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We used an established mediation analysis to investigate the role of adiposity in the relation between serum 25(OH)D with markers of inflammation and glucose and insulin metabolism. We used data from National Health and Nutrition Examination Survey (2005–2010), to evaluate the associations between serum 25(OH)D and markers of insulin resistance (IR) or inflammation, and whether these associations are mediated by adiposity factors. Analysis of co-variance and conceptual causal mediation analysis were conducted taking into consideration the survey design and sample weights. BMI was found to have significant mediation effects (to varied extent) on the associations between serum 25(OH)D and CRP, apo-B, fasting glucose, insulin, HOMA-IR, HOMA-B and HbA1c (all P < 0·05). Both WC and apVAT were also found to partly mediate the associations between serum 25 25(OH)D with CRP, FBG, HbA1c, TAG and HDL-cholesterol (all P < 0·05). These findings support the importance of optimising 25(OH)D status in conditions with abnormal adiposity (i.e. obesity) and treatments for the prevention of cardiometabolic diseases affecting adipose tissue metabolism (i.e. weight loss).

Low-grade inflammation is a mediator of muscle proteostasis. This study aimed to investigate the effects of isolated whey and soy proteins on inflammatory markers. We conducted a systematic literature search of randomised controlled trials (RCT) through MEDLINE, Web of Science, Scopus and Cochrane Library databases from inception until September 2021. To determine the effectiveness of isolated proteins on circulating levels of C-reactive protein (CRP), IL-6 and TNF-α, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42021252603). Thirty-one RCT met the inclusion criteria and were included in the systematic review and meta-analysis. A significant reduction of circulating IL-6 levels following whey protein [Mean Difference (MD): -0·79, 95 % CI: -1·15, -0·42, I = 96 %] and TNF-α levels following soy protein supplementation (MD: -0·16, 95 % CI: -0·26, -0·05, I = 68 %) was observed. The addition of soy isoflavones exerted a further decline in circulating TNF-α levels (MD: -0·20, 95 % CI: -0·31, -0·08, I = 34 %). According to subgroup analysis, whey protein led to a statistically significant decrease in circulating IL-6 levels in individuals with sarcopenia and pre-frailty (MD: -0·98, 95 % CI: -1·56, -0·39, I = 0 %). These findings may be dependent on participant characteristics and treatment duration. These data support that whey and soy protein supplementation elicit anti-inflammatory effects by reducing circulating IL-6 and TNF-α levels, respectively. This effect may be enhanced by soy isoflavones and may be more prominent in individuals with sarcopenia.

Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n  = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort ( n  = 100 people). We developed a machine-learning model that predicted both triglyceride ( r  = 0.47) and glycemic ( r  = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866 . The PREDICT 1 trial shows large inter-individual variations in postprandial metabolic responses to standardized meals in over 1,000 participants, demonstrating potential for development of personalized nutrition strategies.

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease. Analyses from the gut microbiome of over 1,000 individuals from the PREDICT 1 study, for which detailed long-term diet information as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements are available, unveil new associations between specific gut microbes, dietary habits and cardiometabolic health.

We used county level data for T2D prevalence across the mainland USA and matched this to county level ambient PM2.5. Multiple linear regression was used to determine the relation between prevalence of T2D with PM2.5 after adjustment for confounding factors. PM2.5 explained 6.3% of the spatial variation in obesity, and 17.9% of the spatial variation in T2D. After correcting the T2D prevalence for obesity, race, poverty, education and temperature, PM2.5 still explained 8.3% of the residual variation in males (P < 0.0001) and 11.5% in females (P < 0.0001). The effect on obesity prevalence corrected for poverty, race education and temperature was much lower and hence the ratio of T2D to obesity prevalence was significantly associated with PM2.5 in males (R 2  = 11.1%, P < 0.0001) and females (R 2  = 16.8%, P < 0.0001). This association was repeated across non-African countries (R 2  = 14.9%, P < 0.0001). High levels of PM2.5 probably contribute to increased T2D prevalence in the USA, but have a more minor effect on the obesity. Exposure to high environmental levels of PM2.5 (relative to the USA) may explain the disproportional risk of T2D in relation to obesity in Asian populations.

