Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10-11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.

Disruptions in gut microbiome are implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiome disruptors, but their long-term consequences remain underexplored. Here we combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to examine the association between oral antibiotic use over 8 years and gut microbiome. In multivariable confounder-adjusted regression models, antibiotic use <1 year before fecal sampling was associated with the greatest reduction in species diversity, but significant associations were also observed for use 1-4 and 4-8 years earlier. Clindamycin, fluoroquinolones and flucloxacillin accounted for most of the associations with the abundance of individual species. Use of these antibiotics 4-8 years earlier was associated with altered abundance of 10-15% of the species studied; penicillin V, extended-spectrum penicillins and nitrofurantoin were associated with only a few species. Similar results were found comparing one antibiotic course 4-8 years before sampling versus none in the past 8 years. These findings indicate that antibiotics may have long-lasting consequences for the gut microbiome.

CONTEXT:Type 2 diabetes is a growing global concern with serious complications, including kidney damage and cardiovascular morbidity and mortality. Monitoring albuminuria, which is associated with these complications, is crucial in optimal diabetes management. Gut microbiota composition has been suggested to impact albuminuria, but large studies with granular data are lacking. METHODS:We investigated the relationship between 1002 gut microbial species, 1308 plasma metabolites, and albuminuria in 752 participants with type 2 diabetes from the Swedish CArdioPulmonary BioImage Study (SCAPIS). To determine the relative abundance of species, we employed deep shotgun metagenomic sequencing of fecal samples. Plasma metabolites were analyzed using mass spectrometry-based methods. RESULTS:We identified 3 species that were associated with albuminuria, including Sellimonas intestinalis, Eggerthellales sp., and Ellagibacter isourolithinifaciens. Two of these species were replicated in an independent prediabetic population (n = 3423) in SCAPIS. In total, 36 annotated metabolites were associated with the 3 albuminuria-signature species. Functional mapping of the signature species suggests a role in the regulation of the metabolites of imidazole propionate and trigonelline, which have previously been reported to play roles in the progression of albuminuria. CONCLUSION:These findings provide additional evidence of the potential impact of microbial species and contribute to our understanding of the complex relationship between the gut microbiome, plasma metabolites, and albuminuria in individuals with diabetes.

Objective Meat intake is suggested to affect gut microbiome composition and the risk of chronic diseases. We aimed to identify meat-associated gut microbiome features and their association with host factors. Design Gut microbiota species were profiled by deep shotgun metagenomics sequencing in 9,669 individuals. Intake of white meat, unprocessed red meat, and processed red meat was assessed using a food frequency questionnaire. The associations of meat intake with alpha-diversity and relative abundance of gut microbiota species were tested using linear regression models with adjustment for dietary fiber intake, body mass index, and other potential confounders. Meat-associated species were further assessed for association with enrichment of microbial gene function, meat-associated plasma metabolites, and clinical biomarkers. Results Higher intake of processed red meat was associated with reduced alpha microbial diversity. White meat, unprocessed, and processed red meat intakes were associated with 36, 14, and 322 microbiota species, respectively. Species associated with processed red meat were enriched for bacterial pathways like amino acid degradation, while those negatively linked were enriched for pathways like homoacetogenesis. Furthermore, species positively associated with processed red meat were to a large extent associated with reduced trimethylamine N-oxide and glutamine levels but increased creatine and carnitine metabolites, fasting insulin and glucose, C-reactive protein, apolipoprotein A1, and triglyceride levels and higher blood pressure. Conclusion This largest to date population-based study on meat and gut microbiota suggests that meat intake, particularly processed red meat, may modify the gut microbiota composition, functional capacity, and health-related biomarkers.

