Akkermansia muciniphila modifies the association between metal exposure during pregnancy and depressive symptoms in late childhood.

Emerging research suggests that exposures to metals during pregnancy and gut microbiome (GM) disruptions are associated with depressive disorders in childhood. Akkermansia muciniphila, a GM bacteria, has been studied for its potential antidepressant effects. However, its role in the influence of prenatal metal exposures on depressive symptoms during childhood is unknown. Leveraging a well-characterized pediatric longitudinal birth cohort and its microbiome substudy (n=112) and using a state-of-the-art machine-learning model, we investigated whether the presence of A.muciniphila in GM of 9-11-year-olds modifies the associations between exposure to a specific group of metals (or metal-clique) during pregnancy and concurrent childhood depressive symptoms. Among children with no A.muciniphila, a metal-clique of Zinc-Chromium-Cobalt was strongly associated with increased depression score (P<0.0001), whereas, for children with A.muciniphila, this same metal-clique was weakly associated with decreased depression score(P<0.4). Our analysis provides the first exploratory evidence hypothesizing A. muciniphila as a probiotic intervention attenuating the effect of prenatal metal-exposures-associated depressive disorders in late childhood.

Prenatal metal exposures and childhood gut microbial signatures are associated with depression score in late childhood.

BACKGROUND: Childhood depression is a major public health issue worldwide. Previous studies have linked both prenatal metal exposures and the gut microbiome to depression in children. However, few, if any, have studied their interacting effect in specific subgroups of children. OBJECTIVES: Using an interpretable machine-learning method, this study investigates whether children with specific combinations of prenatal metals and childhood microbial signatures (cliques or groups of metals and microbes) were more likely to have higher depression scores at 9-11 years of age. METHODS: We leveraged data from a well-characterized pediatric longitudinal birth cohort in Mexico City and its microbiome substudy (n = 112). Eleven metal exposures were measured in maternal whole blood samples in the second and third trimesters of pregnancy. The gut microbial abundances were measured at 9-11-year-olds using shotgun metagenomic sequencing. Depression symptoms were assessed using the Child Depression Index (CDI) t-scores at 9-11 years of age. We used Microbial and Chemical Exposure Analysis (MiCxA), which combines interpretable machine-learning into a regression framework to identify and estimate joint associations of metal-microbial cliques in specific subgroups. Analyses were adjusted for relevant covariates. RESULTS: We identified a subgroup of children (11.6 % of the sample) characterized by a four-component metal-microbial clique that had a significantly high depression score (15.4 % higher than the rest) in late childhood. This metal-microbial clique consisted of high Zinc in the second trimester, low Cobalt in the third trimester, a high abundance of Bacteroides fragilis, a high abundance of Faecalibacterium prausnitzii. All combinations of cliques (two-, three-, and four-components) were significantly associated with increased log-transformed t-scored CDI (ß = 0.14, 95%CI = [0.05,0.23], P < 0.01 for the four-component clique). SIGNIFICANCE: This study offers a new approach to chemical-microbial analysis and a novel demonstration that children with specific gut microbiome cliques and metal exposures during pregnancy may have a higher likelihood of elevated depression scores.

Prenatal Lead Exposure Is Associated with Reduced Abundance of Beneficial Gut Microbial Cliques in Late Childhood: An Investigation Using Microbial Co-Occurrence Analysis (MiCA).

Many analytical methods used in gut microbiome research focus on either single bacterial taxa or the whole microbiome, ignoring multibacteria relationships (microbial cliques). We present a novel analytical approach to identify microbial cliques within the gut microbiome of children at 9-11 years associated with prenatal lead (Pb) exposure. Data came from a subset of participants (n = 123) in the Programming Research in Obesity, Growth, Environment and Social Stressors cohort. Pb concentrations were measured in maternal whole blood from the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the gut microbiome. Using a novel analytical approach, Microbial Co-occurrence Analysis (MiCA), we paired a machine learning algorithm with randomization-based inference to first identify microbial cliques that were predictive of prenatal Pb exposure and then estimate the association between prenatal Pb exposure and microbial clique abundance. With second-trimester Pb exposure, we identified a two-taxa microbial clique that included Bifidobacterium adolescentis and Ruminococcus callidus and a three-taxa clique that also included Prevotella clara. Increasing second-trimester Pb exposure was associated with significantly increased odds of having the two-taxa microbial clique below the median relative abundance (odds ratio (OR) = 1.03, 95% confidence interval (CI) [1.01-1.05]). Using a novel combination of machine learning and causal inference, MiCA identified a significant association between second-trimester Pb exposure and the reduced abundance of a probiotic microbial clique within the gut microbiome in late childhood.

