Bacteria can be genetically engineered to kill specific pathogens or inhibit their virulence. We previously developed a synthetic genetic system that allows a laboratory strain of Escherichia coli to ...sense and kill Pseudomonas aeruginosa in vitro. Here, we generate a modified version of the system, including a gene encoding an anti-biofilm enzyme, and use the probiotic strain Escherichia coli Nissle 1917 as host. The engineered probiotic shows in vivo prophylactic and therapeutic activity against P. aeruginosa during gut infection in two animal models (Caenorhabditis elegans and mice). These findings support the further development of engineered microorganisms with potential prophylactic and therapeutic activities against gut infections.
We examined the associations of gestational diabetes mellitus (GDM) and women's weight status from pre-pregnancy through post-delivery with the risk of developing dysglycaemia impaired fasting ...glucose, impaired glucose tolerance, and type 2 diabetes (T2D) 4-6 years post-delivery. Using Poisson regression with confounder adjustments, we assessed associations of standard categorisations of prospectively ascertained pre-pregnancy overweight and obesity (OWOB), gestational weight gain (GWG) and substantial post-delivery weight retention (PDWR) with post-delivery dysglycaemia (n = 692). Women with GDM had a higher risk of later T2D relative risk (95% CI) 12.07 (4.55, 32.02) and dysglycaemia 3.02 (2.19, 4.16) compared with non-GDM women. Independent of GDM, women with pre-pregnancy OWOB also had a higher risk of post-delivery dysglycaemia. Women with GDM who were OWOB pre-pregnancy and had subsequent PDWR (≥ 5 kg) had 2.38 times (1.29, 4.41) the risk of post-delivery dysglycaemia compared with pre-pregnancy lean GDM women without PDWR. No consistent associations were observed between GWG and later dysglycaemia risk. In conclusion, women with GDM have a higher risk of T2D 4-6 years after the index pregnancy. Pre-pregnancy OWOB and PDWR exacerbate the risk of post-delivery dysglycaemia. Weight management during preconception and post-delivery represent early windows of opportunity for improving long-term health, especially in those with GDM.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Clostridioides difficile
infection (CDI) results in significant morbidity and mortality in hospitalised patients. The pathogenesis of CDI is intrinsically related to the ability of
C. ...difficile
to shuffle between active vegetative cells and dormant endospores through the processes of germination and sporulation. Here, we hypothesise that dysregulation of microbiome-mediated bile salt metabolism contributes to CDI and that its alleviation can limit the pathogenesis of CDI. We engineer a genetic circuit harbouring a genetically encoded sensor, amplifier and actuator in probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis. We demonstrate that the engineered probiotics limited the germination of endospores and the growth of vegetative cells of
C. difficile
in vitro and further significantly reduced CDI in model mice, as evidenced by a 100% survival rate and improved clinical outcomes. Our work presents an antimicrobial strategy that harnesses the host-pathogen microenvironment as the intervention target to limit the pathogenesis of infection.
We found that the relatively simple microbiota of young infants shifts predictably to a more mature anaerobic microbiota during infancy and the dynamics of this shift are influenced by environmental ...factors. In this longitudinal study of 75 infants, we demonstrate high interindividual variability within the normal range of birth outcomes, especially in the rate of microbiota progression. Most had acquired a microbiota profile high in Bifidobacterium and Collinsella by 6 months of age, but the time point of this acquisition was later in infants delivered by caesarean section and those born after a shorter duration of gestation. Independently of the delivery mode and gestation duration, infants who acquired a profile high in Bifidobacterium and Collinsella at a later age had lower adiposity at 18 months of age.
This study shows that the acquisition of the early microbiota is strongly influenced by environmental factors such as the delivery mode and duration of gestation, even in healthy neonates. The composition of the early microbiota has been linked with long-lasting effects on health and disease. Here we show that the rate of acquisition of certain microbiota predicts adiposity at 18 months of age and so potentially the risk of later obesity.
Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly ...characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD 95% CI: -0.7, -0.2), lighter (-0.6 SD -0.9, -0.3) and have lower skinfold thicknesses (e.g. -14% -24%, -3% suprailiac), and blood pressure (-3 mmHg -6, -0.5 systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.