Background and aimsGut transit time is a key modulator of host–microbiome interactions, yet this is often overlooked, partly because reliable methods are typically expensive or burdensome. The aim of this single-arm, single-blinded intervention study is to assess (1) the relationship between gut transit time and the human gut microbiome, and (2) the utility of the ‘blue dye’ method as an inexpensive and scalable technique to measure transit time.MethodsWe assessed interactions between the taxonomic and functional potential profiles of the gut microbiome (profiled via shotgun metagenomic sequencing), gut transit time (measured via the blue dye method), cardiometabolic health and diet in 863 healthy individuals from the PREDICT 1 study.ResultsWe found that gut microbiome taxonomic composition can accurately discriminate between gut transit time classes (0.82 area under the receiver operating characteristic curve) and longer gut transit time is linked with specific microbial species such as Akkermansia muciniphila, Bacteroides spp and Alistipes spp (false discovery rate-adjusted p values <0.01). The blue dye measure of gut transit time had the strongest association with the gut microbiome over typical transit time proxies such as stool consistency and frequency.ConclusionsGut transit time, measured via the blue dye method, is a more informative marker of gut microbiome function than traditional measures of stool consistency and frequency. The blue dye method can be applied in large-scale epidemiological studies to advance diet-microbiome-health research. Clinical trial registry website https://clinicaltrials.gov/ct2/show/NCT03479866 and trial number NCT03479866.

To investigate the association of triglycerides/glucose index (TyG index), anthropometrically predicted visceral adipose tissue (apVAT), lipid accumulation product (LAP), visceral adiposity index (VAI) and triglycerides (TG):high density lipoprotein-cholesterol (HDL-C) ratio with insulin resistance (IR) in adult Americans. This study was based on data from three NHANES cycles (2005 to 2010). The TyG index was calculated as ln [TG×fasting glucose/2]. VAI was calculated using gender-specific formulas: men [waist circumference (WC)/39.68+(1.88×body mass index (BMI)]×(TG/1.03)×(1.31/HDL-C); women: [WC/36.58+(1.89×BMI)]×(TG/0.81)×(1.52/HDL-C). LAP index was calculated as [WC–65]×[TG] in men, and [WC–58]×[TG] in women. Correlation and regression analyses accounted for the complex sampling of database. A total of 18,318 subjects was included in this analysis [mean age 47.6Years]; 48.7% (n=8918) men]. The homeostatic model assessment of insulin resistance (HOMA-IR) had a significant positive correlation with the TyG index (r=0.502), LAP (r=0.551), apVAT (r=0.454), TG:HDL-C ratio (r=0.441) and VAI (r=451) (p<0.001 for all comparisons). Bland-Altman plots showed no systematic errors. The optimal cut-off to predict HOMA-diagnosed IR was 0.473 (sensitivity=74.5% and specificity=72.7%) for LAP, 0.478 (75.9%, 71.9%) for TyG, 0.391 (70.4%, 67.1%) for VAI, 0.392 (77.1% and 62.0%) for TG:HDL-C ratio and 0.381 (63.8%, 74.8%) for apVAT. The LAP index is a simple, cheap and accurate although not perfect, surrogate marker of HOMA-diagnosed IR among adult Americans. Moreover, it has higher predictability than other screening tools which traditionally applied. Among the markers, apVAT had the highest specificity and the TG:HDL-C ratio had the highest sensitivity.

ObjectivePoor metabolic health and unhealthy lifestyle factors have been associated with risk and severity of COVID-19, but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its interaction with socioeconomic deprivation.DesignWe used data from 592 571 participants of the smartphone-based COVID-19 Symptom Study. Diet information was collected for the prepandemic period using a short food frequency questionnaire, and diet quality was assessed using a healthful Plant-Based Diet Score, which emphasises healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate HRs and 95% CIs for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalisation with oxygen support, respectively.ResultsOver 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation.ConclusionsA diet characterised by healthy plant-based foods was associated with lower risk and severity of COVID-19. This association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.

