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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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Lesión Renal Aguda , Biomarcadores , Factor-23 de Crecimiento de Fibroblastos , Fracturas de Cadera , Humanos , Fracturas de Cadera/cirugía , Fracturas de Cadera/mortalidad , Fracturas de Cadera/sangre , Masculino , Femenino , Biomarcadores/sangre , Anciano , Anciano de 80 o más Años , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/etiología , Lesión Renal Aguda/sangre , Lesión Renal Aguda/diagnóstico , Estudios Prospectivos , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/etiología , Factores de Crecimiento de Fibroblastos/sangre , Tasa de Filtración Glomerular , Inflamación/sangre , Periodo PreoperatorioRESUMEN
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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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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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.
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Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Ácidos Grasos Volátiles/metabolismo , Heces , InflamaciónRESUMEN
Midichloria spp. are intracellular bacterial symbionts of ticks. Representatives of this genus colonise mitochondria in the cells of their hosts. To shed light on this unique interaction we evaluated the presence of an intramitochondrial localization for three Midichloria in the respective tick host species and generated eight high-quality draft genomes and one closed genome, showing that this trait is non-monophyletic, either due to losses or multiple acquisitions. Comparative genomics supports the first hypothesis, as the genomes of non-mitochondrial symbionts are reduced subsets of those capable of colonising the organelles. We detect genomic signatures of mitochondrial tropism, including the differential presence of type IV secretion system and flagellum, which could allow the secretion of unique effectors and/or direct interaction with mitochondria. Other genes, including adhesion molecules, proteins involved in actin polymerisation, cell wall and outer membrane proteins, are only present in mitochondrial symbionts. The bacteria could use these to manipulate host structures, including mitochondrial membranes, to fuse with the organelles or manipulate the mitochondrial network.
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Ixodes , Animales , Ixodes/microbiología , Bacterias/genética , Mitocondrias/genética , Filogenia , SimbiosisRESUMEN
Primary and secondary bile acids (BAs) influence metabolism and inflammation, and the gut microbiome modulates levels of BAs. We systematically explore the host genetic, gut microbial, and habitual dietary contribution to a panel of 19 serum and 15 stool BAs in two population-based cohorts (TwinsUK, n = 2,382; ZOE PREDICT-1, n = 327) and assess changes post-bariatric surgery and after nutritional interventions. We report that BAs have a moderately heritable genetic component, and the gut microbiome accurately predicts their levels in serum and stool. The secondary BA isoursodeoxycholate (isoUDCA) can be explained mostly by gut microbes (area under the receiver operating characteristic curve [AUC] = â¼80%) and associates with post-prandial lipemia and inflammation (GlycA). Furthermore, circulating isoUDCA decreases significantly 1 year after bariatric surgery (ß = -0.72, p = 1 × 10-5) and in response to fiber supplementation (ß = -0.37, p < 0.03) but not omega-3 supplementation. In healthy individuals, isoUDCA fasting levels correlate with pre-meal appetite (p < 1 × 10-4). Our findings indicate an important role for isoUDCA in lipid metabolism, appetite, and, potentially, cardiometabolic risk.
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Cirugía Bariátrica , Ácidos y Sales Biliares , Humanos , Apetito , Cirugía Bariátrica/efectos adversos , Heces , InflamaciónRESUMEN
Osteoarthritis (OA) is the most common arthritis affecting synovial joints such as knees and hips of millions of people globally. Usage-related joint pain and reduced function are the most common symptoms experienced by people with OA. To improve pain management, there is a need to identify validated biomarkers predicting therapeutic responses in targeted clinical trials. Our study aimed to identify the metabolic biomarkers for pain and pressure pain detection thresholds (PPTs) in participants with knee pain and symptomatic OA using metabolic phenotyping. Metabolite and cytokine measurements were done on serum samples using LC-MS/MS (liquid gas chromatography integrated magnetic resonance mass spectrometry) and Human Proinflammatory panel 1 kit respectively. Regression analysis was done in a test (n = 75) and replication study (n = 79) to investigate the metabolites associated with current knee pain scores and pressure pain detection thresholds (PPTs). Meta-analysis and correlation were done estimating precision of associated metabolites and identifying relationship between significant metabolites and cytokines respectively. Acyl ornithine, carnosine, cortisol, cortisone, cystine, DOPA, glycolithocholic acid sulphate (GLCAS), phenylethylamine (PEA) and succinic acid were found to be significantly (FDR <.1) associated with pain scores in meta-analysis of both studies. IL-10, IL-13, IL-1ß, IL2, IL8 and TNF-α were also found to be associated with the significant metabolites. Significant associations of these metabolites and inflammatory markers with knee pain suggests that targeting relevant pathways of amino acid and cholesterol metabolism may modulate cytokines and these could be targeted as novel therapeutics development to improve knee pain and OA management. PERSPECTIVE: Foreseeing the global burden of knee pain in Osteoarthritis (OA) and adverse effects of current pharmacological therapies, this study is envisaged to investigate serum metabolites and molecular pathways involved in knee pain. The replicated metabolites in this study suggests targeting amino-acid pathways for better management of OA knee pain.