Background & Aims:A quarter of the world population is estimated to have metabolic dysfunction-associated steatotic liver disease. Here, we aim to understand the impact of liver trait-associated genetic variants on fat content and tissue volume across organs and body compartments and on a large set of biomarkers. Methods:Genome-wide association analyses were performed on liver fat and liver volume estimated with magnetic resonance imaging in up to 27,243 unrelated European participants from the UK Biobank. Identified variants were assessed for associations with fat fraction and tissue volume in >2 million 'Imiomics' image elements in 22,261 individuals and with circulating biomarkers in 310,224 individuals. Results:We confirmed four liver fat and nine liver volume previously reported genetic variants (p values <5 × 10-8). We further found evidence suggestive of a novel liver volume locus, ADH4, where each additional T allele increased liver volume by 0.05 SD (SE = 0.01, p value = 3.3 × 10-8). The Imiomics analyses showed that liver fat-increasing variants were specifically associated with fat fraction of the liver tissue (p values <2.8 × 10-3) and with higher inflammation, liver and renal injury biomarkers, and lower lipid levels. Associations of liver volume variants with fat content, tissue volume, and biomarkers were more heterogeneous, for example the liver volume-increasing alleles at CENPW and PPP1R3B were associated with higher skeletal muscle volumes and were more pronounced in men, whereas the GCKR variant was negatively associated with lower skeletal muscle volumes in women (p values <2.8 × 10-3). Conclusions:Liver fat-increasing variants were mostly linked to fat fraction of the liver and were positively associated with some adverse metabolic biomarkers and negatively with lipids. In contrast, liver volume-associated variants showed a less consistent pattern across organs and biomarkers. Impact and implications:Liver fat and liver volume are common metabolic traits with a strong genetic component, yet the extent to which they exert organ-specific vs. systemic effects remains poorly defined. By integrating genome-wide association analyses and high-resolution neck-to-knee magnetic resonance imaging data through the Imiomics framework, this study reveals distinct genetic architectures for liver fat and liver volume, including sex-specific effects. These findings provide new insights into the biological, organ-level, tissue-specific, and systemic characteristics of steatotic liver disease and its genetic determinants. The results may inform the development of precision imaging genetic approaches, biomarker discovery, and stratified risk assessment strategies, while reinforcing the importance of incorporating sex-specific analyses in future research and clinical applications.

BACKGROUND:There is mounting evidence supporting the role of the microbiota in hypertension from experimental studies and population-based studies. We aimed to investigate the relationship between specific characteristics of the gut microbiome and 24-h ambulatory blood pressure measurements. METHODS:The association of gut microbial species and microbial functions, determined by shotgun metagenomic sequencing of fecal samples, with 24-h ambulatory blood pressure measurements in 3695 participants and office blood pressure was assessed in multivariable-adjusted models in 2770 participants without antihypertensive medication from the Swedish CArdioPulmonary bioImage Study. RESULTS:Gut microbiome alpha diversity was negatively associated with diastolic blood pressure variability. Additionally, four microbial species were associated with at least one of the 24-h blood pressure traits. Streptococcus sp001556435 was associated with higher systolic blood pressure, Intestinimonas massiliensis and Dysosmobacter sp001916835 with lower systolic blood pressure, Dysosmobacter sp001916835 with lower diastolic blood pressure, and ER4 sp900317525 with lower systolic blood pressure variability. Moreover, office blood pressure data from a subsample without ambulatory blood pressure measurements replicated the association of Intestinimonas massiliensis with systolic blood pressure and Dysosmobacter sp001916835 with diastolic blood pressure. Species associated with 24-h blood pressure were linked to a similar pattern of metabolites. CONCLUSIONS:In this large cross-sectional analysis, gut microbiome alpha diversity negatively associates with diastolic blood pressure variability, and four gut microbial species associate with 24-h blood pressure traits.

