Background: While gut dysbiosis is linked to prevalent hypertension (HTN), microbial features associated with incident HTN and the mediating role of circulating metabolites remain poorly understood. Methods: We conducted a prospective analysis of 1,265 HTN-free adults with concurrently profiling of gut metagenomics (440 core species with prevalance >10% and relative abundance >0.01%) and serum metabolomics (767 named metabolites) from HCHS/SOL (mean age 53 yrs; 65.8% female; 358 incident HTN over a median of 7 yrs of follow-up). Cox proportional hazard models were used to identify gut microbial species and metabolites associated with incident HTN. Mediation analysis was used to quantify the extent to which metabolites explain the microbiome-HTN relationship. Results: We identified 18 bacterial species associated with incident HTN (FDR<0.25, Fig1.a), largely independent of baseline cardiometabolic traits (Fig1.b). Seven species, predominantly Prevotella spp. (e.g., P. nanceiensis and P. histicola ), were associated with higher HTN risk, whereas the other 11 species showed inverse associations, including three Akkermansia spp. , two Firmicutes spp. , and multiple Clostridiales spp. (e.g., Intestinimonas massiliensis ). We further identified 224 metabolites (FDR<0.05) that were associated with both at least one HTN-related species and incident HTN. These metabolites collectively mediated a substantial portion of the observed microbiota-HTN associations, with the proportion of mediated effect ranging from 9% for Parabacteroides merdae to 75.2% for Intestinimonas massiliensis (Fig.1c). Key metabolites with significant mediating effects, especially on the protective association between Intestinimonas massiliensis and incident HTN, included microbially influenced steroids (e.g., androstenediol disulfate, tetrahydrocortisol glucuronide), N-acetyl-amino acids (e.g., N-acetylphenylalanine, N-acetyltyrosine), and markers of endothelial dysfunction and vascular stiffness (e.g., cysteine-glutathione disulfide, 5-hydroxylysine) (Fig1.d) . A combined panel of the identified gut microbiota and metabolites significantly improved HTN risk prediction beyond conventional risk factors (AUC improved from 0.77 to 0.84, p<0.001). Conclusion: Our study characterizes multiple bacterial species associated with incident HTN, and the associations might be partly mediated by circulating metabolites. Inclusion of gut microbiome and associated metabolites facilitates the risk prediction of HTN.

Abstract Introduction: Prostate cancer (PrCa) is the most common solid tumor and the second-leading cause of cancer deaths among U.S. men. Although the multi-factorial etiology of this cancer indicates the involvement of several biological pathways, to date the role of rare vs common genetic variants (SNPs) in risk prediction of more aggressive or fatal PrCa remains unclear. The goal of this project is to examine the associations of rare germline BRCA1/2 mutations and a polygenic risk score (PRS) with risks of total and aggressive PrCa as well as with overall and cancer-specific mortality in a founder population. Methods: Epidemiological and germline genotype data collected from 943 PrCa cases and 1,199 controls of Ashkenazim Jewish descent were used in this analysis. We evaluated associations of BRCA1 (185delAG) and BRCA2 (6174delT) founder mutations and a PRS generated from 77 SNPs with risks of total PrCa and high-grade cancer (defined as Gleason score 7-10) using logistic and multinomial regression models, respectively, and adjusted for age and family history of PrCa. All men were followed for mortality via linkage with the U.S. National Death Index from recruitment into the study (between 1999 and 2003) through 12/31/2022. Cox regression models and competing risk analyses were used to examine associations of BRCA1/2 mutations and PRS with overall and PrCa-specific mortality after adjustment for age, Charlson comorbidity index as well as clinical factors and PrCa treatment. Results: The prevalence of BRCA1 (185delAG: 1.2% vs 0.7%) and BRCA2 (6174delT: 1.3% vs 0.9%) were higher in cases vs controls. Mutation carriers of either BRCA1 or BRCA2 mutations had ORs of 1.92 (95%CI 1.00-3.67) for total PrCa and 3.38 (95%CI 1.63-7.04) for high-grade PrCa compared to non-mutation carriers. The PRS score was also independently associated with a statistically significant 2.2 to 2.3-fold higher risk for total PrCa and aggressive cancer. During a median follow-up of 19.7 years a total of 712 out of 943 (76%) men diagnosed with PrCa had died, of whom 124 (17.4%) were PrCa-specific deaths. BRCA2 mutation carriers had hazard ratios (HR) of 1.92 (p=0.008) and 2.88 (p=0.01) for overall and PrCa-specific mortality compared to non-mutation carriers. However, there was no association of the PRS score with PrCa-specific mortality (HR=0.98, p=0.89) and a borderline significant 9% lower risk (HR=0.91, p=0.05) with overall mortality. Conclusion: Carriers of BRCA1 and particularly BRCA2 mutations have increased risks of more aggressive and fatal PrCa. Although the PRS score was associated with overall risk, it did not confer any elevated risk for higher Gleason score tumors or fatal PrCa. Evaluation for BRCA2 mutations might be helpful for risk-stratification of men for PrCa screening and potentially targeted therapy. Citation Format: Ilir Agalliu, Mykhaylo Usyk, Michael D`Angelo, Victor Kamensky, Robert Burk, . Associations of BRCA1/2 mutations and polygenic risk score with prostate cancer risk and mortality in a founder population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3593.