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Osteoartritis de la Rodilla , Humanos , Estudios Transversales , Cromatografía Liquida , Líquido Sinovial/metabolismo , Espectrometría de Masas en Tándem , Dolor/etiología , Dolor/metabolismo , Metaboloma/fisiología , Citocinas/metabolismo , BiomarcadoresRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a global problem growing in parallel to the epidemics of obesity and diabetes, with South Asians being particularly susceptible. Nutrition and behaviour are important modifiers of the disease; however, studies to date have only described dietary patterns and nutrients associated with susceptibility to NAFLD. METHODS: This cross-sectional case-control study included 993 NAFLD patients and 973 healthy controls from Trivandrum (India). Dietary data was collected using a locally validated food frequency questionnaire. A tree-based classification categorised 2165 ingredients into three levels (food groups, sub-types, and cooking methods) and intakes were associated with clinical outcomes. RESULTS: NAFLD patients had significantly higher consumption of refined rice, animal fat, red meat, refined sugar, and fried foods, and had lower consumption of vegetables, pulses, nuts, seeds, and milk compared to controls. The consumption of red meat, animal fat, nuts, and refined rice was positively associated with NAFLD diagnosis and the presence of fibrosis, whereas consumption of leafy vegetables, fruits, and dried pulses was negatively associated. Fried food consumption was positively associated with NAFLD, whilst boiled food consumption had a negative association. Increased consumption of animal fats was associated with diabetes, hypertension, and cardiovascular outcomes among those with NAFLD, whereas consumption of wholegrain rice was negatively associated with these clinical-related outcomes. CONCLUSIONS: The tree-based approach provides the first comprehensive method of classifying food intakes to enable the identification of specific dietary factors associated with NAFLD and related clinical outcomes. This could inform culturally sensitive dietary guidelines to reduce risk of NAFLD development and/or its progression.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Estudios de Casos y Controles , Estudios Transversales , Dieta/efectos adversos , Morbilidad , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Factores de Riesgo , VerdurasRESUMEN
BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a respiratory illness named coronavirus disease 2019 (COVID-19), which is one of the main global health problems since 2019. Glycans attached to the Fc portion of immunoglobulin G (IgG) are important modulators of IgG effector functions. Fc region binds to different receptors on the surface of various immune cells, dictating the type of immune response. Here, we performed a large longitudinal study to determine whether the severity and duration of COVID-19 are associated with altered IgG glycosylation. METHODS: Using ultra-high-performance liquid chromatography analysis of released glycans, we analysed the composition of the total IgG N-glycome longitudinally during COVID-19 from four independent cohorts. We analysed 77 severe COVID-19 cases from the HR1 cohort (74% males, median age 72, age IQR 25-80); 31 severe cases in the HR2 cohort (77% males, median age 64, age IQR 41-86), 18 mild COVID-19 cases from the UK cohort (17% males, median age 50, age IQR 26-71) and 28 mild cases from the BiH cohort (71% males, median age 60, age IQR 12-78). FINDINGS: Multiple statistically significant changes in IgG glycome composition were observed during severe COVID-19. The most statistically significant changes included increased agalactosylation of IgG (meta-analysis 95% CI [0.03, 0.07], adjusted meta-analysis P= <0.0001), which regulates proinflammatory actions of IgG via complement system activation and indirectly as a lack of sialylation and decreased presence of bisecting N-acetylglucosamine on IgG (meta-analysis 95% CI [-0.11, -0.08], adjusted meta-analysis P= <0.0001), which indirectly affects antibody-dependent cell-mediated cytotoxicity. On the contrary, no statistically significant changes in IgG glycome composition were observed in patients with mild COVID-19. INTERPRETATION: The IgG glycome in severe COVID-19 patients is statistically significantly altered in a way that it indicates decreased immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the severity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in COVID-19. FUNDING: This work has been supported in part by Croatian Science Foundation under the project IP-CORONA-2020-04-2052 and Croatian National Centre of Competence in Molecular Diagnostics (The European Structural and Investment Funds grant #KK.01.2.2.03.0006), by the UKRI/MRC (Cov-0331 - MR/V027883/1) and by the National Institutes for Health Research Nottingham Biomedical Research Centre and by Ministry Of Science, Higher Education and Youth Of Canton Sarajevo, grant number 27-02-11-4375-10/21.