Some observational studies indicate a link between blood lead and kidney function although results remain controversial. In this study, Mendelian randomisation (MR) analysis was applied to obtain unconfounded estimates of the casual association of genetically determined blood lead with estimated glomerular filtration rate (eGFR) and the risk of chronic kidney disease (CKD). Data from the largest genome-wide association studies (GWAS) on blood lead, eGFR and CKD, from predominantly ethnically European populations, were analysed in total, as well as separately in individuals with or without type 2 diabetes mellitus. Inverse variance weighted (IVW) method, weighted median (WM)-based method, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (PRESSO) as well as the leave-one-out method were applied. In a general population, lifetime blood lead levels had no significant effect on risk of CKD (IVW: p = 0.652) and eGFR (IVW: p = 0.668). After grouping by type 2 diabetes status (no diabetes vs. diabetes), genetically higher levels of blood lead had a significant negative impact among subjects with type 2 diabetes (IVW = Beta: −0.03416, p = 0.0132) but not in subjects without (IVW: p = 0.823), with low likelihood of heterogeneity for any estimates (IVW p > 0.158). MR-PRESSO did not highlight any outliers. Pleiotropy test, with very negligible intercept and insignificant p-value, indicated a low likelihood of pleiotropy for all estimations. The leave-one-out method demonstrated that links were not driven by a single SNP. Our results show, for the first time, that among subjects with type 2 diabetes, higher blood lead levels are potentially related to less favourable renal function. Further studies are needed to confirm our results.Key messagesWhat is already known about this subject?Chronic kidney disease is associated with unfavourable lifestyle behaviours and conditions such as type 2 diabetes.Observational studies have reported an association between blood lead and reduced estimated glomerular filtration rate, but the relationship between lead exposure and renal function remains controversial.What is the key question?Using Mendelian randomisation with data from 5433 individuals from the UK and Australian populations, does genetically determined blood lead have a potentially causal effect on estimated glomerular filtration rate and the risk of chronic kidney disease?What are the new findings?Blood lead levels have a potentially causal effect on reduced renal function in individuals with type 2 diabetes.In subjects without diabetes, no such causal relationship was identified.How might this impact on clinical practice in the foreseeable future?This highlights the risk of elevated blood lead, for example, due to environmental exposure, amongst those with type 2 diabetes, which may predispose them to impaired renal function.

Higher vitamin D levels and longer telomere length (TL) have been associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between 25-hydroxyvitamin D (25(OH)D) levels and TL are not well established. Vitamin D could influence TL through its anti-inflammatory properties. This study aimed to assess the relationship between vitamin D levels and TL in US adults. Participants of the National Health and Nutrition Examination Survey (NHANES) with data available on 25(OH)D and TL measures from 2001 to 2002 were included. 25(OH)D levels were measured by the DiaSorin Radioimmunoassay. We used multivariable-adjusted linear regression models, accounting for the survey design and sample weights. Of the 4347 eligible participants, 47.0% ( = 2045) were men. The mean age was 42.7 years overall, 49.2 years in men and 42.5 years in women ( = 0.060). After adjustment for age, race, marital status, education, and C-reactive protein, each 1 ng/ml higher 25(OH)D level was associated with a 0.045 (95% confidence interval (CI): 0.032 to 0.059) longer telomere-to-single copy gene (T/S) ratio. This was driven by a significant association in women (0.054 (0.043 to 0.064)) and in men (0.036 (0.020 to 0.052)). However, after we further adjusted for smoking, body mass index, and physical activity, no significant relation was found in the overall sample (β coefficient -0.026, 95% CI: -3.16, 1.67), for men (-0.016 (-3.72, 2.64)), or for women (-0.052 (-6.85, 2.26)). Our findings support a possible positive association between 25(OH)D levels and telomere length. The implications of this association deserve further investigation.