Noel T. Mueller

The infant microbiome development: mom matters

The infant microbiome plays an essential role in human health and its assembly is determined by maternal-offspring exchanges of microbiota. This process is affected by several practices, including Cesarean section (C-section), perinatal antibiotics, and formula feeding, that have been linked to increased risks of metabolic and immune diseases. Here we review recent knowledge about the impacts on infant microbiome assembly, discuss preventive and restorative strategies to ameliorate the effects of these impacts, and highlight where research is needed to advance this field and improve the health of future generations.

Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity

Background/Objectives:Cesarean section (CS) and antibiotic use during pregnancy may alter normal maternal-offspring microbiota exchange, thereby contributing to aberrant microbial colonization of the infant gut and increased susceptibility to obesity later in life. We hypothesized that (i) maternal use of antibiotics in the second or third trimester of pregnancy and (ii) CS are independently associated with higher risk of childhood obesity in the offspring.Subjects/Methods:Of the 727 mothers enrolled in the Northern Manhattan Mothers and Children Study, we analyzed the 436 mother–child dyads followed until 7 years of age with complete data. We ascertained prenatal antibiotic use by a questionnaire administered late in the third trimester, and delivery mode by medical record. We derived age- and sex-specific body mass index (BMI) z-scores using the CDC SAS Macro, and defined obesity as BMI z⩾95th percentile. We used binary regression with robust variance and linear regression models adjusted for maternal age, ethnicity, pre-gravid BMI, maternal receipt of public assistance, birth weight, sex, breastfeeding in the first year and gestational antibiotics or delivery mode.Results:Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% (33–154%) higher risk of obesity, after multivariable adjustment. Second or third trimester antibiotic exposure was also positively associated with BMI z-scores, waist circumference and % body fat (all P<0.05). Independent of prenatal antibiotic usage, CS was associated with 46% (8–98%) higher offspring risk of childhood obesity. Associations were similar for elective and non-elective CS.Conclusions:In our cohort, CS and exposure to antibiotics in the second or third trimester were associated with higher offspring risk of childhood obesity. Future studies that address the limitations of our study are warranted to determine if prenatal antibiotic use is associated with offspring obesity. Research is also needed to determine if alterations in neonatal gut microbiota underlie the observed associations.

Age at Menarche and Cardiovascular Disease Mortality in Singaporean Chinese Women: The Singapore Chinese Health Study

PURPOSE To examine whether age at menarche was inversely associated with cardiovascular disease (CVD) mortality in Singaporean Chinese women. METHODS We followed prospectively 34,022 Chinese women aged 45 to 74 at enrollment (1993-1998), with complete data on study variables, through 2009 for primary cause of death from CVD, including coronary heart disease (CHD) and cerebrovascular disease (CERE). Hazard ratios (HRs) for CVD mortality were computed across menarcheal age categories and adjusted for potential confounders and body mass index. RESULTS Over 460,374 person-years of follow-up, 1852 women died from CVD, 998 from CHD and 557 from CERE. There was a significant interaction between age at menarche and smoking (P < .05). In nonsmokers, age at menarche was inversely associated with risk for CVD and CHD mortality. HRs (and 95% confidence interval) for CVD mortality across menarcheal age categories (≤ 12, 13-14, 15-16, ≥ 17) were 1.06 (0.87-1.29), 1 (referent), 0.89 (0.79-1.00), and 0.80 (0.69-0.93), respectively (P(trend) < .001); HRs for CHD mortality were 1.06 (0.80-1.34), 1 (referent), 0.76 (0.65-0.90), and 0.72 (0.58-0.88), respectively (P(trend) < .001). Among nonsmokers, there was no association between age at menarche and CERE mortality. Among smokers, menarcheal age was not associated with CVD, CHD or CERE mortality. CONCLUSIONS Menarcheal age was inversely associated with risk of CVD mortality in nonsmoking Chinese women.

Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil).

Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p<0.0001] but not with fasting glucose concentrations (p = 0.07). Coffee was additionally associated with 2-hour postload insulin [Never/almost never: 287.2 pmol/L, ≤1 time/day: 280.1 pmol/L, 2–3 times/day: 275.3 pmol/L, >3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides further evidence of a protective effect of coffee on risk of adult-onset diabetes. This effect appears to act primarily, if not exclusively, through postprandial, as opposed to fasting, glucose homeostasis.