BACKGROUND Disruptions in gut microbiota have been implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiota disruptors, but their long-term consequences on taxonomic composition of the gut microbiome remain underexplored. METHODS We investigated associations between register-based oral antibiotic use over 8 years and gut microbiota composition assessed with fecal shotgun metagenomics in 15,131 adults from the Swedish population-based studies SCAPIS, MOS, and SIMPLER. We applied multivariable regression models with the number of prescriptions in three pre-specified periods before fecal sampling (<1 year, 1-4, 4-8 years) as the main exposures and adjusted for sociodemographics, lifestyle, and comorbidities. Secondary analyses included participants with only one antibiotic course or none. RESULTS Antibiotic use <1 year before fecal sampling was associated with the greatest reduction in gut microbiota species diversity; however, antibiotic use 1-4 years and 4-8 years earlier was also associated with decreased diversity. Clindamycin, fluoroquinolones, and flucloxacillin accounted for most of the associations between antibiotic use and the abundance of individual species across all periods. Use of these three antibiotics 4-8 years earlier was associated with altered abundance of 10-14% of the species studied; use of penicillin V, extended-spectrum penicillins, and nitrofurantoin were associated with altered abundance of only a few species. Similar results were found when comparing one antibiotic course 4-8 years before sampling vs. none in the past 8 years. CONCLUSION Commonly prescribed antibiotics like clindamycin, fluoroquinolones, and the narrow-spectrum flucloxacillin appear to have long-lasting consequences for the gut microbiota. ### Competing Interest Statement J.S. reports direct or indirect stock ownership in companies (Anagram Kommunikation AB, Sence Research AB, Symptoms Europe AB, MinForskning AB) that provide services not related to the present work to companies and authorities in the health sector, including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, and WeMind. J.Ä. has served on the advisory boards for Astella, AstraZeneca, and Boehringer Ingelheim and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present work. J.F.L. has also received financial support from M.S.D. to develop a paper reviewing national healthcare registers in China, has ongoing discussions with M.S.D. about unrelated IBD research, and receives funding for celiac disease research from Takeda. The remaining authors declare no competing interests. The remaining authors declare no competing interests. ### Funding Statement Financial support was obtained in the form of grants from the European Research Council [ERC-STG-2018-801965 (T.F.); ERC-CoG-2014-649021 (M.O.-M.); ERC-STG-2015-679242 (J.G.S.)], the Swedish Heart-Lung Foundation [Hjärt-Lungfonden, 2019-0505 (T.F.); 2018-0343 (J.Ä.); 2020-0711 (M.O.-M.)], the Swedish Research Council [VR, 2019-01471 (T.F.), 2018-02784 (MO-M), 2018-02837 (M.O.-M.), 2019-01015 (J.Ä.), 2020-00243 (J.Ä.), 2022-01460 (S.A.), and EXODIAB 2009-1039 (M.O.-M.)], the Swedish Research Council for Sustainable Development [FORMAS, 2020-00989 (S.A.)], Göran Gustafsson foundation [2016 (T.F.)], Axel and Signe Lagerman's foundation (T.F.), the A.L.F. governmental grant 2018-0148 (M.O.-M.), The Novo Nordic Foundation NNF20OC0063886 (M.O.-M.), The Swedish Diabetes Foundation DIA 2018-375 (M.O.-M.), Center of Clinical Research (CKF) in Region Dalarna (J.Ä.), Epihealth (S.A.), and governmental funding of clinical research within the Swedish National Health Service (J.G.S.). B.K. is supported by a Gullstrand fellow grant from the Uppsala University Hospital. We acknowledge the Swedish Heart-Lung Foundation, the main funding body of SCAPIS. Funding for the SCAPIS study was also provided by the Knut and Alice Wallenberg Foundation, the Swedish Research Council and VINNOVA (Sweden's innovation agency), the University of Gothenburg and Sahlgrenska University Hospital, Karolinska Institutet and Stockholm County Council, Linköping University and University Hospital, Lund University and Skåne University Hospital, Umeå University and University Hospital, Uppsala University and University Hospital. We thank SIMPLER for the providing facilities and experimental support and Anna-Karin Kolseth and Niclas Håkansson for assistance. SIMPLER receives funding through the Swedish Research Council under grant no 2017-00644, 2017-06100, 2021-00160, and Stiftelsen Olle Engkvist Byggmästare. The computations and data handling were enabled by resources in project sens2019512 and simp2023007 provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX), funded by the Swedish Research Council through grant agreement no. 2022-06725. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the Swedish Ethical Review Authority (DNR 2018-315 B and amendments 2020-06597 and 2022-06460-02, DNR 2012-594 and the amendment 2017-768 and 2020-05611, DNR 2022-06137-01 and amendment DNR 2023-04785-02). All participants from each of the three studies provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the conclusions of this article were provided by the SCAPIS, SIMPER, and MOS and are not shared publicly due to confidentiality. Data will be shared upon reasonable request to the corresponding author only after permission from the Swedish Ethical Review Authority (https://etikprovningsmyndigheten.se) and from the boards of SCAPIS, (https://www.scapis.org/data-access), SIMPER (https://www.simpler4health.se), and MOS (https://www.malmo-kohorter.lu.se/malmo-offspring-study-mos). The code used for the statistical analysis and .csv files of the supplementary tables will be available at https://github.com/MolEpicUU/antibiot_gut.

