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BACKGROUND: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). METHODS: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. RESULTS: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10-6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. CONCLUSIONS: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern.
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Caroténoïdes , Microbiome gastro-intestinal , Rétinoïdes , Rétinol , Humains , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Microbiome gastro-intestinal/physiologie , Rétinol/sang , Caroténoïdes/sang , Caroténoïdes/métabolisme , Femelle , Adulte d'âge moyen , Mâle , Rétinoïdes/métabolisme , Sujet âgé , Régime alimentaire , Fèces/microbiologie , AdulteRÉSUMÉ
OBJECTIVE: The ArmeD SerVices TrAuma RehabilitatioN OutComE (ADVANCE) study is investigating long-term combat-injury outcomes; this sub-study aims to understand the association of osteoarthritis (OA) biomarkers with knee radiographic OA (rOA), pain and function in this high-risk population for post-traumatic OA. DESIGN: ADVANCE compares combat-injured participants with age, rank, deployment and job-role frequency-matched uninjured participants. Post-injury immunoassay-measured serum biomarkers, knee radiographs, Knee Injury and Osteoarthritis Outcome Scale, and six-minute walk tests are reported. The primary analysis, adjusted for age, body mass, socioeconomic status, and ethnicity, was to determine any differences in biomarkers between those with/without combat injury, rOA and pain. Secondary analyses were performed to compare post-traumatic/idiopathic OA, painful/painfree rOA and injury patterns. RESULTS: A total of 1145 male participants were recruited, aged 34.1 ± 5.4, 8.9 ± 2.2 years post-injury (n = 579 trauma-exposed, of which, traumatic-amputation n = 161) or deployment (n = 566 matched). Cartilage oligomeric matrix protein (COMP) was significantly higher in the combat-injured group compared to uninjured (p = 0.01). Notably, COMP was significantly lower in the traumatic-amputation group compared to non-amputees (p < 0.001), decreasing relative to number of amputations (p < 0.001). Leptin was higher (p = 0.005) and adiponectin lower (p = 0.017) in those with v without knee pain, associated with an increased risk of 22% and 17% for pain, and 46% and 34% for painful rOA, respectively. There were no significant differences between trauma-exposed and unexposed participants with rOA. CONCLUSIONS: The most notable findings of this large, unique study are the similarities between those with rOA regardless of trauma-exposure, the injury-pattern and traumatic-amputation-associated differences in COMP, and the relationship between adipokines and pain.
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Background: Hip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients. Methods: In a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers. Results: Of the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76-40.51], and with both markers plus estimated glomerular filtration rate (eGFR)- cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI. Conclusion: High postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group.
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Atteinte rénale aigüe , Marqueurs biologiques , Facteur-23 de croissance des fibroblastes , Fractures de la hanche , Humains , Fractures de la hanche/chirurgie , Fractures de la hanche/mortalité , Fractures de la hanche/sang , Mâle , Femelle , Marqueurs biologiques/sang , Sujet âgé , Sujet âgé de 80 ans ou plus , Atteinte rénale aigüe/mortalité , Atteinte rénale aigüe/étiologie , Atteinte rénale aigüe/sang , Atteinte rénale aigüe/diagnostic , Études prospectives , Complications postopératoires/sang , Complications postopératoires/mortalité , Complications postopératoires/étiologie , Facteurs de croissance fibroblastique/sang , Débit de filtration glomérulaire , Inflammation/sang , Période préopératoireRÉSUMÉ
Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin supplementation. Elastic net regressions were used to separately identify the serum and stool metabolites whose change in concentration discriminated between the two types of supplementations. Random forest was used to explore the gut microbiome's contribution to the levels of the identified metabolites from matching stool samples. Changes in serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate and indoleproprionate levels accurately discriminated between fibre and omega-3 (area under the curve (AUC) = 0.87 [95% confidence interval (CI): 0.63-0.99]), while stool eicosapentaenoate indicated omega-3 supplementation (AUC = 0.86 [95% CI: 0.64-0.98]). Univariate analysis also showed significant increases in indoleproprionate with fibre, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, and eicosapentaenoate with omega-3. Out of these, only the change in indoleproprionate was partly explained by changes in the gut microbiome composition (AUC = 0.61 [95% CI: 0.58-0.64] and Rho = 0.21 [95% CI: 0.08-0.34]) and positively correlated with the increase in the abundance of the genus Coprococcus (p = 0.005). Changes in three metabolites discriminated between fibre and omega-3 supplementation. The increase in indoleproprionate with fibre was partly explained by shifts in the gut microbiome, particularly Coprococcus, previously linked to better health.
