Faculty Bibliography

Soil-transmitted helminths colonize more than 1.5 billion people worldwide, yet little is known about how they interact with bacterial communities in the gut microbiota. Differences in the gut microbiota between individuals living in developed and developing countries may be partly due to the presence of helminths, since they predominantly infect individuals from developing countries, such as the indigenous communities in Malaysia we examine in this work. We compared the composition and diversity of bacterial communities from the fecal microbiota of 51 people from two villages in Malaysia, of which 36 (70.6%) were infected by helminths. The 16S rRNA V4 region was sequenced at an average of nineteen thousand sequences per samples. Helminth-colonized individuals had greater species richness and number of observed OTUs with enrichment of Paraprevotellaceae, especially with Trichuris infection. We developed a new approach of combining centered log-ratio (clr) transformation for OTU relative abundances with sparse Partial Least Squares Discriminant Analysis (sPLS-DA) to enable more robust predictions of OTU interrelationships. These results suggest that helminths may have an impact on the diversity, bacterial community structure and function of the gut microbiota.

Objectives:To assess associations of caesarean section with body mass from birth through adolescence.Design:Longitudinal birth cohort study, following subjects up to 15 years of age.Setting and participants:Children born in 1991-1992 in Avon, UK who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=10 219).Outcome measures:Primary outcome: standardized measures of body mass (weight-for length z-scores at 6 weeks, 10 and 20 months; and body mass index (BMI) z-scores at 38 months, 7, 9, 11 and 15 years). Secondary outcome: categorical overweight or obese (BMI >/=85th percentile) for age and gender, at 38 months, 7, 9, 11 and 15 years.Results:Of the 10 219 children, 926 (9.06%) were delivered by caesarean section. Those born by caesarean had lower-birth weights than those born vaginally (-46.1 g, 95% confidence interval(CI): 14.6-77.6 g; P=0.004). In mixed multivariable models adjusting for birth weight, gender, parental body mass, family sociodemographics, gestational factors and infant feeding patterns, caesarean delivery was consistently associated with increased adiposity, starting at 6 weeks (+0.11 s.d. units, 95% CI: 0.03-0.18; P=0.005), through age 15 (BMI z-score increment+0.10 s.d. units, 95% CI: 0.001-0.198; P=0.042). By age 11 caesarean-delivered children had 1.83 times the odds of overweight or obesity (95% CI: 1.24-2.70; P=0.002). When the sample was stratified by maternal pre-pregnancy weight, the association among children born of overweight/obese mothers was strong and long-lasting. In contrast, evidence of an association among children born of normal-weight mothers was weak.Conclusion:Caesarean delivery is associated with increased body mass in childhood and adolescence. Research is needed to further characterize the association in children of normal weight women. Additional work is also needed to understand the mechanism underlying the association, which may involve relatively enduring changes in the intestinal microbiome.International Journal of Obesity advance online publication, 14 May 2013; doi:10.1038/ijo.2013.49.

Diet, host gene composition, and alterations in the intestinal microbiota can contribute to obesity. In microbe-induced obesity, metabolic changes stem from primary perturbation of the microbiota, consequent to modern changes in human biology. Microbiota disruption during early development can result in syndromes of metabolic dysfunction. We focus on the pathways involved in these interactions, particularly related to energy extraction and the role of inflammation in the metabolic phenotypes. Model physiologic systems and perturbations including gastric bypass surgery, pregnancy, and hibernation provide insight into the respective roles of the critical participants.

Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited. To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high-fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low-fat diet (LFD). Compared to control treatment, both LFD and HPMC reduced weight gain (11.8 and 5.7 g, respectively), plasma cholesterol (23.1 and 19.6%), and liver triglycerides (73.1 and 44.6%), and, as revealed by 454-pyrosequencing of the microbial 16S rRNA gene, decreased microbial alpha-diversity and differentially altered intestinal microbiota. Both LFD and HPMC increased intestinal Erysipelotrichaceae (7.3- and 12.4-fold) and decreased Lachnospiraceae (2.0- and 2.7-fold), while only HPMC increased Peptostreptococcaceae (3.4-fold) and decreased Ruminococcaceae (2.7-fold). Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations. This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism.

Objectives:To examine the associations of antibiotic exposures during the first 2 years of life and the development of body mass over the first 7 years of life.Design:Longitudinal birth cohort study.Subjects:A total of 11 532 children born at >/=2500 g in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based study of children born in Avon, UK in 1991-1992.Measurements:Exposures to antibiotics during three different early-life time windows (<6 months, 6-14 months, 15-23 months), and indices of body mass at five time points (6 weeks, 10 months, 20 months, 38 months and 7 years).Results:Antibiotic exposure during the earliest time window (<6 months) was consistently associated with increased body mass (+0.105 and +0.083 s.d. unit, increase in weight-for-length Z-scores at 10 and 20 months, P<0.001 and P=0.001, respectively; body mass index (BMI) Z-score at 38 months +0.067 s.d. units, P=0.009; overweight OR 1.22 at 38 months, P=0.029) in multivariable, mixed-effect models controlling for known social and behavioral obesity risk factors. Exposure from 6 to 14 months showed no association with body mass, while exposure from 15 to 23 months was significantly associated with increased BMI Z-score at 7 years (+0.049 s.d. units, P=0.050). Exposures to non-antibiotic medications were not associated with body mass.Conclusions:Exposure to antibiotics during the first 6 months of life is associated with consistent increases in body mass from 10 to 38 months. Exposures later in infancy (6-14 months, 15-23 months) are not consistently associated with increased body mass. Although effects of early exposures are modest at the individual level, they could have substantial consequences for population health. Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and define life-course implications for body mass and cardiovascular risks.

Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.

Background. When compared with Mycobacterium tuberculosis, individuals that live in the same household as an active case of smear-positive pulmonary tuberculosis exposed to M. africanum progress less frequently to active disease within 2 years. A putative ESX-1 secretion apparatus member, Rv3879c, is mutated in M. africanum, and individuals infected with M. africanum less frequently demonstrate T-cell responses to the ESX-1-secreted virulence factor ESAT-6 than those infected with M. tuberculosis. We hypothesized that less frequent progression is caused by impaired secretion of ESAT-6. Methods. We analyzed in vivo growth and in vitro secretion of ESAT-6 and CFP-10, comparing M. tuberculosis to M. africanum and a strain of M. africanum complemented with M. tuberculosis Rv3879c. Results. ESAT-6 and CFP-10 secretion were similar for all strains, although these were enriched in M. africanum cell lysates, suggesting a modest ESX-1 secretion defect unrelated to the Rv3879c mutation. In mice, M. africanum demonstrated smaller bacterial population sizes than M. tuberculosis but similar numbers and frequencies of ESAT-6-responsive T cells in the lungs. Conclusions. These results confirm impaired fitness of M. africanum in vivo and indicate that Rv3879c is not required for secretion of ESAT-6 or for its presentation as an antigen to T cells in vivo.