Chemoprevention-the use of medication to prevent cancer-can be augmented by the consumption of produce enriched with natural metabolites. However, chemopreventive metabolites are typically inactive ...and have low bioavailability and poor host absorption. Here, we show that engineered commensal microbes can prevent carcinogenesis and promote the regression of colorectal cancer through a cruciferous vegetable diet. The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates-natural components of cruciferous vegetables-to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.
Dental caries, although preventable, remains one of the most prevalent chronic disease worldwide. Most studies focused on the relationship between sugar intake and caries. However, examining ...multidimensional dietary patterns is becoming increasingly important. Here, we examined the relationship between dietary patterns from ages 6 to 12 months and early childhood caries (ECC) at age 2 to 3-years. Infant dietary data was collected from caregivers and dietary pattern trajectories from 6 to 12 months derived. Oral examinations were carried out by trained calibrated dentists at ages 2 and 3 years. Associations between dietary pattern and ECC were estimated using generalized estimating equation. We found a 3.9 fold lower prevalence of decayed surfaces among children with high Guidelines dietary pattern scores at 6-months (IRR 0.26; CI 0.12-0.53; p-value < 0.001) and 100% reduction of decayed surfaces with increased intakes of Guidelines dietary pattern foods from 6 to 12-month (IRR 2.4 × 10
; CI 4.2 × 10
-0.13; p-value = 0.01). Suggesting that following the Guideline dietary pattern, which corresponds most closely to current World Health Organization weaning guidelines, at 6 months and an increase in pattern score between 6 and 12 months were protective against ECC development compared to Predominantly breastmilk, Easy-to-prepare foods and Noodles (in soup) and seafood dietary patterns.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We aimed to determine the relationship between puberty and growth spurts with peak spherical equivalent (SE) or axial length (AL) velocity in Singapore schoolchildren.
In the Singapore Cohort Study ...of the Risk Factors for Myopia of 1779 schoolchildren, the longitudinal refractive and pubertal status of 892 boys and 887 girls from ages 6 to 14 years were assessed. The study sample included 1329 Chinese, 316 Malays, 114 Indians, and 20 children of other races. Information regarding puberty parameters, age of peak height velocity, age of menarche, and break of voice (BOV) was obtained. Peak velocity was defined as the greatest change in measurements over a period of 1 year. Tanner stage 1 for pubic hair or breast development, in boys and girls, respectively, at age 12 was categorized as "later puberty," whereas stages 2 to 5 corresponded to "earlier puberty." Refractive error was determined by cycloplegic autorefraction using the Canon RK-F5, and AL was measured using the A-scan biometry machine.
The children were examined annually, and the mean number of visits was 5.7 ± 1.3. Age of peak height velocity occurred earlier in girls than in boys (11.0 ± 1.2 vs. 12.0 ± 1.7 years, P < 0.001). Girls with earlier peak height velocity experienced peak AL velocity and peak SE velocity approximately half a year earlier than those with later puberty (mean age of 10.3 ± 1.6 vs. 10.8 ± 1.7 years, P < 0.001; and 10.0 ± 1.5 vs. 10.6 ± 1.25 years, P < 0.001, respectively). Similarly, boys who had earlier peak height velocity also achieved peak AL and peak SE velocity earlier than those who experienced later peak height velocity (mean age of 10.4 ± 1.6 vs. 11.1 ± 1.8 years, P < 0.001; and 10.1 ± 1.5 vs. 10.6 ± 1.7 years, P = 0.01). Both girls and boys who had early peak height velocity had earlier age of onset of myopia than those with later peak height velocity (9.7 ± 1.4 vs. 10.1 ± 1.5 years for girls, P = 0.04; and 9.9 ± 1.5 vs. 10.4 ± 1.6 years for boys, P = 0.03). Myopia progression, in terms of AL velocity, also occurred earlier in boys and girls with earlier peak height velocity (10.2 ± 1.5 vs. 11.0 ± 1.9 for boys, P < 0.001; and 10.2 ± 1.5 vs. 10.7 ± 1.7 for girls, P = 0.004, respectively). The associations were not significant when Tanner staging, age of menarche, or BOV was used to determine stage of puberty.
Boys and girls with earlier peak height velocity experienced earlier peak SE and AL velocity, and age of myopia onset. Thus, variations in the onset and peak progression of myopia may be associated with height spurts.