Background: Coffee intake has been linked to improved cardiometabolic (CM) health, yet underlying microbial and metabolic pathways remain unclear. Methods: At HCHS/SOL Visit 1 (2008-11), usual coffee intake was estimated from two 24-hour dietary recalls and food propensity questionnaires among 13634 adults. Serum metabolomics (653 metabolites) were profiled by LC-MS at Visit 1 (n=6180) and Visit 2 (2014-17; n=718). Gut microbiome was characterized by shotgun metagenomics at Visit 2 (n=2758). CM traits, including adiposity, glycemic, lipid, blood pressure, kidney, and liver markers, were measured at both visits. Among 10730 participants free of diabetes, CVD, and cancer at baseline, 2493 diabetes cases occurred during a median follow-up of 10.2 years. Results: Higher coffee intake was correlated with lower levels of waist-to-hip ratio, liver enzymes (AST, ALT, GGT), glucose/insulin indices (2-h OGTT glucose, fasting insulin, HOMA-IR, HOMA-b), TG, and blood pressure, but higher LDLC levels (all P <.05). Each additional serving/d of coffee intake was related to an HR of 0.89 (95% CI 0.80-0.98; Fig1 ) for diabetes. Coffee intake was positively related to gut microbial α-diversity and four species ( e.g., Clostridium phoceensis ), while inversely related to 27 species, including pro-inflammatory Ruminococcus gnavus , Clostridium glycyrrhizinilyticum , and Blautia hansenii , and opportunistic Klebsiella oxytoca ( q <.05), which were linked to unfavorable CM traits ( Fig2 ). We identified 165 coffee-related and 154 microbiota-related metabolites, with 55 overlapping. These 264 metabolites were clustered into 18 modules using WGCNA, one of which was mainly composed of caffeine metabolites and positively correlated with coffee intake and Clostridium phoceensis . A sphingomyelin module was positively related to coffee intake and lower diabetes risk (HR=0.88 [0.82-0.95] per SD increase in the module; Fig3 ). Modules of branched-chain amino acid (BCAA) and microbial bile acid metabolites were inversely related to coffee intake and higher diabetes risk, with HRs of 1.34 (1.24-1.45) and 1.07 (1.00-1.14), respectively. Glycerophospholipid module was positively related to Ruminococcus gnavus (inversely related to coffee intake) and an HR of 1.17 (1.09-1.26) for diabetes. Conclusions: Coffee intake was associated with gut microbial and metabolomics signatures converging on lipid, BCAA, and bile acid metabolism, and these pathways may illuminate the biological basis of coffee’s CM benefits.