Neighborhood socioeconomic status is associated with low diversity gut microbiomes and multi-drug resistant microorganism colonization.

Social disparities continue to limit universal access to health care, directly impacting both lifespan and quality of life. Concomitantly, the gut microbiome has been associated with downstream health outcomes including the global rise in antibiotic resistance. However, limited evidence exists examining socioeconomic status (SES) associations with gut microbiome composition. To address this, we collected information on the community-level SES, gut microbiota, and other individual cofactors including colonization by multidrug-resistant organisms (MDROs) in an adult cohort from Wisconsin, USA. We found an association between SES and microbial composition that is mediated by food insecurity. Additionally, we observed a higher prevalence of MDROs isolated from individuals with low diversity microbiomes and low neighborhood SES. Our integrated population-based study considers how the interplay of several social and economic factors combine to influence gut microbial composition while providing a framework for developing future interventions to help mitigate the SES health gap.

Prenatal lead exposure is negatively associated with the gut microbiome in childhood.

Background: Metal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood. Objectives: This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Methods: Data come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders. Results: Of the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6 (SE = 2.1) ug/L and 34.9 (SE = 2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2Tß = -0.17, 95%CI = [-0.46,0.11]; 3Tß = -0.17, 95%CI = [-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure. Discussion: Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

The interconnection between obesity and executive function in adolescence: The role of the gut microbiome.

In the United States, adolescent obesity is a growing epidemic associated with maladaptive executive functioning. Likewise, data link the microbiome to obesity. Emerging microbiome research has demonstrated an interconnection between the gut microbiome and the brain, indicating a bidirectional communication system within the gut-microbiome-brain axis in the pathophysiology of obesity. This narrative review identifies and summarizes relevant research connecting adolescent obesity as it relates to three core domains of executive functioning and the contribution of the gut microbiome in the relationship between obesity and executive functions in adolescence. The review suggests that (1) the interconnection between obesity, executive function, and the gut microbiome is a bidirectional connection, and (2) the gut microbiome may mediate the neurobiological pathways between obesity and executive function deficits. The findings of this review provide valuable insights into obesity-associated executive function deficits and elucidate the possible mediation role of the gut microbiome.

Prenatal Lead Exposure is Negatively Associated with the Gut Microbiome in Childhood.

Background: Metal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood. Objectives: This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Methods: Data come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders. Results: Of the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6(SE=2.1) ug/L and 34.9(SE=2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2Tß=-0.17,95%CI=[-0.46,0.11]; 3Tß=-0.17,95%CI=[-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure. Discussion: Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

Individual Nutrition Is Associated with Altered Gut Microbiome Composition for Adults with Food Insecurity.

Diet is widely recognized as a key contributor to human gut microbiome composition and function. However, overall nutrition can be difficult to compare across a population with varying diets. Moreover, the role of food security in the relationship with overall nutrition and the gut microbiome is unclear. This study aims to investigate the association between personalized nutrition scores, variation in the adult gut microbiome, and modification by food insecurity. The data originate from the Survey of the Health of Wisconsin and the Wisconsin Microbiome Study. Individual nutrition scores were assessed using My Nutrition Index (MNI), calculated using data from food frequency questionnaires, and additional health history and demographic surveys. Food security and covariate data were measured through self-reported questionnaires. The gut microbiome was assessed using 16S amplicon sequencing of DNA extracted from stool samples. Associations, adjusted for confounding and interaction by food security, were estimated using Weighted Quantile Sum (WQS) regression models with Random Subset and Repeated Holdout extensions (WQSRSRH), with bacterial taxa used as components in the weighted index. Of 643 participants, the average MNI was 66.5 (SD = 31.9), and 22.8% of participants were food insecure. Increased MNI was significantly associated with altered gut microbial composition (ß = 2.56, 95% CI = 0.52−4.61), with Ruminococcus, Oscillospira, and Blautia among the most heavily weighted of the 21 genera associated with the MNI score. In the stratified interaction WQSRSRH models, the bacterial taxa most heavily weighted in the association with MNI differed by food security, but the level of association between MNI and the gut microbiome was not significantly different. More bacterial genera are important in the association with higher nutrition scores for people with food insecurity versus food security, including Streptococcus, Parabacteroides Faecalibacterium, and Desulfovibrio. Individual nutrition scores are associated with differences in adult gut microbiome composition. The bacterial taxa most associated with nutrition vary by level of food security. While further investigation is needed, results showed a higher nutrition score was associated with a wider range of bacterial taxa for food insecure vs. secure, suggesting nutritional quality in food insecure individuals is important in maintaining health and reducing disparities.