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Large variability exists in people's responses to foods. However, the efficacy of personalized dietary advice for health remains understudied. We compared a personalized dietary program (PDP) versus general advice (control) on cardiometabolic health using a randomized clinical trial. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses to foods, microbiomes and health history, to produce personalized food scores in an 18-week app-based program. The control group received standard care dietary advice (US Department of Agriculture Guidelines for Americans, 2020-2025) using online resources, check-ins, video lessons and a leaflet. Primary outcomes were serum low-density lipoprotein cholesterol and TG concentrations at baseline and at 18 weeks. Participants (n = 347), aged 41-70 years and generally representative of the average US population, were randomized to the PDP (n = 177) or control (n = 170). Intention-to-treat analysis (n = 347) between groups showed significant reduction in TGs (mean difference = -0.13 mmol l-1; log-transformed 95% confidence interval = -0.07 to -0.01, P = 0.016). Changes in low-density lipoprotein cholesterol were not significant. There were improvements in secondary outcomes, including body weight, waist circumference, HbA1c, diet quality and microbiome (beta-diversity) (P < 0.05), particularly in highly adherent PDP participants. However, blood pressure, insulin, glucose, C-peptide, apolipoprotein A1 and B, and postprandial TGs did not differ between groups. No serious intervention-related adverse events were reported. Following a personalized diet led to some improvements in cardiometabolic health compared to standard dietary advice. ClinicalTrials.gov registration: NCT05273268 .
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Médecine de précision , Triglycéride , Humains , Femelle , Mâle , Adulte d'âge moyen , Sujet âgé , Adulte , Triglycéride/sang , Médecine de précision/méthodes , Glycémie/métabolisme , Cholestérol LDL/sang , Maladies cardiovasculaires/prévention et contrôle , Maladies cardiovasculaires/diétothérapie , Régime alimentaireRÉSUMÉ
OBJECTIVE: To examine associations between serum oxylipins, which regulate tissue repair and pain signalling, and knee pain/radiographic osteoarthritis (OA) at baseline and knee pain at 3 year follow-up. METHOD: Baseline, and 3 year follow-up, knee pain phenotypes were assessed from 154 participants in the Knee Pain in the Community (KPIC) cohort study. Serum and radiographic Kellgren and Lawrence (KL) and Nottingham line drawing atlas OA scores were collected at baseline. Oxylipin levels were quantified using liquid chromatography coupled with mass spectrometry. Associations were measured by linear regression and receiver operating characteristics (ROC). RESULTS: Serum levels of 8,9-epoxyeicosatrienoic acid (EET) (ß(95% confidence intervals (CI)) = 1.809 (-0.71 to 2.91)), 14,15-dihydroxyeicosatrienoic acid (DHET) (ß(95%CI) = 0.827 (0.34-1.31)), and 12-hydroxyeicosatetraenoic acid (HETE) (ß(95%CI) = 4.090 (1.92-6.26)) and anandamide (ß(95%CI) = 3.060 (1.35-4.77)) were cross-sectionally associated with current self-reported knee pain scores (numerical rating scale (NRS) item 3, average pain). Serum levels of 9- (ß(95%CI) = 0.467 (0.18-0.75)) and 15-HETE (ß(95%CI) = 0.759 (0.29-1.22)), 14-hydroxydocosahexaenoic acid (ß(95%CI) = 0.483(0.24-0.73)), and the ratio of 8,9-EET:DHET (ß(95%CI) = 0.510(0.19-0.82)) were cross-sectionally associated with KL scores. Baseline serum concentrations of 8,9-EET (ß(95%CI) = 2.166 (0.89-3.44)), 5,6-DHET (ß(95%CI) = 152.179 (69.39-234.97)), and 5-HETE (ß(95%CI) = 1.724 (0.677-2.77) showed positive longitudinal associations with follow-up knee pain scores (NRS item 3, average pain). Combined serum 8,9-EET and 5-HETE concentration showed the strongest longitudinal association (ß(95%CI) = 1.156 (0.54-1.77) with pain scores at 3 years, and ROC curves distinguished between participants with no pain and high pain scores at follow-up (area under curve (95%CI) = 0.71 (0.61-0.82)). CONCLUSIONS: Serum levels of a combination of hydroxylated metabolites of arachidonic acid may have prognostic utility for knee pain, providing a potential novel approach to identify people who are more likely to have debilitating pain in the future.