BACKGROUND:Diagnostic testing is essential for disease surveillance and test-trace-isolate efforts. We aimed to investigate if residential area sociodemographic characteristics and test accessibility were associated with Coronavirus Disease 2019 (COVID-19) testing rates. METHODS:We included 426 224 patient-initiated COVID-19 polymerase chain reaction tests from Uppsala County in Sweden from 24 June 2020 to 9 February 2022. Using Poisson regression analyses, we investigated if postal code area Care Need Index (CNI; median 1.0, IQR 0.8-1.4), a composite measure of sociodemographic factors used in Sweden to allocate primary healthcare resources, was associated with COVID-19 daily testing rates after adjustments for community transmission. We assessed if the distance to testing station influenced testing, and performed a difference-in-difference-analysis of a new testing station targeting a disadvantaged neighbourhood. RESULTS:We observed that CNI, i.e. primary healthcare need, was negatively associated with COVID-19 testing rates in inhabitants 5-69 years. More pronounced differences were noted across younger age groups and in Uppsala City, with test rate ratios in children (5-14 years) ranging from 0.56 (95% CI 0.47-0.67) to 0.87 (95% CI 0.80-0.93) across three pandemic waves. Longer distance to the nearest testing station was linked to lower testing rates, e.g. every additional 10 km was associated with a 10-18% decrease in inhabitants 15-29 years in Uppsala County. The opening of the targeted testing station was associated with increased testing, including twice as high testing rates in individuals aged 70-105, supporting an intervention effect. CONCLUSIONS:Ensuring accessible testing across all residential areas constitutes a promising tool to decrease inequalities in testing.

The potential impact of childhood bereavement—a severe psychological stressor—on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact. We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (<18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics). During follow-up, 86,226 children (2.4

Background Previous population -based studies investigating the relationship between physical activity and the gut microbiota have relied on self -reported activity, prone to reporting bias. Here, we investigated the associations of accelerometer -based sedentary (SED), moderate -intensity (MPA), and vigorous -intensity (VPA) physical activity with the gut microbiota using cross-sectional data from the Swedish CArdioPulmonary bioImage Study. Methods In 8416 participants aged 50-65, time in SED, MPA, and VPA were estimated with hip -worn accelerometer. Gut microbiota was profiled using shotgun metagenomics of faecal samples. We applied multivariable regression models, adjusting for sociodemographic, lifestyle, and technical covariates, and accounted for multiple testing. Findings Overall, associations between time in SED and microbiota species abundance were in opposite direction to those for MPA or VPA. For example, MPA was associated with lower, while SED with higher abundance of Escherichia coli. MPA and VPA were associated with higher abundance of the butyrate -producers Faecalibacterium prausnitzii and Roseburia spp. We observed discrepancies between specific VPA and MPA associations, such as a positive association between MPA and Prevotella copri, while no association was detected for VPA. Additionally, SED, MPA and VPA were associated with the functional potential of the microbiome. For instance, MPA was associated with higher capacity for acetate synthesis and SED with lower carbohydrate degradation capacity. Interpretation Our findings suggest that sedentary and physical activity are associated with a similar set of gut microbiota species but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain gut microbiota species.

ObjectivesOur principal objectives were to identify the level of adherence and identify the attitudes, beliefs, and behaviors that influence adherence to antihypertensive treatment among Vietnamese patients in New Orleans, Louisiana.MethodsBy partnering with a community health center serving the Vietnamese community in New Orleans, we conducted reviews of 250 medical records of hypertensive patients receiving care there, 3 provider interviews, and 8 patient interviews. Descriptive and thematic analyses were used.ResultsThe level of treatment nonadherence in our sample population was 20.40%. Findings highlighted several key factors that may contribute to adherence, including easy access to providers, who are culturally competent and have used several strategies to help increase adherence, and the social support network of patients within a close-knit community. Other sociodemographic factors, such as age, sex, and tobacco and alcohol use also may play a role in adherence.ConclusionsAdherence to antihypertensive treatment among Vietnamese patients in New Orleans was relatively high compared with other ethnic and racial groups in the United States. Further assessment of the characteristics of patients, providers, and the community may improve adherence to other chronic conditions in this population and patients of other ethnicities and races.

