates, increase muscle mass and function and augment adaptations to resistance training in older adults. Yet, these effects are not consistent across all studies. Emerging evidence indicates that an older person's dietary, phenotypic and behavioural characteristics may modulate the efficacy of protein and LC n-3 PUFA interventions for promoting improvements in muscle mass and function, highlighting the potential inadequacy of a 'one-size-fits-all' approach. The application of personalised or precision nutrition to sarcopenia represents an exciting and highly novel field of research with the potential to help resolve inconsistencies in the literature and improve the efficacy of dietary interventions for sarcopenia.

Systems biology approaches to inform precision nutrition.

The precision nutrition paradigm is based on the premise that substantial variation exists between human subjects in terms of diet-related disease risk and response to dietary interventions. In terms of better defining, 'the right diet for the right person at the right time' may be more appropriate than 'one-diet-fits-all'. This review will explore how systems biology and nutrigenomics approaches have advanced the precision nutrition paradigm. We will draw upon a number of elegant mechanistic studies that have enhanced our understanding with respect to the complex biology and inter-organ crosstalk, relating to inflammation and metabolism, that underpin cardio-metabolic health. Also, this review will explore the extent to which more targeted, precision nutrition approaches may attenuate adverse risk factors associated with cardio-metabolic disease. We will focus on the key characteristics or 'metabotypes' of high- v. low-risk individuals and response v. non-response to interventions, to generate greater insights with respect to risk stratification and therapeutic interventions to enhance disease prevention. The goal is to utilise systems biology to enhance understanding by underpinning more targeted nutritional approaches, which may improve efficacy of personalised nutrition interventions.

Prevalence and determinants of sarcopenia in community-dwelling older adults in Ireland.

BACKGROUND: Data on the prevalence of sarcopenia among older adults in Ireland are lacking. AIMS: To assess the prevalence and determinants of sarcopenia among community-dwelling older adults in Ireland. METHODS: This cross-sectional analysis involved n = 308 community-dwelling adults aged ≥ 65 y living in Ireland. Participants were recruited via recreational clubs and primary healthcare services. Sarcopenia was defined according to the 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Skeletal muscle mass was estimated using bioelectrical impedance analysis, strength was measured via handgrip dynamometry, and physical performance was assessed using the Short Physical Performance Battery. Detailed information was collected on demographics, health, and lifestyle. Dietary macronutrient intake was measured via a single 24 h recall. Binary logistic regression was used to examine potential demographic, health, lifestyle, and dietary determinants of sarcopenia (where both probable and confirmed sarcopenia were combined). RESULTS: The prevalence of EWGSOP2-defined probable sarcopenia was 20.8% and confirmed sarcopenia was 8.1% (5.8% had severe sarcopenia). Polypharmacy (OR 2.60, 95% confidence interval [CI] 1.3, 5.23), height (OR 0.95, 95% CI 0.91, 0.98), and Instrumental Activities Of Daily Living (IADL) score (OR 0.71, 95% CI 0.59, 0.86) were independently associated with sarcopenia (probable and confirmed combined). There were no independent associations between energy-adjusted macronutrient intakes, as determined by 24 h recall, and sarcopenia. CONCLUSION: Sarcopenia prevalence within this sample of community-dwelling older adults in Ireland is broadly similar to other European cohorts. Polypharmacy, lower height, and lower IADL score were independently associated with EWGSOP2-defined sarcopenia.

Perspectives on the application of CONSORT guidelines to randomised controlled trials in nutrition.

PURPOSE: Reporting guidelines facilitate quality and completeness in research reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement is widely applied to dietary and nutrition trials but has no extension specific to nutrition. Evidence suggests poor reporting in nutrition research. The Federation of European Nutrition Societies led an initiative to make recommendations for a nutrition extension to the CONSORT statement towards a more robust reporting of the evidence base. METHODS: An international working group was formed of nutrition researchers from 14 institutions in 12 different countries and on five continents. Using meetings over a period of one year, we interrogated the CONSORT statement specifically for its application to report nutrition trials. RESULTS: We provide a total of 28 new nutrition-specific recommendations or emphasised recommendations for the reporting of the introduction (three), methods (twelve), results (five) and discussion (eight). We also added two additional recommendations that were not allocated under the standard CONSORT headings. CONCLUSION: We identify a need to provide guidance in addition to CONSORT to improve the quality and consistency of the reporting and propose key considerations for further development of formal guidelines for the reporting of nutrition trials. Readers are encouraged to engage in this process, provide comments and conduct specific studies to inform further work on the development of reporting guidelines for nutrition trials.

Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma.

Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-ß and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes.

An innovative food system approach to diversifying protein intake: Protein-I: Shared Island sustainable healthy nutrition.