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Arthralgie , Évolution de la maladie , Gonarthrose , Humains , Femelle , Mâle , Gonarthrose/sang , Adulte d'âge moyen , Études transversales , Sujet âgé , Arthralgie/sang , Études longitudinales , Études de cohortes , Oxylipines/sang , Articulation du genou , Acide hydroxyeïcosatétraénoïque/sang , Acides arachidoniques/sang , Marqueurs biologiques/sang , Mesure de la douleur , Acide arachidonique/sangRÉSUMÉ
BACKGROUND: Despite an acute knee injury being a major risk factor for osteoarthritis, the factors that initiate and maintain this risk of longer-term knee symptoms are poorly understood. Bioactive lipids derived from omega-3 and -6 polyunsaturated fatty acids have key roles in the regulation of the inflammatory response and have been linked to joint damage and osteoarthritis pain in translational models. HYPOTHESIS: There would be associations between systemic levels of bioactive lipids and knee symptoms longitudinally after an acute knee injury and related knee surgery. STUDY DESIGN: Controlled laboratory study. METHODS: This study analyzed a subset of young, active adults who had sustained an acute knee injury (recruited via a surgical care pathway) and healthy age- and sex-matched controls. Surgery, if performed, was conducted after the baseline serum sample was taken and before the 3-month and 2-year visits. Liquid chromatography-tandem mass spectrometry of 41 bioactive lipids was carried out in sera of (1) 47 injured participants (median age, 28 years) collected at baseline (median, 24 days after injury), 3 months, and 2 years, along with the Knee injury and Osteoarthritis Outcome Score, and (2) age- and sex-matched controls. RESULTS: Levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (P≤ .0001) and docosahexaenoic acid (P≤ .0001) and the pro-resolving lipid mediators 17- and 14-hydroxydocosahexaenoic acid, and 18-hydroxyeicosapentaenoic acid were all significantly greater at baseline in injured participants compared with the later time points and also higher than in healthy controls (P = .0019 and P≤ .0001, respectively). Levels of pro-inflammatory prostaglandins E2 and D2, leukotriene B4, and thromboxane B2 were significantly lower at baseline compared with the later time points. Higher levels of 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid (DHET) were cross-sectionally associated with more severe knee pain/symptoms according to the Knee injury and Osteoarthritis Outcome Score at 2 years (P = .0004, R2 = 0.251; P = .0002, R2 = 0.278; and P = .0012, R2 = 0.214, respectively). CONCLUSION: The profile of pro-resolving versus pro-inflammatory lipids at baseline suggests an initial activation of pro-resolution pathways, followed by the later activation of pro-inflammatory pathways. CLINICAL RELEVANCE: In this largely surgically managed cohort, the association of soluble epoxide hydrolase metabolites, the DHETs, with more severe knee symptoms at 2 years provides a rationale for further investigation into the role of this pathway in persisting knee symptoms in this population, including potential therapeutic strategies.