Human Microbiome Mixture Analysis Using Weighted Quantile Sum Regression.

Studies of the health effects of the microbiome often measure overall associations by using diversity metrics, and individual taxa associations in separate analyses, but do not consider the correlated relationships between taxa in the microbiome. In this study, we applied random subset weighted quantile sum regression with repeated holdouts (WQSRSRH), a mixture method successfully applied to 'omic data to account for relationships between many predictors, to processed amplicon sequencing data from the Human Microbiome Project. We simulated a binary variable associated with 20 operational taxonomic units (OTUs). WQSRSRH was used to test for the association between the microbiome and the simulated variable, adjusted for sex, and sensitivity and specificity were calculated. The WQSRSRH method was also compared to other standard methods for microbiome analysis. The method was further illustrated using real data from the Growth and Obesity Cohort in Chile to assess the association between the gut microbiome and body mass index. In the analysis with simulated data, WQSRSRH predicted the correct directionality of association between the microbiome and the simulated variable, with an average sensitivity and specificity of 75% and 70%, respectively, in identifying the 20 associated OTUs. WQSRSRH performed better than all other comparison methods. In the illustration analysis of the gut microbiome and obesity, the WQSRSRH analysis identified an inverse association between body mass index and the gut microbe mixture, identifying Bacteroides, Clostridium, Prevotella, and Ruminococcus as important genera in the negative association. The application of WQSRSRH to the microbiome allows for analysis of the mixture effect of all the taxa in the microbiome, while simultaneously identifying the most important to the mixture, and allowing for covariate adjustment. It outperformed other methods when using simulated data, and in analysis with real data found results consistent with other study findings.

Urinary lead level and colonization by antibiotic resistant bacteria: Evidence from a population-based study.

BACKGROUND: Infection by antibiotic resistant bacteria (ARB) is a global health crisis and asymptomatic colonization increases risk of infection. Nonhuman studies have linked heavy metal exposure to the selection of ARB; however, few epidemiologic studies have examined this relationship. This study analyzes the association between urinary lead level and colonization by ARB in a nonclinical human population. METHODS: Data came from the Survey of the Health of Wisconsin 2016-2017, and its ancillary Wisconsin Microbiome Study. Urinary lead levels, adjusted for creatinine, were used to assess exposure. ARB included methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), fluoroquinolone resistant Gram-negative bacilli (RGNB), and Clostridium difficile (C. diff), from skin, nose, and mouth swabs, and saliva and stool samples. Logistic regression, adjusted for covariates, was used to evaluate associations between Pb and ARB. Secondary analysis investigated Pb resistance from ARB isolates. RESULTS: Among 695 participants, 239 (34%) tested positive for ARB. Geometric mean urinary Pb (unadjusted) was 0.286 µg/L (95% confidence intervals [CI] = 0.263, 0.312) for ARB negative participants and 0.323 µg/L (95% CI = 0.287, 0.363) for ARB positive participants. Models adjusted for demographics, diet, and antibiotic use showed elevated odds of positive colonization for those in the 95th percentile (vs. below) of Pb exposure (odds ratio [OR] = 2.05, 95% CI = 0.95, 4.44), and associations were highest in urban residents (OR = 2.85, 95% CI = 1.07, 7.59). RGNB isolates were most resistant to Pb. DISCUSSION: These novel results suggest that Pb exposure is associated with increased colonization by ARB, and that RGNB are particularly resistant to Pb.

Lead exposure and serum metabolite profiles in pregnant women in Mexico City.