Higher parity is associated with an increased risk of type‐II diabetes in Chinese women: the Singapore Chinese Health Study

The association between parity and type‐II diabetes has been studied primarily in Western populations, and the findings have been inconsistent. Here, we examine whether parity was positively associated with incident type‐II diabetes in Singaporean Chinese women.

Age at Menarche and Cardiometabolic Risk in Adulthood: The Coronary Artery Risk Development in Young Adults Study

OBJECTIVE To examine the association of menarche timing with cardiometabolic risk factors into early to mid-adulthood, comparing African American and White women. STUDY DESIGN Analyses included 2583 women (African American = 1333; White = 1250) from the Coronary Artery Risk Development in Young Adults cohort study over 25 years of follow-up (1985-2011). Outcomes included type 2 diabetes, metabolic syndrome, adiposity, glucose, insulin, blood pressure, and blood lipids. Cox models or repeated measures linear regression models estimated the association between age at menarche and the outcomes. RESULTS Each 1-year earlier age at menarche was associated with higher mean body mass index among African American (0.88 ± 0.12 kg/m(2), P < .0001) and White (0.89 ± 0.10 kg/m(2), P < .0001) women. After body mass index adjustment, each 1-year earlier age at menarche was associated with higher triglycerides (2.26 ± 0.68 mg/dL, P = .001) and glucose (0.34 ± 0.11 mg/dL, P = .002), and greater risk for incident impaired fasting glucose (hazard ratio = 1.13, 95% CI 1.04-1.20) and metabolic syndrome (hazard ratio 1.19, 95% CI 1.11-1.26) among White women only. CONCLUSIONS Excess adiposity associated with earlier menarche is sustained through mid-adulthood, and primarily drives higher cardiometabolic risk factor levels. However, White women with earlier menarche had increased risk of a number of insulin-resistance related conditions independent of adiposity. The cardiometabolic impact of earlier menarche was weaker in African American women despite higher average adiposity. Weight maintenance would likely reduce but may not completely eliminate the elevated cardiometabolic risk of earlier menarche.

Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche

BACKGROUND Early menarche has been linked to risk of several chronic diseases. Prospective research on whether the intake of soft drinks containing caffeine, a modulator of the female reproductive axis, is associated with risk of early menarche is sparse. OBJECTIVE We examined the hypothesis that consumption of caffeinated soft drinks in childhood is associated with higher risk of early menarche. DESIGN The National Heart, Lung, and Blood Institute Growth and Health Study recruited and enrolled 2379 (1213 African American, 1166 Caucasian) girls aged 9-10 y (from Richmond, CA; Cincinnati, OH; and Washington, DC) and followed them for 10 y. After exclusions were made, there were 1988 girls in whom we examined prospective associations between consumption of caffeinated and noncaffeinated sugar- and artificially sweetened soft drinks and early menarche (defined as menarche age <11 y). We also examined associations between intakes of caffeine, sucrose, fructose, and aspartame and early menarche. RESULTS Incident early menarche occurred in 165 (8.3%) of the girls. After adjustment for confounders and premenarcheal percentage body fat, greater consumption of caffeinated soft drinks was associated with a higher risk of early menarche (RR for 1 serving/d increment: 1.47; 95% CI: 1.22, 1.79). Consumption of artificially sweetened soft drinks was also positively associated with risk of early menarche (RR for 1 serving/d increment: 1.43; 95% CI: 1.08, 1.88). Consumption of noncaffeinated soft drinks was not significantly associated with early menarche (RR for 1 serving/d increment: 0.88; 95% CI: 0.62, 1.25); nor was consumption of sugar-sweetened soft drinks (RR for 1 serving/d increment: 1.15; 95% CI: 0.95, 1.39). Consistent with the beverage findings, intakes of caffeine (RR for 1-SD increment: 1.22; 95% CI: 1.08, 1.37) and aspartame (RR for 1-SD increment: 1.20; 95% CI: 1.10, 1.31) were positively associated with risk of early menarche. CONCLUSION Consumption of caffeinated and artificially sweetened soft drinks was positively associated with risk of early menarche in a US cohort of African American and Caucasian girls.