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Traumatismes du genou , Arthrose , Adulte , Humains , Anti-inflammatoires , Acides gras insaturés , Traumatismes du genou/chirurgie , DouleurRÉSUMÉ
Cardiometabolic diseases are leading causes of mortality in Western countries. Well-established risk factors include host genetics, lifestyle, diet, and the gut microbiome. Moreover, gut bacterial communities and their activities can be altered by bacteriophages (also known simply as phages), bacteria-infecting viruses, making these biological entities key regulators of human cardiometabolic health. The manipulation of bacterial populations by phages enables the possibility of using phages in the treatment of cardiometabolic diseases through phage therapy and fecal viral transplants. First, however, a deeper understanding of the role of the phageome in cardiometabolic diseases is required. In this review, we first introduce the phageome as a component of the gut microbiome and discuss fecal viral transplants and phage therapy in relation to cardiometabolic diseases. We then summarize the current state of phageome research in cardiometabolic diseases and propose how the phageome might indirectly influence cardiometabolic health through gut bacteria and their metabolites.
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Bactériophages , Maladies cardiovasculaires , Microbiome gastro-intestinal , Humains , Bactéries , Transplantation de microbiote fécal , Maladies cardiovasculaires/thérapieRÉSUMÉ
BACKGROUND: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHOD: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. FINDING: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. INTERPRETATION: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. FUNDING: National Institute for Health and Care Research.
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Vaccins contre la COVID-19 , COVID-19 , Glycoprotéine de spicule des coronavirus , Adulte , Mâle , Humains , Femelle , Adolescent , Adulte d'âge moyen , Vaccins contre la COVID-19/effets indésirables , Méthotrexate/usage thérapeutique , SARS-CoV-2RÉSUMÉ
BACKGROUND: Snacking is a common diet behaviour which accounts for a large proportion of daily energy intake, making it a key determinant of diet quality. However, the relationship between snacking frequency, quality and timing with cardiometabolic health remains unclear. DESIGN: Demography, diet, health (fasting and postprandial cardiometabolic blood and anthropometrics markers) and stool metagenomics data were assessed in the UK PREDICT 1 cohort (N = 1002) (NCT03479866). Snacks (foods or drinks consumed between main meals) were self-reported (weighed records) across 2-4 days. Average snacking frequency and quality [snack diet index (SDI)] were determined (N = 854 after exclusions). Associations between snacking frequency, quality and timing with cardiometabolic blood and anthropometric markers were assessed using regression models (adjusted for age, sex, BMI, education, physical activity level and main meal quality). RESULTS: Participants were aged (mean, SD) 46.1 ± 11.9 years, had a mean BMI of 25.6 ± 4.88 kg/m2 and were predominantly female (73%). 95% of participants were snackers (≥ 1 snack/day; n = 813); mean daily snack intake was 2.28 snacks/day (24 ± 16% of daily calories; 203 ± 170 kcal); and 44% of participants were discordant for meal and snack quality. In snackers, overall snacking frequency and quantity of snack energy were not associated with cardiometabolic risk markers. However, lower snack quality (SDI range 1-11) was associated with higher blood markers, including elevated fasting triglycerides (TG (mmol/L) ß; - 0.02, P = 0.02), postprandial TGs (6hiAUC (mmol/L.s); ß; - 400, P = 0.01), fasting insulin (mIU/L) (ß; - 0.15, P = 0.04), insulin resistance (HOMA-IR; ß; - 0.04, P = 0.04) and hunger (scale 0-100) (ß; - 0.52, P = 0.02) (P values non-significant after multiple testing adjustments). Late-evening snacking (≥ 9 pm; 31%) was associated with lower blood markers (HbA1c; 5.54 ± 0.42% vs 5.46 ± 0.28%, glucose 2hiAUC; 8212 ± 5559 vs 7321 ± 4928 mmol/L.s, P = 0.01 and TG 6hiAUC; 11,638 ± 8166 vs 9781 ± 6997 mmol/L.s, P = 0.01) compared to all other snacking times (HbA1c remained significant after multiple testing). CONCLUSION: Snack quality and timing of consumption are simple diet features which may be targeted to improve diet quality, with potential health benefits. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: NCT03479866, https://clinicaltrials.gov/ct2/show/NCT03479866?term=NCT03479866&draw=2&rank=1.