Objectives Limited evidence exists on the association between dietary phytosterol intake and the risk of type 2 diabetes (T2D). We aimed to investigate this association and identify the underlying plasma metabolic, metabolomic, and gut microbial features. Methods We followed 204,633 participants (79% women) from three large US prospective cohorts for up to 36 years. Validated food-frequency questionnaires were used to estimate dietary intake of total phytosterol and three subtypes: β-sitosterol, campesterol, and stigmasterol. We applied Cox proportional hazards models to evaluate their associations with T2D risk. In a subset of 39,879 participants with plasma metabolic biomarkers and 9,528 participants with plasma metabolomics data, we examined the association between phytosterol intake and metabolic biomarkers related to insulinemia, glycemia, lipids, and inflammation, as well as T2D-related metabolomic profiles. Additionally, we explored the gut microbial species and enzymes involved in these associations in a subset of 465 participants with gut microbiome data. Results During follow-up, we documented 20,708 incident T2D cases. After adjustment for covariates, higher intake of total phytosterol was associated with a lower T2D risk (HR comparing extreme quintiles = 0.87, 95% CI: 0.82, 0.92; P trend<0.001). Similar associations were observed for β-sitosterol (HR=0.86, 95% CI: 0.81, 0.91; P trend<0.001) and campestrol (HR=0.89, 95% CI: 0.84, 0.94; P trend<0.001), but not for stigmasterol.β-sitosterol and campestrol were also associated with favorable plasma metabolic profiles, such as lower levels of C-reactive protein, leptin, and C-peptide, as well as beneficial T2D-relevant metabolomic profiles. Moreover, we identified several gut microbial species, and their enzymes involved in these associations. For example, Faecalibacterium prausnitzii and its β-sitosterol-degrading enzyme 3-oxosteroid 1-dehydrogenase (EC1.3.99.4) were associated with higher β-sitosterol intake and a metabolomic profile indicative of lower T2D risk. Conclusions A higher intake of phytosterols, particularly β-sitosterol and campesterol, was associated with a lower risk of T2D, with consistent findings across epidemiological and multi-omics analyses. These findings support the role of a healthy plant-based dietary pattern rich in phytosterol-containing foods such as whole grains, nuts, seeds, fruits, vegetables, and vegetable oils in lowering T2D risk.

Introduction: Lactation has been associated with improved long-term cardiometabolic health in women, but the underlying mechanisms remain unclear. Methods: We studied 194 parous women (mean age: 32.8 years) from the HCHS/SOL with singleton births and self-reported lactation information. A total of 694 serum metabolites were profiled a median of 3 years (IQR: 1-4) after delivery. Lactation duration was categorized as <6 months or ≥6 months. Lactation-related metabolites were identified by metabolome-wide association analyses with an Empirical Bayes method and adjusting for sociodemographic and reproductive factors (|fold change|>1.2 and FDR-adjusted p<0.05). We examined the correlations between selected metabolites and cardiometabolic traits. We further examined the prospective associations of selected metabolites with incident diabetes (without baseline diabetes, n=2,341) and CVD (without baseline CVD, n=2,968) over 12 years of follow-up among parous women in the HCHS/SOL. Results: In this study, 26 (13.4%) women reported no lactation for this birth, 100 (51.5%) lactated <6 months, and 68 (35.1%) lactated ≥6 months. Compared with <6 months (n=126), lactation for ≥6 months (n=68) was associated with 46 metabolites, including lower levels of 37 metabolites (e.g., amino acid derivatives [involved in energy balance and methylation process] and glycerophospholipids [key membrane and lipoprotein components linked to dyslipidemia]), and higher levels of 9 metabolites (e.g. certain plasmalogens [antioxidant phospholipids] and sulfated steroids [involved in hormonal and metabolic regulation]). Most lactation-increased metabolites were positively correlated with triglycerides and LDL cholesterol, while many lactation-decreased metabolites were positively correlated with HDL cholesterol. Furthermore, 17 metabolites (e.g., N-acetylvaline and 3,4-dihydroxybutyrate) that were higher in women with <6 months lactation, were associated with increased risk of incident diabetes or CVD (HRs per SD range:1.12-1.64, p<0.05); while 2 metabolites (pregnenolone sulfate and a plasmalogen), higher in women with ≥6 months lactation, were inversely associated with incident diabetes (HRs per SD: 0.88 and 0.90, p<0.05) ( Figure 1 ). Conclusion: Longer lactation duration was associated with a favorable maternal serum metabolomic profile 1-4 years after delivery, which may partly explain the protective effects of sustained lactation on diabetes and CVD risk among Hispanic/Latino women.