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COVID-19 , Inmunoglobulina G , Adolescente , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Observacionales como Asunto , Polisacáridos/metabolismo , SARS-CoV-2RESUMEN
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.
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Microbioma Gastrointestinal , Melanoma , Neoplasias Cutáneas , Microbioma Gastrointestinal/genética , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Reproducibilidad de los Resultados , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genéticaRESUMEN
SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.
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COVID-19 , Anticuerpos Antivirales , COVID-19/genética , Vacunas contra la COVID-19 , Cadenas HLA-DRB1/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , SARS-CoV-2RESUMEN
The endocannabinoid (EC) system has pleiotropic functions in the body. It plays a key role in energy homeostasis and the development of metabolic disorders being a mediator in the relationship between the gut microbiota and host metabolism. In the current study we explore the functional interactions between the endocannabinoid system and the gut microbiome in modulating inflammatory markers. Using data from a 6 week exercise intervention (treatment n = 38 control n = 40) and a cross sectional validation cohort (n = 35), we measured the associations of 2-arachidonoylglycerol (2-AG), anandamide (AEA), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) with gut microbiome composition, gut derived metabolites (SCFAs) and inflammatory markers both cross-sectionally and longitudinally. At baseline AEA and OEA were positively associated with alpha diversity (ß(SE) = .32 (.06), P = .002; .44 (.04), P < .001) and with SCFA producing bacteria such as Bifidobacterium (2-AG ß(SE) = .21 (.10), P < .01; PEA ß(SE) = .23 (.08), P < .01), Coprococcus 3 and Faecalibacterium (PEA ß(SE) = .29 (.11), P = .01; .25 (.09), P < .01) and negatively associated with Collinsella (AEA ß(SE) = -.31 (.12), P = .004). Additionally, we found AEA to be positively associated with SCFA Butyrate (ß(SE) = .34 (.15), P = .01). AEA, OEA and PEA all increased significantly with the exercise intervention but remained constant in the control group. Changes in AEA correlated with SCFA butyrate and increases in AEA and PEA correlated with decreases in TNF-É and IL-6 statistically mediating one third of the effect of SCFAs on these cytokines. Our data show that the anti-inflammatory effects of SCFAs are partly mediated by the EC system suggesting that there may be other pathways involved in the modulation of the immune system via the gut microbiome.