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Maladies cardiovasculaires , Casse-croute , Femelle , Humains , Mâle , Régime alimentaire , Ration calorique , Comportement alimentaire , Hémoglobine glyquée , Adulte , Adulte d'âge moyenRÉSUMÉ
Background: Continuous glucose monitors (CGMs) provide high-frequency information regarding daily glucose variation and are recognised as effective for improving glycaemic control in individuals living with diabetes. Despite increased use in individuals with non-diabetic blood glucose concentrations (euglycemia), their utility as a health tool in this population remains unclear. Objectives: To characterise variation in time in range (TIR) and glycaemic variability in large populations without diabetes or impaired glucose tolerance; describe associations between CGM-derived glycaemic metrics and metabolic and cardiometabolic health traits; identify key diet and lifestyle factors associated with TIR and glycaemic variability. Design: Glycaemic variability (coefficient of variation) and time spent in both the ADA secondary target range (TIRADA; 3.9-7.8 mmol/L) and a more stringent range (TIR3.9-5.6; 3.9-5.6 mmol/L) were calculated during free-living in PREDICT 1, PREDICT 2, and PREDICT 3 euglycaemic community-based volunteer cohorts. Associations between CGM derived glycaemic metrics, markers of cardiometabolic health, diet (food frequency questionnaire and logged diet records), diet-habits, and lifestyle were explored. Results: Data from N=4135 participants (Mean SD; Age: 47 12 y; Sex: 83% Female, BMI: 27 6 kg/m2). Median glycaemic variability was 14.8% (IQR 12.6-17.6%), median TIRADA was 95.8% (IQR 89.6-98.6%) and TIR3.9-5.6 was 75.0% (IQR 64.6-82.8%). Greater TIR3.9-5.6 was associated with lower HbA1c, ASCVD 10y risk and HOMA-IR (all p < 0.05). Lower glycaemic variability was associated with lower % energy derived from carbohydrate (rs: 0.17, p < 0.01), ultra-processed foods (NOVA 4, % EI; rs: 0.12, p = 0.01) and a longer overnight fasting duration (rs: -0.10, p = 0.01). Conclusions: A stringent TIR target provides sensitivity to detect changes in HOMA-IR, ASCVD 10 y risk and HbA1c that were not detected using ADA secondary targets. Associations among TIR, glycaemic variability, dietary intake (e.g. carbohydrate and protein) and habits (e.g. nocturnal fasting duration) highlight potential strategic targets to improve glycaemic metrics derived from continuous glucose monitors.
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The gut microbiome is a significant contributor to mental health, with growing evidence linking its composition to anxiety and depressive disorders. Gut microbiome composition is associated with signs of anxiety and depression both in clinically diagnosed mood disorders and subclinically in the general population and may be influenced by dietary fibre intake and the presence of chronic pain. We provide an update of current evidence on the role of gut microbiome composition in depressive and anxiety disorders or symptoms by reviewing available studies. Analysing data from three independent cohorts (osteoarthritis 1 (OA1); n = 46, osteoarthritis 2 (OA2); n = 58, and healthy controls (CON); n = 67), we identified microbial composition signatures of anxiety and depressive symptoms at genus level and cross-validated our findings performing meta-analyses of our results with results from previously published studies. The genera Bifidobacterium (fixed-effect beta (95% CI) = -0.22 (-0.34, -0.10), p = 3.90e-04) and Lachnospiraceae NK4A136 group (fixed-effect beta (95% CI) = -0.09 (-0.13, -0.05), p = 2.53e-06) were found to be the best predictors of anxiety and depressive symptoms, respectively, across our three cohorts and published literature taking into account demographic and lifestyle covariates, such as fibre intake. The association with anxiety was robust in accounting for heterogeneity between cohorts and supports previous observations of the potential prophylactic effect of Bifidobacterium against anxiety symptoms.