Introduction: ABO blood type is related to cardiovascular disease (CVD) and influence gut microbiota (GMB). ABO antigen glycans in the gut may influence GMB composition, with effects further modulated by fiber intake. Hypothesis: Higher fiber intake is associated with lower CVD risk and favorable GMB and blood metabolite profiles in O blood group but not in non-O blood group. Methods: We examined associations of total, soluble, and insoluble fiber intake with CVD risk in 11,238 participants free of CVD at baseline from the Hispanic Community Health Study/Study of Latinos during ~12 years of follow-up, stratified by O (53%) and non-O blood groups. In subsamples (N up to 3940), we identified fiber-associated GMB species and serum metabolites in O and non-O blood groups separately, followed by examining their associations with cardiometabolic traits and CVD risk. Results: Higher fiber intake, especially insoluble fiber, was associated with lower CVD risk in O blood group (4 th vs. 1 st quartile: HR: 0.37; 95% CI: 0.19–0.72), but not in non-O group ( P -interaction = 0.02; Fig. A ). Insoluble fiber intake, specifically in O blood group, was associated with differences in 14 GMB species (e.g., increased Butyrivibrio crossotus ) and 50 metabolites (35 are known to relate to GMB), compared to 6 GMB species and 22 metabolites specifically in non-O group. An overall higher fiber-related serum metabolite profile (indicated by an O-specific metabolite score) was associated with a higher fiber-related GMB profile (O-specific GMB score; Fig. B ), more favorable cardiometabolic traits (Fig. C) and lower CVD risk (Fig. D ). No such associations were observed in non-O group. The interaction between ABO blood type and insoluble fiber intake on CVD risk was attenuated ( P -interaction = 0.07) after additional adjustment for O-specific metabolite score. Conclusions: ABO blood group modifies the association between fiber intake and CVD, which might be related to different GMB and blood metabolite profiles associated with fiber intake between O and non-O blood groups.

Introduction: Hippuric acid is a gut microbiota-derived metabolite of polyphenols. Few population studies have characterized human gut microbial features related to this metabolite. Hypothesis: To identify gut microbial species associated with plasma hippuric acid levels, investigate the relationships between diet, gut microbiota composition, and hippuric acid, and explore the prospective associations of circulating hippuric acid with the risks of type 2 diabetes (T2D), cardiovascular disease (CVD), and weight gain (WG) through a systematic, integrated approach. Methods: We included 287 men from Men's Lifestyle Validation Study (MLVS) with plasma metabolomics, fecal metagenomic data, and 7-day diet records. Findings were replicated in 207 women from Mind Body Study (MBS), 1833 women from Microbiome Among Nurses (MICRO-N), and 3,035 men and women from the Hispanic Community Health Study/Study of Latinos Gut Origins of Latino Diabetes (GOLD). Prospective associations between hippuric acid concentrations and risks of T2D, CVD, and WG were examined in 5,472 participants from the Nurses' Health Study (NHS), NHSII, and HPFS. Results: We identified 26 microbial species significantly associated with plasma hippuric acid, mainly from Lachnospiraceae and Oscillospiraceae families. A gut microbiome (GMB) species score developed in MLVS was strongly correlated with hippuric acid (Pearson r =0.73), replicating in MBS ( r =0.29) and GOLD ( r =0.14). Dietary fiber correlated with hippuric acid ( r =0.35) and 68% of this relationship was mediated by hippuric acid–associated bacteria, primarily fiber-fermenting Firmicutes . The GMB score was inversely associated with prevalent T2D (per SD: OR = 0.97, 0.95–0.99) in GOLD, and incident T2D (0.80, 0.66–1.00) and WG (-0.17 kg/2 years) in MICRO-N. In NHS and HPFS, higher plasma hippuric acid was associated with lower incident T2D risk (Q5 vs. Q1: HR = 0.77, 0.64–0.94) and slower BMI gain (β=-0.01 per SD). No association with CVD was observed. Conclusions: Our findings confirm gut microbiota's essential role in hippuric acid production in humans, and highlight its potential role in mediating the relationship between dietary fiber and plasma hippuric acid. Overall these data elucidate novel pathways partially underlying the health benefits of fiber intake on improving cardiometabolic health. Further studies are needed to clarify how fiber facilitates the hippuric acid production via interactions with polyphenol intake and the gut microbiome.