Adiposity indices in the prediction of insulin resistance in prepubertal Colombian children

OBJECTIVE To compare BMI with abdominal skinfold thickness (ASF), waist circumference and waist-to-height ratio in the prediction of insulin resistance (IR) in prepubertal Colombian children. DESIGN We calculated age- and sex-specific Z-scores for BMI, ASF, waist circumference, waist-to-height ratio and three other skinfold-thickness sites. Logistic regression with stepwise selection (P = 0·80 for entry and P = 0·05 for retention) was performed to identify predictors of IR and extreme IR, which were determined by age- and sex-specific Z-scores to identify the ≥ 90th and ≥ 95th percentile of homeostasis model assessment (HOMAIR), respectively. We used receiver operating characteristic curves to compare the area under the curve between models. SETTING Bucaramanga, Colombia. SUBJECTS Children (n 1261) aged 6-10 years in Tanner stage 1 from a population-based study. RESULTS A total of 127 children (seventy girls and fifty-seven boys) were classified with IR, including sixty-three children (thirty-three girls and thirty boys) classified with extreme IR. Only ASF and BMI Z-scores were retained as predictors of IR by stepwise selection. Adding ASF Z-score to BMI Z-score improved the area under the curve from 0·794 (95 % CI 0·752, 0·837) to 0·811 (95 % CI 0·770, 0·851; P for contrast = 0·01). In predicting extreme IR, the addition of ASF Z-score to BMI Z-score improved the area under the curve from 0·837 (95 % CI 0·790, 0·884) to 0·864 (95 % CI 0·823, 0·905; P for contrast = 0·01). CONCLUSIONS ASF Z-score predicted IR independent of BMI Z-score in our population of prepubertal children. ASF and BMI Z-scores together improved IR risk stratification compared with BMI Z-score alone, opening new perspectives in the prediction of cardiometabolic risk in prepubertal children.

Asthma and the risk of type 2 diabetes in the Singapore Chinese Health Study

AIM Asthma is believed to increase the risk for several proinflammatory diseases, yet epidemiologic studies on asthma in relation to risk of developing type 2 diabetes are sparse and have reported inconsistent results. In the present study, we investigated the hypothesis that asthma is associated with an increased risk of incident type 2 diabetes in Chinese adults. METHODS We used data from the Singapore Chinese Health Study, including Chinese men and women aged 45-74 years, free of cancer, heart disease, stroke, and diabetes at baseline (1993-1998) and followed through 2004 for incident physician-diagnosed diabetes. Cox regression models were used to examine the associations between self-reported history of physician-diagnosed asthma and risk of diabetes. RESULTS During an average follow-up of 5.7 years per person, 2234 of the 42,842 participants included in the current analyses reported diagnoses of type 2 diabetes. After adjustment for potential confounders, not including body mass index (BMI), asthma was associated with a 31% increased risk of incident diabetes (HR=1.31; 95% CI: 1.00-1.72). The association was attenuated after adjustment for adult BMI (HR=1.25; 95% CI: 0.95-1.64). The asthma-diabetes association appeared stronger for adult- vs. child-diagnosed asthma cases, and for participants who were obese compared to non-obese. CONCLUSIONS In Singaporean Chinese adults we observed a positive association between self-reported, physician-diagnosed asthma and risk of developing type 2 diabetes that was modestly attenuated by adjustment for BMI.

Cesarean delivery and metabolic risk factors in young adults: a Brazilian birth cohort study

BACKGROUND Cesarean delivery (CD) perturbs the assembly of the neonatal gut microbiome and has been associated with child and adult obesity. However, it is still unknown whether CD is associated with metabolic risk factors in young adults. OBJECTIVE We investigated the association of CD and metabolic risk factors in young adults in a cohort study who were 23-25 y of age at follow-up. DESIGN We used data from a cohort study in Ribeirão Preto, Brazil. Baseline data on 6827 singleton pregnancies were collected in 1978-1979, and a sample of 2063 subjects were followed up 23-25 y later (2002-2004). Information on the type of delivery, birth weight, maternal age, parity, maternal schooling, and maternal smoking was obtained after birth. Anthropometric data, biochemical measurements, and information on participant schooling and smoking history were collected at 23-25 y of age. A linear regression was performed to assess the association between CD and biochemical measurements in early adulthood, controlling for a minimum set of confounders that were identified in a directed acyclic graph. RESULTS The mean ± SD age of the subjects was 23.9 ± 0.71 y, and 51.8% of the sample were women. The CD rate was 32.0% and was more common in older (P < 0.001) and more educated mothers (P < 0.001). Compared with vaginal delivery, CD was associated with higher body mass index (BMI) after multivariable adjustment (P < 0.001) but not with glucose, homeostasis model assessment of insulin resistance, the quantitative insulin-sensitivity check index, total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides (all P > 0.05). CONCLUSION In our sample of Brazilian adults, CD was associated with higher BMI but not with other metabolic risk factors.