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Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (ß = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.
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Post-traumatic OA (PTOA) can occur within 5 years after a significant injury and is a valuable paradigm for identifying biomarkers. This systematic review aims to summarise published literature in human studies on the associations of known serum and synovial fluid biomarkers at least a year from injury to structural, symptomatic changes and underlying PTOA processes. A systematic review was performed using PRISMA guidelines, prospectively registered on PROSPERO (CRD42022371838), for all 'wet' biomarkers a year or more post-injury in 18-45-year-old participants. Three independent reviewers screened search results, extracted data, and performed risk of bias assessments (Newcastle-Ottawa Scale). Study heterogeneity meant a narrative synthesis was undertaken, utilising SWiM guidelines. 952 studies were identified, 664 remaining after deduplication. Following first-round screening, 53 studies underwent second-round screening against pre-determined criteria. Eight studies, with 879 participants (49 â% male), were included, measuring serum (n â= â7), synovial fluid (SF, n â= â6), or both (n â= â5). The pooled participant mean age was 29.1 (±4). 51 biomarkers were studied (serum â= â38, SF â= â13), with no correlation between paired serum and SF samples. One serum biomarker, cartilage oligomeric matrix protein (COMP), and four SF biomarkers, interleukin (IL)-1ß, IL-6, tumour necrosis factor (TNF), and COMP, were measured in multiple studies. Associations were described between 11 biomarkers related to catabolism (n â= â4), anabolism (n â= â2), inflammation (n â= â4) and non-coding RNA (n â= â1), with OA imaging changes (X-ray and MRI), pain, quality of life and function. Widespread differences in study design and methodology prevented meta-analysis, and evidence was generally weak. A unified approach is required before widespread research and clinical biomarker use.
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Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02-5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16-1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97-8], P = 0.0002). Although these are host-produced metabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset. ARTICLE HIGHLIGHTS: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics.
Sujet(s)
Diabète de type 2 , Acide nicotinique , État prédiabétique , Adulte , Humains , État prédiabétique/complications , Diabète de type 2/complications , Jeûne , Glucose , Glycémie/métabolismeRÉSUMÉ
PURPOSE: In this study, we explore the relationship between social jetlag (SJL), a parameter of circadian misalignment, and gut microbial composition, diet and cardiometabolic health in the ZOE PREDICT 1 cohort (NCT03479866). METHODS: We assessed demographic, diet, cardiometabolic, stool metagenomics and postprandial metabolic measures (n = 1002). We used self-reported habitual sleep (n = 934) to calculate SJL (difference in mid-sleep time point of ≥ 1.5 h on week versus weekend days). We tested group differences (SJL vs no-SJL) in cardiometabolic markers and diet (ANCOVA) adjusting for sex, age, BMI, ethnicity, and socio-economic status. We performed comparisons of gut microbial composition using machine learning and association analyses on the species level genome bins present in at least 20% of the samples. RESULTS: The SJL group (16%, n = 145) had a greater proportion of males (39% vs 25%), shorter sleepers (average sleep < 7 h; 5% vs 3%), and were younger (38.4 ± 11.3y vs 46.8 ± 11.7y) compared to the no-SJL group. SJL was associated with a higher relative abundance of 9 gut bacteria and lower abundance of 8 gut bacteria (q < 0.2 and absolute Cohen's effect size > 0.2), in part mediated by diet. SJL was associated with unfavourable diet quality (less healthful Plant-based Diet Index), higher intakes of potatoes and sugar-sweetened beverages, and lower intakes of fruits, and nuts, and slightly higher markers of inflammation (GlycA and IL-6) compared with no-SJL (P < 0.05 adjusted for covariates); rendered non-significant after multiple testing adjustments. CONCLUSIONS: Novel associations between SJL and a more disadvantageous gut microbiome in a cohort of predominantly adequate sleepers highlight the potential implications of SJL for health.