Circulating metabolites may reflect biological homeostasis and have been linked to dietary intakes and human health, and may hold the promises to facilitate objective assessments of intakes and metabolic response to diets. Here, we integrated metabolomic, genetic, and metagenomic data from five longitudinal cohorts comprising 21,474 participants of diverse ethnic backgrounds, to develop metabolomic signatures for popular dietary patterns (i.e., three guideline-based diets, three plant-based diets, and two mechanism-based diets) and systematically investigated their clinical relevance. Applying machine-learning models in two deeply-phenotyped lifestyle validation studies, we identified eight metabolomic signatures (each included 37 to 66 metabolites) significantly correlated with their respective dietary pattern indices, consistently across multiple independent validation cohorts (r = 0.11-0.38; P < 8.06*10-9). These signatures included shared metabolites between diets (e.g., up to 67% among guideline-based diets, including hippuric and 3-indolepropionic acid), and metabolites unique to specific diets (e.g., N6,N6,N6-trimethyllysine to proinflammatory diet). In multivariable-adjusted analyses of 5 prospective cohorts (1,832 incident cases during up to 27 years of follow-up), the metabolomic signatures of healthful diets (i.e., Mediterranean and healthful plant-based diets) were associated with lower T2D risk (HR: 0.82-0.90; ; P < 3*10-6), while signatures for unhealthy diets (e.g., proinflammatory and hyperinsulinemia diets) were associated with higher T2D risk (HR: 1.23-1.26; P < 2*10-15); these associations were further supported by Mendelian randomization analysis incorporating genetic data. Finally, through genome-wide and taxa-wide associating analyses, we identified 15 genetic loci, including those involved in fatty acid and energy metabolism (e.g., FADS1/2 and CERS4; P < 5*10-8), and 39 gut microbial species, including those relevant to butyric acid metabolism (e.g., E. eligens and F. pranusnitzii; FDR < 0.05), significantly associated with the metabolomic signatures of diets. Genetic variants and gut microbial diversity explained up to 19.1% and 10.6% of the variation in these signatures, respectively, underscoring a potential role of host genetics and gut microbiota in dietary metabolism. In conclusion, our study identified metabolomic signatures reflecting both intakes and individual metabolic response to various diets and are associated with future T2D risk. These signatures may facilitate individualized dietary assessments and risk stratification in future nutritional research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is supported by R00DK122128 from the National Institute of Diabetes and Digestive and Kidney Diseases and U2CDK129670. The NHS, NHSII, and HPFS, and their metabolomic studies were supported by National Institutes of Health grants U01 HL145386, UM1 CA186107, R01 CA49449, R01 HL034594, R01 HL088521, U01 CA176726, R01 CA67262, U01 CA167552, R01 HL35464, HL60712, R01 CA50385, P01 CA87969, and R01 AR049880. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I / N01- HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Dr. Kaplan was supported by 2R01HL105756, R01GM145772, 1R01DK134672, and 1R01MD011389 from the National Institutes of Health. The metabolomic and gut microbiome studies from HCHS/SOL were supported by R01DK119268, R01 DK126698, R01HL060712, R01MD011389, R01HL141824, and UM1 HG008898. The WHI is funded by NHLBI through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. ### 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: Ethics committee of Harvard T.H. Chan School of Public Health and Brigham and Women's Hospital gave ethical approval for this work. 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 All data produced in the present study are available upon reasonable request to the authors.

OBJECTIVES:Assess the relationships of gut microbiota (GMB)-related metabolites in feces and blood with GMB and type 2 diabetes (T2D) in the context of HIV infection, the presence of which could disrupt host metabolism. DESIGN:We conducted a cross-sectional study among 111 women with HIV (WWH) and 56 women without HIV (WWOH) in the MACS/WIHS Combined Cohort Study. METHODS:We measured 62 targeted metabolites in both feces and plasma and examined their associations with GMB composition (243 species) and prevalent T2D. RESULTS:We observed 44 metabolites with detection rates ≥25% in both feces and plasma. Correlations between fecal and plasma metabolites were stronger in WWOH than in WWH (median r : 0.13 vs. 0.04). Fecal metabolites showed stronger correlations with GMB than plasma metabolites among all participants (median r [IQR] of measured vs. GMB-predicted metabolites: 0.24 [0.11, 0.33] vs. 0.08 [-0.03, 0.24]; P  = 0.002), and the difference in this comparison was more pronounced in WWOH compared to WWH. We found a moderate consistency for the associations of fecal and plasma metabolites with T2D in WWH ( r for effect sizes of fecal and plasma metabolites on T2D = 0.36; P  = 0.03), but not in WWOH ( r  = 0.13; P  = 0.45). Fecal and plasma kynurenate, a tryptophan catabolism metabolite, showed opposite associations with T2D, with a positive association for plasma (odds ratio (OR): 2.54, 95% confidence interval (CI): [1.28-5.76]; P  = 0.01) and an inverse association for feces (0.59 [0.27-1.23]; P  = 0.18) in WWH. CONCLUSIONS:Fecal metabolites are more strongly associated with GMB than plasma metabolites, especially among WWOH. HIV infection might also influence associations of fecal and plasma metabolites with T2D.