BACKGROUND: OSA is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent upper airway obstruction and hypoxia, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition, and subsequent transplantation of fecal matter to other animals induced changes in BP and glucose metabolism. RESEARCH QUESTION: Does OSA in adults associate with the composition and functional potential of the human gut microbiota? STUDY DESIGN AND METHODS: We used respiratory polygraphy data from up to 3,570 individuals 50 to 64 years of age from the population-based Swedish Cardiopulmonary bioimage Study combined with deep shotgun metagenomics of fecal samples to identify crosssectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia, and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, onsite anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register. RESULTS: We found that all three OSA parameters were associated with lower diversity of species in the gut. Furthermore, in multivariable-adjusted analysis, the OSA-related hypoxia parameters were associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsella aerofaciens. The latter species was also independently associated with increased systolic BP. Furthermore, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Finally, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively. INTERPRETATION: OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA.

Background: To prepare for rollout of a COVID-19 vaccine in fall 2020, there was an urgent need to understand barriers to ensuring equitable access and addressing vaccine skepticism and resistance. This study aimed to understand the association between trusted sources of COVID-19 information and likelihood of vaccination during that time, focusing on lessons learned to prepare for future public health crises.Methods: From December 2020-March 2021, we surveyed a probability-based, cross-sectional sample of 955 patients across seven federally qualified health centers (FQHCs) serving predominantly low-income, Black and White populations in southeastern Louisiana. Vaccination likelihood was measured on a 7-point scale; "very likely to vaccinate" was defined as score=7. Trust in healthcare provider was measured with a single survey item. High trust in personal contacts, government, and media, respectively, were defined as the highest tertiles of summative scores of trust items. Weighted multivariable logistic regression estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for being very likely to vaccinate.Results: Participants were 56% Black, 64% women, mean age 44.6 years; 33% were very likely to vaccinate. High trust in healthcare provider (aOR=4.14, 95% CI 2.26-7.57) and government sources (aOR=3.23, 95% CI 1.98-5.28) were associated with being very likely to vaccinate.Conclusions: During initial COVID-19 vaccination rollout, trust in healthcare providers and government sources of COVID-19 information was associated with likelihood to vaccinate in FQHC patients. To inform public health planning for future crises, we highlight lessons learned for translating community-relevant insights into direct action to reach those most impacted.