There is a need to transform our current food system if we are to feed the rapidly expanding global population while maintaining planetary health. Within the island of Ireland, there is an urgent need to diversify the foods that currently contribute to our populations' protein intake. A Shared Island Innovative Food System approach is required to achieve this in a manner that is sustainable and provides benefits to producers, consumers and other supply chain participants. The Protein-I project employs such an approach, with the paradigm focusing on production of plant food through to human health, while paying particular attention to the development of the rural bioeconomy. Using an interdisciplinary approach, the team will develop strategies to maximise sustainable plant protein production in a traceable/transparent fashion and assess the impact of changes to existing value chains and the development of new value chains for the rural economy. A smart supply chain technology solution tailored to the needs of the agri-food industry will be developed and tested. Additionally, we will co-design consumer-led approaches to diversify plant protein intake, model the impact of changes at the population level and perform human interventions to demonstrate efficacy in terms of achieving adequate nutrition and improved health. Comprehensive engagement with stakeholders is embedded throughout the whole project to embrace the multi-actor approach. Overall, the project will be a key step towards future-proofing our food system on the island of Ireland and moving towards protecting planetary and population health, within the context of a just transition.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Yeast ß-Glucan Improves Insulin Sensitivity and Hepatic Lipid Metabolism in Mice Humanized with Obese Type 2 Diabetic Gut Microbiota.

SCOPE: Gut microbiota alterations are associated with obesity and type 2 diabetes. Yeast ß-glucans are potential modulators of the innate immune-metabolic response, by impacting glucose, lipid, and cholesterol homeostasis. The study examines whether yeast ß-glucan interacts differentially with either an obese healthy or obese diabetic gut microbiome, to impact metabolic health through hepatic effects under high-fat dietary challenge. METHODS AND RESULTS: Male C57BL/6J mice are pre-inoculated with gut microbiota from obese healthy (OBH) or obese type 2 diabetic (OBD) subjects, in conjunction with a high-fat diet (HFD) with/without yeast ß-glucan. OBD microbiome colonization adversely impacts metabolic health compared to OBH microbiome engraftment. OBD mice are more insulin resistant and display hepatic lipotoxicity compared to weight matched OBH mice. Yeast ß-glucan supplementation resolves this adverse metabolic phenotype, coincident with increasing the abundance of health-related bacterial taxa. Hepatic proteomics demonstrates that OBD microbiome transplantation increases HFD-induced hepatic mitochondrial dysfunction, disrupts oxidative phosphorylation, and reduces protein synthesis, which are partly reverted by yeast ß-glucan supplementation. CONCLUSIONS: Hepatic metabolism is adversely affected by OBD microbiome colonization with high-fat feeding, but partially resolved by yeast ß-glucan. More targeted dietary interventions that encompass the interactions between diet, gut microbiota, and host metabolism may have greater treatment efficacy.

Interindividual variability in response to protein and fish oil supplementation in older adults: a randomized controlled trial.

BACKGROUND: Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. METHODS: A 24 week, randomized, double-blind, placebo-controlled trial tested the impact of leucine-enriched protein (LEU-PRO), LEU-PRO plus long-chain n-3 PUFA (LEU-PRO+n-3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within-subject variation), the standard deviation of individual responses (SDR ) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up-and-go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. RESULTS: The SDR was below the MCID for ALM (LEU-PRO: -0.12 kg [90% CI: -0.38, 0.35], LEU-PRO+n-3: -0.32 kg [-0.45, 0.03], MCID: 0.21 kg), TUG (LEU-PRO: 0.58 s [0.18, 0.80], LEU-PRO+n-3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU-PRO: -0.38 mmol/L [-0.80, 0.25], LEU-PRO+n-3: -0.44 mmol/L [-0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU-PRO (25 Nm [-29, 45]) and LEU-PRO+n-3 (23 Nm [-29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU-PRO, LEU-PRO+n-3, and CON groups (P > 0.05). Baseline LC n-3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU-PRO or LEU-PRO+n-3 supplementation. CONCLUSIONS: Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU-PRO and LEU-PRO+n-3 supplementation in older adults at risk of sarcopenia.

Sodium salicylate rewires hepatic metabolic pathways in obesity and attenuates IL-1ß secretion from adipose tissue: The implications for obesity-impaired reverse cholesterol transport.

INTRODUCTION: High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, namely ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). In the current study, we hypothesized that the development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and that such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS). MATERIALS AND METHODS: C57BL/6J mice, fed HFD ± NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing. The 3H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analyzed using Ingenuity Pathway Analysis. RESULTS: NaS delayed HFD-induced weight gain, abrogated priming of pro-IL-1ß in SVFs, attenuated insulin resistance, and prevented steatohepatitis (ectopic fat accumulation in the liver). Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins. The latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection shown against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter, ABCG5/8, could not be rescued with NaS. DISCUSSIONS AND CONCLUSIONS: The cardiometabolic health benefits of NaS may be attributed to the reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the settings of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie the lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis.

Peripheral Amino Acid Appearance Is Lower Following Plant Protein Fibre Products, Compared to Whey Protein and Fibre Ingestion, in Healthy Older Adults despite Optimised Amino Acid Profile.