Human papillomavirus type 45 (HPV45) causes ~6% of all cervical cancers and an even greater proportion of adenocarcinomas, the latter of which are challenging to detect using current cervical cancer screening. Little is known about how HPV45 genetic variation is related to the risk of cervical precancer/cancer. To investigate this, we whole-genome sequenced a total of 1,083 HPV45-positive samples from two large studies. We evaluated associations of HPV45 genetic variation (sublineages, subclades, and SNPs) with histology-specific precancer/cancer risk using logistic regression and evaluated risk modification by self-reported race/ethnicity. Compared to the common A1 sublineage, A2 and B1 were associated with increased precancer/cancer (A2, OR = 3.9, 95% CI = 1.9-8.5; B1, OR = 2.7, 95% CI = 1.3-5.8; B2, OR = 3.3, 95% CI = 1.6-7.3), and most strongly with the glandular precancers/cancers (AIS/ADC; A2, OR = 6.9, 95% CI = 1.0-184; B1, OR = 6.2, 95% CI = 1.1-159). The A2 sublineage was most prevalent in women in East Asia and women who self-reported as Asian/Pacific Islander (PI) in the U.S.; East Asian and Asian/PI women had the greatest precancer/cancer risk associated with A2 infections (OR = 5.8, 95% CI = 1.3-37.4) compared to all other sublineages among these women. We further evaluated precancer/cancer risk associations for 262 individual HPV45 SNPs and identified four SNPs significantly associated with only glandular precancers/cancers after correction for multiple tests (ORs ranged 7.8-20.7). One of these SNPs was a nonsynonymous variant in both overlapping viral E2/E4 ORFs. In summary, we show that HPV45 genetic variation influences the risk of precancer/cancer, specifically glandular precancer/cancer. Further studies of these genetic variants may improve our understanding of glandular lesions.

Introduction: The relationships among gut microbial alterations, host inflammation, and cardiac dysfunction remain understudied, particularly in the context of HIV. Hypothesis: We hypothesized that higher abundance of pro-inflammatory gut bacteria is associated with higher levels of host circulating inflammatory makers and cardiac dysfunction. Methods: We examined associations of gut microbial features (16S rRNA sequencing) with cardiac dysfunction (Echocardiography) in 973 women from the MACS/WIHS Combined Cohort Study. Cardiac dysfunction was defined as the presence of left ventricular systolic (LV ejection fraction<54%) or diastolic (ASE 2016 criteria) dysfunction. In a subset (n=397), we further integrated cardiac dysfunction-associated microbial features (Shotgun metagenomics sequencing) with serum proteomic inflammatory markers (Olink platform inflammation panel) in relation to cardiac dysfunction. Results: The potentially pathogenic bacteria Streptococcus, Eggerthella and Anaeroglobus , were positively associated with cardiac dysfunction, while the beneficial genera Roseburia and Alistipes were linked to lower odds of cardiac dysfunction ( Fig. 1A ). Results were consistent in women with and without HIV. These cardiac dysfunction-associated bacteria were associated with a number of circulating proteomic inflammatory markers ( Fig. 1B ). For example, the pathogenic Streptococcus was positively associated with the pro-inflammatory cytokines IL-8 and IL-6, the chemokine MCP-3 (linked to immune response and atherosclerosis), and the inflammatory mediator OSM (associated with vascular inflammation and heart failure). Proteomic inflammatory scores were generated for each genus based on their specific inflammatory marker profiles. The inflammatory score for Streptococcus was significantly associated with cardiac dysfunction ( Fig. 1C ). Associations between bacterial genera and cardiac dysfunction were attenuated after further adjustment for specific microbial associated inflammatory markers ( Fig. 1D ). Conclusion: Among women living with or at risk of HIV, we identified gut microbial features associated with cardiac dysfunction, with certain microbiota-related inflammatory markers partially explaining these associations.