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Antiinflamatorios/farmacología , Bacterias/metabolismo , Endocannabinoides/inmunología , Ácidos Grasos Volátiles/farmacología , Antiinflamatorios/metabolismo , Bacterias/química , Bacterias/clasificación , Bacterias/genética , Estudios de Cohortes , Estudios Transversales , Ácidos Grasos Volátiles/metabolismo , Femenino , Microbioma Gastrointestinal , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: A Low Glycaemic Index (LGI) diet is a proposed lifestyle intervention in non-alcoholic fatty liver diseases (NAFLD) which is designed to reduce circulating blood glucose levels, hepatic glucose influx, insulin resistance and de novo lipogenesis. A significant reduction in liver fat content through following a 1-week LGI diet has been reported in healthy volunteers. Changes in dietary fat and carbohydrates have also been shown to alter gut microbiota composition and lead to hepatic steatosis through the gut-liver axis. There are no available trials examining the effects of an LGI diet on liver fat accumulation in patients with NAFLD; nor has the impact of consuming an LGI diet on gut microbiota composition been studied in this population. The aim of this trial is to investigate the effects of LGI diet consumption on liver fat content and its effects on gut microbiota composition in participants with NAFLD compared with a High Glycaemic Index (HGI) control diet. METHODS AND ANALYSIS: A 2×2 cross-over randomised mechanistic dietary trial will allocate 16 participants with NAFLD to a 2-week either HGI or LGI diet followed by a 4-week wash-out period and then the LGI or HGI diet, alternative to that followed in the first 2 weeks. Baseline and postintervention (four visits) outcome measures will be collected to assess liver fat content (using MRI/S and controlled attenuation parameter-FibroScan), gut microbiota composition (using 16S RNA analysis) and blood biomarkers including glycaemic, insulinaemic, liver, lipid and haematological profiles, gut hormones levels and short-chain fatty acids. ETHICS AND DISSEMINATION: Study protocol has been approved by the ethics committees of The University of Nottingham and East Midlands Nottingham-2 Research Ethics Committee (REC reference 19/EM/0291). Data from this trial will be used as part of a Philosophy Doctorate thesis. Publications will be in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04415632.
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Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Dieta , Índice Glucémico , Humanos , Hígado , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Aims: The current study investigates the role of diet in mediating the gut microbiome-cardiovascular association which has not yet been explored in humans. Methods and Results: Using a two-arm dietary intervention study in healthy participants (N = 70), we assessed the effects of omega-3 and fibre supplementation on gut microbiome composition and short-chain fatty acid (SCFA) production. We then investigated how changes in gut microbiome composition correlated with changes in traditional cardiovascular risk factors (cholesterol, triglycerides, blood pressure), cytokines, and novel validated markers such as GlycA and ceramides, previously linked to CVD incidence and mortality. Both interventions resulted in significant drops in blood pressure, cholesterol, proinflammatory cytokines, GlycA and ceramides (all P < 0.05). Decreases in the atherogenic low-density lipoprotein triglyceride fraction, in total serum cholesterol were correlated with increases in butyric acid-production [ß(SE) = -0.58 (0.06), P < 0.001; -0.53 (0.04), P < 0.001] and nominally associated with increases in some butyrogenic bacteria. Drops in GlycA were linked to increases in Bifidobacterium [ß(SE) = -0.32 (0.04), P = 0.02] and other SCFAs including acetic acid [ß(SE) = -0.28 (0.04), P = 0.02] and propionic acid [ß(SE) = -0.3 (0.04), P = 0.02]. Additionally, we report for the first-time reductions in specific ceramide ratios that have been shown to predict CVD mortality and major adverse cardiovascular events such as d18:1/16:0, d18:0/24:0, and d18:1/24:1 which were associated with the reduction in the abundance in Colinsella and increases in Bifidobacteriuim and Coprococcus 3 and SCFAs (all P < 0.05). Conclusion: Overall, these findings support the potential of using simple dietary interventions to alter validated biomarkers linked to cardiovascular risk via the gut microbiome composition and its metabolic functions.
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Understanding the impact of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the response to vaccination is a priority for responding to the coronavirus disease 2019 (COVID-19) pandemic. In particular, it is necessary to understand how prior infection plus vaccination can modulate immune responses against variants of concern. To address this, we sampled 20 individuals with and 25 individuals without confirmed previous SARS-CoV-2 infection from a large cohort of health care workers followed serologically since April 2020. All 45 individuals had received two doses of the Pfizer-BioNTech BNT162b2 vaccine with a delayed booster at 10 weeks. Absolute and neutralizing antibody titers against wild-type SARS-CoV-2 and variants were measured using enzyme immunoassays and pseudotype neutralization assays. We observed antibody reactivity against lineage A, B.1.351, and P.1 variants with increasing antigenic exposure, through either vaccination or natural infection. This improvement was further confirmed in neutralization assays using fixed dilutions of serum samples. The impact of antigenic exposure was more evident in enzyme immunoassays measuring SARS-CoV-2 spike proteinspecific IgG antibody concentrations. Our data show that multiple exposures to SARS-CoV-2 spike protein in the context of a delayed booster expand the neutralizing breadth of the antibody response to neutralization-resistant SARS-CoV-2 variants. This suggests that additional vaccine boosts may be beneficial in improving immune responses against future SARS-CoV-2 variants of concern.