Sujet(s)
Maladies cardiovasculaires , Microbiome gastro-intestinal , Humains , Mâle , Maladies cardiovasculaires/complications , Rythme circadien , Régime alimentaire , Syndrome du décalage horaire/complications , SommeilRÉSUMÉ
Introduction: Osteoarthritis (OA) results from various aetiologies, including joint morphology, biomechanics, inflammation, and injury. The latter is implicated in post-traumatic OA, which offers a paradigm to identify potential biomarkers enabling early identification and intervention. This review aims to describe imaging features associated with structural changes or symptoms at least one year following injury. Methodology: A systematic review was conducted using PRISMA guidance, prospectively registered on PROSPERO (CRD42022371838). Three independent reviewers screened titles and abstracts, followed by full-texts, performed data extraction, and risk of bias assessments (Newcastle-Ottawa Scale). Inclusion criteria included imaging studies involving human participants aged 18-45 who had sustained a significant knee injury at least a year previously. A narrative synthesis was performed using synthesis without meta-analysis methodology. Results: Six electronic databases and conference proceedings were searched, identifying 11 studies involving 776 participants. All studies included participants suffering an anterior cruciate ligament (ACL) injury and utilised MRI. Different, and not directly comparable, techniques were used. MRI features could be broadly divided into structural, including joint position and morphology, and compositional. Promising biomarkers for diagnosing and predicting osteoarthritis include T1rho and T2 relaxation time techniques, bone morphology changes and radiomic modelling. Discussion: As early as 12 months after injury, differences in tibia position, bone morphology, presence of effusion and synovitis, and cartilage/subchondral bone composition can be detected, some of which are linked with worse patient-reported or radiological progression. Standardisation, including MR strength, position, sequence, scoring and comparators, is required to utilise clinical and research OA imaging biomarkers fully.
RÉSUMÉ
Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h2: serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.
Sujet(s)
Microbiome gastro-intestinal , Humains , Microbiome gastro-intestinal/génétique , Acides gras volatils/métabolisme , Fèces , InflammationRÉSUMÉ
BACKGROUND: A dysregulated postprandial metabolic response is a risk factor for chronic diseases, including type 2 diabetes mellitus (T2DM). The plasma protein N-glycome is implicated in both lipid metabolism and T2DM risk. Hence, we first investigate the relationship between the N-glycome and postprandial metabolism and then explore the mediatory role of the plasma N-glycome in the relationship between postprandial lipaemia and T2DM. METHODS: We included 995 individuals from the ZOE-PREDICT 1 study with plasma N-glycans measured by ultra-performance liquid chromatography at fasting and triglyceride, insulin, and glucose levels measured at fasting and following a mixed-meal challenge. Linear mixed models were used to investigate the associations between plasma protein N-glycosylation and metabolic response (fasting, postprandial (Cmax), or change from fasting). A mediation analysis was used to further explore the relationship of the N-glycome in the prediabetes (HbA1c = 39-47 mmol/mol (5.7-6.5%))-postprandial lipaemia association. RESULTS: We identified 36 out of 55 glycans significantly associated with postprandial triglycerides (Cmax ß ranging from -0.28 for low-branched glycans to 0.30 for GP26) after adjusting for covariates and multiple testing (padjusted < 0.05). N-glycome composition explained 12.6% of the variance in postprandial triglycerides not already explained by traditional risk factors. Twenty-seven glycans were also associated with postprandial glucose and 12 with postprandial insulin. Additionally, 3 of the postprandial triglyceride-associated glycans (GP9, GP11, and GP32) also correlate with prediabetes and partially mediate the relationship between prediabetes and postprandial triglycerides. CONCLUSIONS: This study provides a comprehensive overview of the interconnections between plasma protein N-glycosylation and postprandial responses, demonstrating the incremental predictive benefit of N-glycans. We also suggest a considerable proportion of the effect of prediabetes on postprandial triglycerides is mediated by some plasma N-glycans.