BACKGROUND: Lead (Pb) exposure is a global health hazard causing a wide range of adverse health outcomes. Yet, the mechanisms of Pb toxicology remain incompletely understood, especially during pregnancy. To uncover biological pathways impacted by Pb exposure, this study investigated serum metabolomic profiles during the third trimester of pregnancy that are associated with blood Pb and bone Pb. METHODS: We used data and specimens from 99 women enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors birth cohort in Mexico City. Maternal Pb exposure was measured in whole blood samples from the third trimester of pregnancy and in the tibia and patella bones at 1 month postpartum. Third-trimester serum samples underwent metabolomic analysis; metabolites were identified based on matching to an in-house analytical standard library. A metabolome-wide association study was performed using multiple linear regression models. Class- and pathway-based enrichment analyses were also conducted. RESULTS: The median (interquartile range) blood Pb concentration was 2.9 (2.6) µg/dL. Median bone Pb, measured in the tibia and patella, were 2.5 (7.3) µg/g and 3.6 (9.5) µg/g, respectively. Of 215 total metabolites identified in serum, 31 were associated with blood Pb (p < 0.05). Class enrichment analysis identified significant overrepresentation of metabolites classified as fatty acids and conjugates, amino acids and peptides, and purines. Tibia and patella Pb were associated with 14 and 8 metabolites, respectively (p < 0.05). Comparing results from bone and blood Pb, glycochenodeoxycholic acid, glycocholic acid, and 1-arachidonoylglycerol were positively associated with blood Pb and tibia Pb, and 7-methylguanine was negatively associated with blood Pb and patella Pb. One metabolite, 5-aminopentanoic acid, was negatively associated with all three Pb measures. CONCLUSIONS: This study identified serum metabolites in pregnant women associated with Pb measured in blood and bone. These findings provide insights on the metabolic profile around Pb exposure in pregnancy and information to guide mechanistic studies of toxicological effects for mothers and children.

Fetal and early postnatal lead exposure measured in teeth associates with infant gut microbiota.

BACKGROUND: Lead (Pb) is an environmentally ubiquitous heavy metal associated with a wide range of adverse health effects in children. Both lead exposure and the early life microbiome- which plays a critical role in human development-have been linked to similar health outcomes, but it is unclear if the adverse effects of lead are partially driven by early life gut microbiota dysbiosis. The objective of this study was to examine the association between in utero and postnatal lead levels (measured in deciduous baby teeth) and early life bacterial and fungal gut microbiota in the first year of life. METHODS: Data from the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort were analyzed. Tooth lead levels during the 2nd and 3rd trimesters and postnatally (<1 year of age) were quantified using high-resolution microspatial mapping of dentin growth rings. Early life microbiota were measured in stool samples collected at approximately 1 and 6 months of age, using both 16S rRNA (bacterial) and ITS2 (fungal) sequencing. Of the 1,258 maternal-child pairs in WHEALS, 146 had data on both tooth metals and early life microbiome. RESULTS: In utero tooth lead levels were significantly associated with gut fungal community composition at 1-month of age, where higher levels of 2nd trimester tooth lead was associated with lower abundances of Candida and Aspergillus and higher abundances of Malassezia and Saccharomyces; 3rd trimester lead was also associated with lower abundances of Candida. Though lead did not significantly associate with the overall structure of the infant gut bacterial community, it associated with the abundance of some specific bacterial taxa, including the increased abundance of Collinsella and Bilophila and a decreased abundance of Bacteroides taxa. CONCLUSIONS: The observed associations between lead exposure and infant gut microbiota could play a role in the impact of lead on childhood development. Given the paucity of research examining these associations in humans-particularly for fungal microbiota-further investigation is needed.

Exposure to environmental chemical mixtures is associated with nasal colonization by Staphylococcus aureus: NHANES 2001-2004.