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COVID-19 , SARS-CoV-2 , Formación de Anticuerpos , Vacuna BNT162 , Vacunas contra la COVID-19 , HumanosRESUMEN
Background: COVID-19 has a broad clinical spectrum. We investigated the role of serum markers measured on admission on severity as assessed at discharge and investigated those which relate to the effect of BMI on severity. Methods: Clinical and laboratory data from 610 COVID-19 cases hospitalized in the province of Zheijang, China were investigated as risk factors for severe COVID-19 (assessed by respiratory distress) compared to mild or common forms using logistic regression methods. Biochemical markers were correlated with severity using spearman correlations, and a ROC analysis was used to determine the individual contribution of each of the biochemical markers on severity. We carried out formal mediation analyses to investigate the extent of the effect of body mass index (BMI) on COVID-19 severity mediated by hypertension, glycemia, Lactose Dehydrogenase (LDH) at the time of hospitalization and C-Reactive Protein levels (CRP), in units of standard deviations. Results: The individual markers measured on admission contributing most strongly to prediction of COVID-19 severity as assessed at discharge were LDH, CRP and glucose. The proportion of the effect of BMI on severity of COVID-19 mediated by CRP, glycemia or hypertension, we find that glucose mediated 79% (p < .0001), LDH mediated 78% (p < .0001), hypertension mediated 66% (p < .0001); however, only 44% (p < .005) was mediated by systemic inflammation (CRP). Conclusion: Our data indicate that a larger proportion of the effect of BMI on severity of COVID-19 is mediated by glycemia and LDH levels whereas less than half of it is mediated by systemic inflammation.
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Glucemia/metabolismo , COVID-19/sangre , COVID-19/patología , Hipertensión/complicaciones , L-Lactato Deshidrogenasa/sangre , Adulto , Biomarcadores/sangre , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , COVID-19/complicaciones , COVID-19/fisiopatología , China , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: : Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics. METHODS: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314. FINDINGS: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups. INTERPRETATION: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role.
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Undernutrition is a leading contributor to disease and disability in people of all ages. Several studies have reported significant association between nutritional status and gut microbiome composition but other factors such as demographic settings may also influence the adult microbiome. The relationship between undernourishment and gut microbiome in adults has not been described to date. In this study, we compared the gut microbiome in fecal samples of 48 individuals, from two demographic settings (rural and urban slum) in Karnataka, India using 16S rRNA sequencing. Nutritional status was assessed based on BMI, with a BMI of < 18.5 kg/m2 classified as undernourished, and a BMI in the range 18.5-25 kg/m2 as nourished. We analyzed 25 individuals from rural settings (12 undernourished and 13 nourished) and 23 individuals from urban slum settings (11 undernourished and 12 nourished). We found no significant difference in overall gut microbial diversity (Shannon and Unweighted UniFrac) between undernourished and nourished individuals in either geographical settings, however, microbial taxa at the phylum level (i.e., Firmicutes and Proteobacteria) and beta diversity (unweighted UniFrac) differed significantly between the rural and urban slum settings. By predicting microbial function from 16S data profiling we found significant differences in metabolic pathways present in the gut microbiota from people residing in different settings; specifically, those related to carbohydrate and lipid metabolism. The weighted sum of the KEGG Orthologs associated with carbohydrate metabolism (Spearman's correlation coefficient, ρ = -0.707, p < 0.001), lipid metabolism (Spearman's correlation coefficient, ρ = -0.330, p < 0.022) and biosynthesis of secondary metabolites (Spearman's correlation coefficient, ρ = -0.507, p < 0.001) were decreased in the urban slum group compared to the rural group. In conclusion, we report that the geographical location of residence is associated with differences in gut microbiome composition in adults. We found no significant differences in microbiome composition between nourished and undernourished adults from urban slum or rural settings in India.