Plant-based proteins are generally characterised by lower Indispensable Amino Acid (IAA) content, digestibility, and anabolic properties, compared to animal-based proteins. However, they are environmentally friendlier, and wider consumption is advocated. Older adults have higher dietary protein needs to prevent sarcopenia, a disease marked by an accelerated loss of muscle mass and function. Given the lower environmental footprint of plant-based proteins and the importance of optimising dietary protein quality among older adults, this paper aims to assess the net peripheral Amino Acid (AA) appearance after ingestion of three different plant protein and fibre (PPF) products, compared to whey protein with added fibre (WPF), in healthy older adults. In a randomised, single-blind, crossover design, nine healthy men and women aged ≥65 years consumed four test meals balanced in AA according to the FAO reference protein for humans, matched for leucine, to optimally stimulate muscle protein synthesis in older adults. A fasted blood sample was drawn at each visit before consuming the test meal, followed by postprandial arterialise blood sampling every 30 min for 3 h. The test meal was composed of a soup containing either WPF or PPF 1-3. The PPF blends comprised pea proteins with varying additional rice, pumpkin, soy, oat, and/or almond protein. PPF product ingestion resulted in a lower maximal increase of postprandial leucine concentration and the sum of branched-chain AA (BCAA) and IAA concentrations, compared to WPF, with no effect on their incremental area under the curve. Plasma methionine and cysteine, and to a lesser extent threonine, appearance were limited after consuming the PPF products, but not WPF. Despite equal leucine doses, the WPF induced greater postprandial insulin concentrations than the PPF products. In conclusion, the postprandial appearance of AA is highly dependent on the protein source in older adults, despite providing equivalent IAA levels and dietary fibre. Coupled with lower insulin concentrations, this could imply less anabolic potential. Further investigation is required to understand the applicability of plant-based proteins in healthy older adults.

Opposing Immune-Metabolic Signature in Visceral Versus Subcutaneous Adipose Tissue in Patients with Adenocarcinoma of the Oesophagus and the Oesophagogastric Junction.

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Previous work in our group has demonstrated that overweight/obese OAC patients have better responses to neoadjuvant therapy, but the underlying mechanisms are unknown. Unravelling the immune-metabolic signatures of adipose tissue may provide insight for this observation. We hypothesised that different metabolic pathways predominate in visceral (VAT) and subcutaneous adipose tissue (SAT) and inflammatory secretions will differ between the fat depots. Real-time ex vivo metabolic profiles of VAT and SAT from 12 OAC patients were analysed. These samples were screened for the secretion of 54 inflammatory mediators, and data were correlated with patient body composition. Oxidative phosphorylation (OXPHOS) was significantly higher in VAT when compared to SAT. OXPHOS was significantly higher in the SAT of patients receiving neoadjuvant treatment. VEGF-A, VEGF-C, P1GF, Flt-1, bFGF, IL-15, IL-16, IL-17A, CRP, SAA, ICAM-1, VCAM-1, IL-2, IL-13, IFN-γ, and MIP-1ß secretions were significantly higher from VAT than SAT. Higher levels of bFGF, Eotaxin-3, and TNF-α were secreted from the VAT of obese patients, while higher levels of IL-23 and TARC were secreted from the SAT of obese patients. The angiogenic factors, bFGF and VEGF-C, correlated with visceral fat area. Levels of OXPHOS are higher in VAT than SAT. Angiogenic, vascular injury and inflammatory cytokines are elevated in VAT versus SAT, indicating that VAT may promote inflammation, linked to regulating treatment response.

Targeting the Gut Microbiota to Improve Dietary Protein Efficacy to Mitigate Sarcopenia.

Sarcopenia is characterised by the presence of diminished skeletal muscle mass and strength. It is relatively common in older adults as ageing is associated with anabolic resistance (a blunted muscle protein synthesis response to dietary protein consumption and resistance exercise). Therefore, interventions to counteract anabolic resistance may benefit sarcopenia prevention and are of utmost importance in the present ageing population. There is growing speculation that the gut microbiota may contribute to sarcopenia, as ageing is also associated with [1) dysbiosis, whereby the gut microbiota becomes less diverse, lacking in healthy butyrate-producing microorganisms and higher in pathogenic bacteria, and [2) loss of epithelial tight junction integrity in the lining of the gut, leading to increased gut permeability and higher metabolic endotoxemia. Animal data suggest that both elements may impact muscle physiology, but human data corroborating the causality of the association between gut microbiota and muscle mass and strength are lacking. Mechanisms wherein the gut microbiota may alter anabolic resistance include an attenuation of gut-derived low-grade inflammation and/or the increased digestibility of protein-containing foods and consequent higher aminoacidemia, both in favour of muscle protein synthesis. This review focuses on the putative links between the gut microbiota and skeletal muscle in the context of sarcopenia. We also address the issue of plant protein digestibility because plant proteins are increasingly important from an environmental sustainability perspective, yet they are less efficient at stimulating muscle protein synthesis than animal proteins.