BACKGROUND: Understanding the health effects of exposure to chemical mixtures is critically important given the broad range of concurrent exposures throughout the life-course. While investigations of environmental chemicals and components of the human microbiome are becoming more common, few have examined associations with chemical mixtures. This study assesses the association between exposure to mixtures of 66 different environmental chemicals and nasal colonization of Staphylococcus aureus (SA) and methicillin resistant SA (MRSA). METHODS: Data came from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. The analytical sample consists of 10,312 participants, age 6 years and older, subdivided into 8 groups with different chemical exposure mixtures. Within each of 6 chemical classes (metals, phthalates, polycyclic aromatic hydrocarbons (PAHs), polybrominated diphenyl ethers (PBDEs), polyfluorochemicals (PFCs), and phenols), weighted quantile sum (WQS) regression was used to analyze the joint association of the component compounds and nasal SA colonization. WQS was also used to assess the joint association of 3 chemical mixtures (metals, metal and PAHs, and metal and triclosan) and nasal MRSA colonization. All regression models were adjusted for confounders. RESULTS: The analytical sample was between ages 6-85, slightly more female, and predominantly non-smokers. Prevalence of SA carriage was 29.2%, and MRSA colonization prevalence was 1.2%. Within each chemical class, odds of SA colonization increased statistically significantly with exposure to mixtures of metals (OR = 1.11, 95% CI = 1.02-1.20), phthalates (OR = 1.09, 95% CI = 1.04-1.14), and phenols (OR = 1.08, 95% CI = 1.01-1.15). Exposure to a mixture of metals combined with PAHs was also associated with increased odds of MRSA carriage (OR = 1.38, 95% CI = 1.02-1.86). CONCLUSION: Results indicate an association between multiple environmental chemical mixtures and SA colonization, including MRSA. These findings support the need for further analysis of associations between chemical mixtures and SA colonization, as well as other components of the human microbiome.

Bicycling Rates and the Prevalence of Bicycle Helmet Usage in Wisconsin.

INTRODUCTION: Bicycles are a source of transportation, recreation, and exercise throughout the world. Bicycling is associated with both health and environmental benefits but also poses a risk of injury. The use of bicycle helmets has been shown to reduce morbidity and mortality associated with cycling. It is unknown if helmet use differs across Wisconsin geographic areas and sociodemographic groups. METHODS: Data were obtained from the Survey of the Health of Wisconsin (SHOW). Bicycle use and helmet use frequency were determined from a self-administered questionnaire that contained questions specific to preventative health behaviors. Descriptive statistics summarized overall bicycle ridership. Chi-square and Student t tests were performed to assess relationships between bicycle and helmet use across geographic categories and sociodemographic groups. RESULTS: Differences between sex, race or ethnicity, and education level were found to be associated with bicycle ridership and the frequency of helmet use. Men were significantly more likely to report riding a bicycle and never wearing a helmet. Individuals from urban communities reported always wearing a helmet more often than rural communities. Higher education levels were associated with higher levels of bicycle and helmet use. Race or ethnicity was not associated with bicycle ridership but was associated with differences in helmet use frequency. CONCLUSION: Nearly half of those who ride bicycles in Wisconsin report never wearing a helmet. Since bicycle ridership and helmet use were found to be associated with a number of sociodemographic characteristics, any solution should consider the role of equity when attempting to increase ridership or helmet use.

Urinary lead concentration and composition of the adult gut microbiota in a cross-sectional population-based sample.

BACKGROUND: Lead (Pb) is a ubiquitous environmental contaminant with an array of detrimental health effects in children and adults, including neurological and immune dysfunction. Emerging evidence suggests that Pb exposure may alter the composition of the gut microbiota, however few studies have examined this association in human populations. The purpose of this study was to examine the association between urinary Pb concentration and the composition of the adult gut microbiota in a population-based sample of adults. METHODS: Data used in this study were collected as part of the Survey of the Health of Wisconsin (SHOW) and its ancillary microbiome study. The SHOW is a household-based health examination survey of Wisconsin residents, collecting a variety of survey data on health determinants and outcomes, as well as objective measurements of body habitus, and biological specimens including urine. The ancillary microbiome study added additional questions and biological specimen collection, including stool, from participants age 18+. Pb concentration was analyzed in urine samples, and gut microbiota composition was assessed using DNA sequencing of the 16S rRNA V4 region, extracted from stool samples. Data processing and statistical analyses were performed in mothur, Python, R, and SAS. RESULTS: Of 696 participants, urinary Pb concentration was highest in those age 70+, females, those with a high school diploma or lower, current and former smokers, and those without indoor pets. In adjusted models, increasing urinary Pb levels were associated with increases in microbial α-diversity (p = 0.071) and richness (p = 0.005). Differences in microbial ß-diversity were significantly associated (p = 0.003) with differences in urinary Pb level. Presence of Proteobacteria, including members of the Burkholderiales, was significantly associated with increased urinary Pb. CONCLUSION: These results suggest that Pb exposure is associated with differences in the composition of the adult gut microbiota in a population-based human sample. Further investigation of this association is warranted.