Introduction and Objective: To examine associations of serum imidazole propionate (ImP), histidine and their ratio with incident type 2 diabetes (T2D) and related dietary and gut microbial factors in US Hispanics/Latinos. Methods: In the Hispanic Community Health Study/Study of Latinos, we evaluated serum ImP, histidine and ImP-to-histidine ratio at baseline (2008-2011) and their cross-sectional associations with dietary intake and prospective associations with incident T2D over ~12 years (n=4632). In a subsample with gut microbiota data during a follow-up visit (2016-2018), we examined gut microbial species associated with serum ImP and their potential interactions with dietary intake. Results: Serum ImP and ImP-to-histidine ratio were positively associated with incident T2D (Hazard ratio=1.17 [95% CI:1.00-1.36] and 1.33 [1.14-1.55], respectively, comparing highest to lowest tertile), while histidine was inversely associated with incident T2D (Hazard ratio=0.75 [0.64-0.86]). Higher fiber intake was associated with lower serum ImP and ImP-to-histidine ratio, while histidine intake was not associated with serum ImP in overall sample. Fifty-three bacterial species, including 19 putative ImP-producers, were associated with serum ImP. Histidine intake was positively associated with serum ImP and ImP-to-histidine ratio only in participants with high abundances of putative ImP-producers but not in those with low abundances (P-interaction=0.02 and 0.009, respectively). The associations of fiber intake with serum ImP and ImP-to-histidine ratio were partly mediated by ImP-associated gut microbiota (proportion mediated=31.4% and 19.8%, respectively). Conclusion: This study suggested an unfavorable relationship between histidine metabolism toward ImP production, regulated by dietary intake and gut microbiota, and risk of T2D in US Hispanics/Latinos. K. Luo: None. H. Yang: None. B. Peters: None. Y. Wang: None. Y. Zhang: None. M.L. Daviglus: None. A. Pirzada: None. C. Cordero: None. B. Yu: None. R. Burk: None. R. Kaplan: None. Q. Qi: None. National Heart, Lung, and Blood Institute (R.C.K. R01HL148094, R01HL140976, R01MD011389; U01HL146204-04S1; Q.Q. R01HL140976, R01DK119268, R01DK126698; S.R.L. 5U01HL146202; A.C.M. K01HL150406).

Purpose of reviewTo summarize the relationship of vaginal and gut microbiomes with HIV transmission, pathogenesis, and treatment, focusing on women's health.Recent findingsBacterial vaginosis (i.e., vaginal microbiome dysbiosis) is a well established risk factor for HIV acquisition, and recent research focused on molecular mechanisms and biomarkers for HIV acquisition related to vaginal microbiota. Recent clinical trials reported on probiotics to treat bacterial vaginosis with the goal of HIV prevention; however, durability of treatment response remains sub-optimal. The vaginal microbiome may impact efficacy of preexposure prophylaxis (PrEP) and antiretroviral therapy (ART) in vaginal tissue, with recent literature examining vaginal microbiota and long-acting PrEP vaginal rings. Some research also suggests effects of PrEP or ART initiation on the vaginal microbiome. Regarding the gut microbiome, associations with HIV status may differ more by sexual practices than biological sex, and sex-specific roles of gut microbiota in HIV pathogenesis and treatment are unknown. Interactions of the gut microbiome with estrogens could underlie a role of gut microbiota in health of women with HIV.SummaryThe vaginal microbiome remains an important factor in HIV acquisition, prevention, and treatment in women. The gut microbiome has roles in HIV pathogenesis and treatment, but women-specific effects are unclear.

Background There is limited work on the association between the gut microbiome and Alzheimer's disease and related dementia (AD/ADRD) in Latinos.Objective We examined, within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, the association between gut microbiome and cognitive function.Methods We analyzed the fecal metagenomes of 2471 HCHS/SOL participants to identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.Results Eubacterium species (E. siraeum and E. eligens), and C phoceensis, among other species were associated with better cognition. Several KEGG modules, most strongly Ornithine, Serine biosynthesis and Urea Cycle, were associated with worse cognition.Conclusions In a large Hispanic/Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition.