Background and Aims Large population-based studies on gut microbiota and hypertension have been conducted using methods with low taxonomic resolution and office blood pressure. This study aims to investigate the relationship between specific characteristics of the gut microbiome and 24-hour blood pressure measurements. Methods and results The association of gut microbial species, determined by shotgun metagenomic sequencing of fecal samples, with 24-hour ambulatory blood pressure measurements was assessed in 4063 participants without antihypertensive medication from the Swedish CArdioPulmonary bioImage Study. Multivariable-adjusted models identified 140 microbial species associated with at least one of the 24-hour blood pressure traits. Notably, Roseburia faecis , R. inulinivorans , and Dorea longicatena were strongly positively associated with mean systolic and diastolic blood pressure, while Alistipes communis and A. shahii were inversely associated with diastolic blood pressure. An enrichment of threonine degradation I, Bifidobacterium shunt, and lactate production was observed in species associated with mean systolic and diastolic blood pressure. Species positively associated with blood pressure were in general also positively associated with secondary bile acids but negatively associated with primary bile acids and vitamin A-related metabolites. Conclusions In this large cross-sectional analysis, we identified a group of gut microbial species and microbial functions associated with blood pressure. Our findings provide insights into the relation of the gut microbiome and blood pressure, which can lead to a new understanding of the etiology of hypertension. ### Competing Interest Statement The authors declare the following competing interests: N.N., A.C.E. and J.B.H., and H.B.N. are employees of Clinical Microbiomics. The funders had no role in study design, data collection and analysis, decision to publish, nor preparation of the manuscript. J.Ä. has received lecture fees from Novartis and AstraZeneca, and served on advisory boards for AstraZeneca and Boerhinger Ingelheim, all unrelated to the present paper. J.S. reports stock ownership in Anagram kommunikation AB and Symptoms Europe AB, unrelated to the present study. All other authors report no conflicts of interest in connection with this study. ### Funding Statement We acknowledge the financial support from the European Research Council [ERC-STG-2018-801965 (T.F.); ERC-CoG-2014-649021 (M.O-M.), ERC-STG-2015-679242 (J.G.S.)], the Swedish Research Council [VR 2019-01471 (T.F.); 2018-02784 (M.O-M.); 2018-02837 (M.O-M.); 2021-03291 (M.O-M.); EXODIAB 2009-1039 (M.O-M.); 2019-01015 (J.Ä.); 2020-00243 (J.Ä.); 2019-01236 (G.E.); 2021-02273 (J.G.S.)], the Swedish Heart-Lung Foundation [HjÄrt-Lungfonden, 20190505 (T.F.); 20200711 (M.O-M.); 20180343, 20210357 (J.Ä.); 20200173 (G.E.); 20190526 (J.G.S.)], the A.L.F. governmental grant [2018-0148 (M.O-M.)], the Novo Nordic Foundation [NNF20OC0063886 (M.O-M.)], the Swedish Diabetes foundation [DIA 2018-375 (M.O-M.)], the Swedish Foundation for Strategic Research [LUDC-IRC 15-0067 (M.O-M.)], Göran Gustafsson foundation [2016 (T.F.)]; and Axel and Signe Lagerman's foundation (T.F.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Declaration of Helsinki. The Swedish Ethical Review Authority approved the Swedish CardioPulmonary bioImage Study (DNR 2010-228-31M) and the present study (DNR 2018-315). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified de-hosted metagenomic sequencing data for SCAPIS samples can be accessed from the European Nucleotide Archive under accession number PRJEB51353 (https://www.ebi.ac.uk/ena/browser/view/prjeb51353). Access to pseudonymized SCAPIS phenotype data requires ethical approval from the Swedish Ethical Review Board and approval from the SCAPIS Data access board (https://www.scapis.org/data-access/). The source code and the summary data underlying all figures used to generate the results for the analysis are available at https://github.com/MolEpicUU/24hBP-mgs.

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 46% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p -cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography–based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis ( P <1×10 –5 ). Associations were largely similar across coronary computed tomography angiography–based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

ABSTRACTObjectivePopulation-based studies investigating the relationship between physical activity and the gut microbiota composition have mainly relied on self-reported activity, potentially influenced by reporting bias. Here, we investigated associations of accelerometer-based sedentary behaviour and physical activity with the gut microbiota composition and functional profile in the large Swedish CArdioPulmonary bioImage Study.MethodsIn 8507 participants aged 50-65, the proportion of time in sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity were estimated with hip-worn accelerometer. The gut microbiota was profiled using shotgun metagenomics of fecal samples. We fitted multivariable regression models, and adjusted for sociodemographic, lifestyle, and technical covariates while also accounting for multiple testing.ResultsOverall, SED and MPA were associated with microbiota species in opposite directions. For example, the strongest positive regression coefficient for MPA and the strongest negative for SED were withPrevotella copri, a plant-polysaccharide-degrading bacteria. Species associated with VPA aligned with the MPA associations, although with clear discrepancies. For instance,Phocaeicola vulgatuswas negatively associated with MPA, while the association with VPA was non-significant and in the positive direction. Additional adjustment for dietary variables or adiposity attenuated some of the associations. For the functional profile, MPA and VPA were generally associated with lower capacity for amino acid degradation.ConclusionOur findings suggest that sedentary behaviour and physical activity are associated with a similar set of gut microbiota species and functions, but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain species of the gut microbiota.

Throughout the coronavirus disease 2019 (COVID-19) pandemic, there have been numerous demands on primary care practices and providers affecting work engagement and burnout, which can affect health-care delivery and patient outcomes. We determined potentially modifiable factors associated with work engagement among employees of federally qualified health centers (FQHCs) throughout Louisiana. Resilient coping, spirituality, and social support were associated with being engaged at work. FQHC employees perceiving a more chaotic work environment and those with depressive or anxiety symptoms were less likely to be engaged at work. Being engaged was associated with confidence in COVID-19 vaccine recommendation for adults.

Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used 16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life.