•Neuroimaging of the caudate in relation to metabolic syndrome score (MetS).•Microstructure at 4.5 and functional activity at 7.5 years correlated with MetS.•Functional activity fully mediates the ...link between microstructure and MetS.•Inhibitory control is not a mediator for caudate functional activity and MetS.
Metabolic syndrome score in children assesses the risk of developing cardiovascular disease in future. We aim to probe the role of the caudate in relation to the metabolic syndrome score. Furthermore, using both functional and structural neuroimaging, we aim to examine the interplay between functional and structural measures.
A longitudinal birth cohort study with functional and structural neuroimaging data obtained at 4.5, 6.0 and 7.5 years and metabolic syndrome scores at 8.0 years was used. Pearson correlation and linear regression was used to test for correlation fractional anisotropy (FA) and fractional amplitude of low frequency fluctuations (fALFF) of the caudate with metabolic syndrome scores. Mediation analysis was used to test if later brain measures mediated the relation between earlier brain measures and metabolic syndrome scores. Inhibitory control was also tested as a mediator of the relation between caudate brain measures and metabolic syndrome scores.
FA at 4.5 years and fALFF at 7.5 years of the left caudate was significantly correlated with metabolic syndrome scores. Post-hoc mediation analysis showed that fALFF at 7.5 years fully mediated the relation between FA at 4.5 years and metabolic syndrome scores. Inhibitory control was significantly correlated with fALFF at 7.5 years, but did not mediate the relation between fALFF at 7.5 years and metabolic syndrome scores.
We found that variations in caudate microstructure at 4.5 years predict later variation in functional activity at 7.5 years. This later variation in functional activity fully mediates the relation between microstructural changes in early childhood and metabolic syndrome scores at 8.0 years.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The Role of Melanocortin 3 Receptor Gene in Childhood Obesity
Yung Seng Lee ,
Larry Kok Seng Poh ,
Betty Lay Kee Kek and
Kah Yin Loke
From the Department of Pediatrics, National University of ...Singapore, and the Children's Medical Institute, National University
Hospital, Singapore
Address correspondence and reprint requests to Dr. Yung Seng Lee, Department of Paediatrics, National University Hospital,
5 Lower Kent Ridge Rd., Singapore 119074. E-mail: paeleeys{at}nus.edu.sg
Abstract
OBJECTIVE— Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear.
The objective of this study was to identify genetic variants of the MC3R gene and determine its association with childhood obesity.
RESEARCH DESIGN AND METHODS— We screened 201 obese children for MC3R gene mutations with anthropometric measurements, blood tests, feeding behavior, and body composition assessment. We identified
three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found
in 188 control subjects, and two common polymorphisms Thr6Lys and Val81Ile.
RESULTS— In vitro functional studies of the resultant mutant receptors revealed impaired signaling activity but normal ligand binding
and cell surface expression. The heterozygotes demonstrated higher leptin levels and adiposity and less hunger compared with
obese control subjects, reminiscent of the MC3R knockout mice. Family studies showed that these mutations may be associated with childhood or early-onset obesity. The common
variants Thr6Lys and Val81Ile were in complete linkage disequilibrium, and in vitro studies revealed reduced signaling activity
compared with wild-type MC3R. Obese subjects with the 6Lys/81Ile haplotype had significantly higher leptin levels, percentage
body fat, and insulin sensitivity, and the causative role of the 6Lys/81Ile variants is supported by the presence of an additive
effect in which heterozygotes had an intermediate phenotype compared with homozygotes.
CONCLUSIONS— MC3R mutations may not result in autosomal dominant forms of obesity but may contribute as a predisposing factor to childhood
obesity and exert an effect on the human phenotype. Our report supports the role of MC3R in human weight regulation.
BIA, bioimpedance analysis
DEXA, dual-energy X-ray absorptiometry
DMEM, Dulbecco's modified Eagle's medium
HOMA, homeostasis model assessment
MC3R, melanocortin 3 receptor
MC4R, melanocortin 4 receptor
MSH, melanocyte-stimulating hormone
NDP, Nle4, D-Phe7
POMC, proopiomelanocortin
QUICKI, quantitative insulin sensitivity check index
TRF, time-resolved fluorometry
WFH, weight for height
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 July 2007. DOI: 10.2337/db07-0225
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 10, 2007.
Received February 16, 2007.
DIABETES
PDF