Background Aging-related comorbidities are more common in people with human immunodeficiency virus (HIV) compared to people without HIV. The gut microbiome may play a role in healthy aging; however, this relationship remains unexplored in the context of HIV. Methods 16S rRNA gene sequencing was conducted on stool from 1409 women (69% with HIV; 2304 samples) and 990 men (54% with HIV; 1008 samples) in the MACS/WIHS Combined Cohort Study. Associations of age with gut microbiome diversity, uniqueness, and genus-level abundance were examined in women and men separately, followed by examining relationships of aging-related genera with frailty (Fried frailty phenotype) and mortality risk (Veterans Aging Cohort Study [VACS] index). Results Older age was associated with greater microbiome diversity and uniqueness, greater abundance of Akkermansia and Streptococcus, and lower abundance of Prevotella and Faecalibacterium, among others; findings were generally consistent by sex and HIV status. An aging-related microbiome score, generated via combination of 18 age-related genera, significantly increased with age in both women and men independently of demographic, behavioral, and cardiometabolic factors. In general, age was more strongly related to microbiome features (eg, diversity, microbiome score) in men without compared to with HIV, but age-microbiome associations were similar in women with and without HIV. Some age-related genera associated with healthy/unhealthy aging, such as Faecalibacterium (related to reduced frailty) and Streptococcus (related to higher VACS index). Conclusions Age is associated with consistent changes in the gut microbiome in both women and men with or without HIV. Some aging-related microbiota are associated with aging-related declines in health.

This study investigated the cervicovaginal microbiome’s (CVM’s) impact on Chlamydia trachomatis (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the molBV algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM’s contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.

You have accessJournal of UrologyCME1 May 2022MP26-06 PREVALENCE OF KIDNEY STONE DISEASE IN U.S. HISPANIC/LATINO ADULTS: FINDINGS FROM THE HISPANIC COMMUNITY HEALTH STUDY / STUDY OF LATINOS (HCHS/SOL) Marcelino Rivera, Jinsong Chen, Ana Ricardo, Robert Burk, Jianwen Cai, Martha Daviglus, and James Lash Marcelino RiveraMarcelino Rivera More articles by this author , Jinsong ChenJinsong Chen More articles by this author , Ana RicardoAna Ricardo More articles by this author , Robert BurkRobert Burk More articles by this author , Jianwen CaiJianwen Cai More articles by this author , Martha DaviglusMartha Daviglus More articles by this author , and James LashJames Lash More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002569.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There is limited data available regarding the prevalence of kidney stone disease history in U.S. Hispanics/Latinos. The objective of this study is to investigate the prevalence of and risk factors for kidney stones among a diverse population of U.S. Hispanic/Latino adults. METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a community-based cohort of self-identified Hispanic/Latino adults from diverse backgrounds in the U.S. aged 18-74 years at enrollment through a multi-stage probability sampling design. We used data from 10,965 participants who completed a survey on self-reported history of kidney stone disease which was collected at a second study visit (2014-2017). Prevalence estimation accounted for the complex sampling design. Multivariable logistic regression was used to evaluate the association of risk factors with stone disease. RESULTS: The prevalence of kidney stone disease history was 10.6% (95% CI, 9.1%, 12.2%) in men and 7.8% (6.9%, 8.7%) in women. The prevalence varied by Hispanic/Latino background, and was lowest in persons of Mexican background (5.0%, [4.2%, 5.9%]) and highest in persons of Cuban background (16.2 [13.4%, 19.0%]. On multivariable logistic regression analysis, risk factors for prevalent kidney stone disease included older age and male sex (Table). CONCLUSIONS: Kidney stone disease prevalence varied considerably by Hispanic/Latino background. Further investigation is required to determine reasons for these findings, as well as intrinsic and extrinsic causes of stone disease among Hispanic/Latino adults. Source of Funding: The Hispanic Community Health Study / Study of Latinos is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other centers and Institutes of the National Institutes of Health (NIH) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e440 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marcelino Rivera More articles by this author Jinsong Chen More articles by this author Ana Ricardo More articles by this author Robert Burk More articles by this author Jianwen Cai More articles by this author Martha Daviglus More articles by this author James Lash More articles by this author Expand All Advertisement PDF downloadLoading ...