Wisconsin microbiome study, a cross-sectional investigation of dietary fibre, microbiome composition and antibiotic-resistant organisms: rationale and methods.

INTRODUCTION: Prevention of multidrug-resistant organism (MDRO) infections, such as those caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, fluoroquinolone-resistant Gram-negative bacteria and Clostridium difficile is crucial. Evidence suggests that dietary fibre increases gut microbial diversity, which may help prevent colonisation and subsequent infection by MDROs. The aim of the Winning the War on Antibiotic Resistance (WARRIOR) project is to examine associations of dietary fibre consumption with the composition of the gut microbiota and gut colonisation by MDROs. The secondary purpose of the study is to create a biorepository of multiple body site specimens for future microbiota research. METHODS AND ANALYSIS: The WARRIOR project collects biological specimens, including nasal, oral and skin swabs and saliva and stool samples, along with extensive data on diet and MDRO risk factors, as an ancillary study of the Survey of the Health of Wisconsin (SHOW). The SHOW is a population-based health survey collecting data on several different health determinants and outcomes, as well as objective body measurements and biological specimens. WARRIOR participants include 600 randomly selected Wisconsin residents age 18 and over. Specimens are screened for MDRO colonisation and DNA is extracted for 16S ribosomal RNA-based microbiota sequencing. Data will be analysed to assess the relationship between dietary fibre, the gut microbiota composition and gut MDRO colonisation. ETHICS AND DISSEMINATION: The WARRIOR project is approved by the University of Wisconsin Institutional Review Board. The main results of this study will be published in a peer-reviewed scientific journal.

Effect of Lactobacillus rhamnosus HN001 on carriage of Staphylococcus aureus: results of the impact of probiotics for reducing infections in veterans (IMPROVE) study.

BACKGROUND: Infection by Staphylococcus aureus (S. aureus) is a major cause of morbidity and mortality. Colonization by S. aureus increases the risk of infection. Little is known about decolonization strategies for S. aureus beyond antibiotics, however probiotics represent a promising alternative. A randomized controlled trial was conducted to determine the efficacy of Lactobacillus rhamnosus (L. rhamnosus) HN001 in reducing carriage of S. aureus at multiple body sites. METHODS: One hundred thirteen subjects, positive for S. aureus carriage, were recruited from the William S. Middleton Memorial Medical Center, Madison, WI, USA, and randomized by initial site of colonization, either gastrointestinal (GI) or extra-GI, to 4-weeks of oral L. rhamnosus HN001 probiotic, or placebo. Nasal, oropharyngeal, and axillary/groin swabs were obtained, and serial blood and fecal samples were collected. Differences in prevalence of S. aureus carriage at the end of the 4-weeks of treatment were assessed. RESULTS: The probiotic and placebo groups were similar in age, gender, and health history at baseline. S. aureus colonization within the stool samples of the extra-GI group was 15% lower in the probiotic than placebo group at the endpoint of the trial. Those in the probiotic group compared to the placebo group had 73% reduced odds (OR 0.27, 95% CI 0.07-0.98) of methicillin-susceptible S. aureus presence, and 83% reduced odds (OR 0.17, 95% CI 0.04-0.73) of any S. aureus presence in the stool sample at endpoint. CONCLUSION: Use of daily oral L. rhamnosus HN001 reduced odds of carriage of S. aureus in the GI tract, however it did not eradicate S. aureus from other body sites. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01321606 . Registered March 21, 2011.

Heavy metal exposure and nasal Staphylococcus aureus colonization: analysis of the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Heavy metals including lead and cadmium can disrupt the immune system and the human microbiota. and are increasingly of concern with respect to the propogation of antibiotic-resistence. Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of global morbidity and mortality. Heavy metal exposure may be associated with increased MRSA colonization and infection, and a decrease in methicillin-susceptible Staphylococcus aureus (MSSA) through co-selection mechanisms and natural selection of antibiotic resistance in the presence of heavy metals. This study examines the association between blood lead (Pb) and cadmium (Cd) level, and MRSA and MSSA nasal colonization. METHODS: All data used for this analysis came from the 2001-2004 National Health and Nutrition Examination Survey (NHANES). The analytical sample consisted of 18,626 participants aged 1 year and older. Multivariate logistic regression, including adjustment for demographic and dietary factors, was used to analyze the association between blood Pb and Cd, and nasal colonization by MRSA and MSSA. RESULTS: Prevalence of MRSA and MSSA carriage were 1.2%, and 29.3% respectively. MRSA was highest in women, individuals age 70 and older, who self-identified as black, had only a high school diploma, lived below 200% of the Federal Poverty Level, and had a history of smoking. While not significantly different from those colonized with MSSA, geometric mean blood Pb (1.74 µg/dL) and blood Cd (0.31 µg/L) were highest in those colonized with MRSA. Associations with MRSA colonization appeared to increase in a dose-dependent manner with increasing quartile of blood Pb level. Blood Cd level in the fourth quartile was also significantly associated with lower odds of MRSA colonization. Both metals were associated with lower odds of MSSA colonization. CONCLUSIONS: Both MRSA and MSSA results suggest that general population levels of blood Pb but not Cd are associated with differences in nasal carriage of S. aureus. While further research is needed, reduction in heavy metal exposures such as lead, concurrently with maintaining a healthy microbiota may be two modifiable options to consider in the fight against antibiotic-resistance.

Risk factors for infection with multidrug-resistant organisms in Haryana, India.

BACKGROUND: The objective of this study was to investigate risk factors for multidrug-resistant organism (MDRO) infection within patients from a tertiary care hospital in Northern India. This case-control study examined MDRO infection risk factors, including diet, health history, and medical device use. We administered a diet questionnaire to collect data on usual diet and collected data on other risk factors from chart review. All participants were inpatients identified through hospital microbiology reports. A total of 39 MDRO patient cases and 91 controls were included. METHODS: Descriptive statistics, univariate analysis, and multivariate logistic regression were performed to evaluate the association between risk factors and MDRO infection. RESULTS: All cases had gram-negative MDRO infections. Univariate analyses found length of hospital stay, connective tissue disease, hospitalization in the last 12 months, hospitalization of a family member, in-hospital antibiotic use, antibiotic use in the last 12 months, and feeding tube, central venous line, and urinary catheter use to be significantly different between cases and controls. Logistic regression showed a >3-fold increase in the odds of infection with antibiotic use in the last 12 months (odds ratio [OR], 3.30; 95% confidence interval [CI], 1.22-8.91) and urinary catheter use (OR, 3.63; 95% CI, 1.14-11.58). Differences in dietary preferences and fruit, vegetable, and fiber consumption were not significantly associated with infection. CONCLUSIONS: Antibiotic use is a major driver of MDRO infections. Our findings suggest that interventions optimizing antibiotic stewardship and reducing device use should be a priority to prevent MDRO infections.

Impact of Probiotics for Reducing Infections in Veterans (IMPROVE): Study protocol for a double-blind, randomized controlled trial to reduce carriage of Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus (S. aureus) is an organism of great public health importance, causing 20,000 deaths annually. Decolonization of patients with S. aureus may prevent infections, yet current options are limited to antimicrobials that promote antibiotic resistance and can cause adverse side effects. Probiotics have potential to reduce colonization of pathogenic bacteria, representing a promising alternative for S. aureus decolonization, but thus far lack rigorous evaluation. METHODS: Potential subjects were recruited from inpatient and outpatient settings within a VA medical center and screened for S. aureus gastrointestinal (GI) or extra-GI colonization using swabs at multiple body sites. Positive, eligible, consenting participants were stratified by colonization site and randomized in a 1:1 ratio to 4-weeks of daily placebo or Lactobacillus rhamnosus (L. rhamnosus) HN001 probiotic treatment. Blood and stool samples, and treatment adherence reports were collected from each subject throughout the study, along with a final set of swabs at study completion to detect S. aureus carriage. The outcomes of this study are GI or extra-GI carriage by S. aureus at the end of 4weeks of therapy, change in phagocytic activity of polymorphonuclear cells from pre-intervention to post-intervention, and symptomatic S. aureus infection at any site during the study period. CONCLUSION: 114 participants have been recruited for this study. Analysis of outcomes is underway. This is the first clinical trial to examine the efficacy of L. rhamnosus HN001 for decolonization of S. aureus, and investigates the mechanism by which L. rhamnosus HN001 mediates its effect on S. aureus colonization. ClinicalTrials.govIdentifier NCT01321606.