BACKGROUND More than 30 million children worldwide suffer from moderate acute malnutrition (MAM). Current treatments have limited effectiveness and much remains unknown about pathogenesis. Children with MAM exhibit perturbed development of their gut microbiota. METHODS Slum-dwelling Bangladeshi children, aged 12 to 18 months, with moderate acute malnutrition (n=124) received a microbiota-directed complementary food (MDCF-2) or an existing ready-to-use supplementary food (RUSF), twice daily for three months followed by a 1-month period of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age Z-scores and mid-upper arm circumference at baseline and fortnightly, through four months. We compared the rate of change of these related phenotypes between baseline and three months, and between baseline and four months. We also measured levels of 4,977 proteins in plasma plus 209 bacterial taxa in fecal samples. RESULTS 118 children completed the intervention (n=59/arm). The rate of change in weight-for-length Z-score (β-WLZ), weight-for-age Z-score, and mid upper arm circumference is consistent with a benefit of MDCF-2 on growth over the course of the study including the one-month follow-up. Receipt of MDCF-2 was linked to the magnitude of change in levels of 70 β-WLZ-positively correlated plasma proteins including mediators of bone growth, neurodevelopment and inflammation (gene set enrichment analysis [GSEA];p<0.001) and the abundances of 23 WLZ-associated bacterial taxa (GSEA;p<0.001). CONCLUSIONS These findings provide support for further clinical investigation of MDCF-2 as a dietary supplement for young children with MAM and provide insight into mechanisms by which this targeted manipulation of microbiota components may be linked to growth. (Supported by the Bill and Melinda Gates Foundation and the NIH; ClinicalTrials.gov identifier: NCT04015999 )
BACKGROUND Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of EED, its pathophysiology, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota). METHODS Slum-dwelling Bangladeshi children aged 18±2 months, with linear growth-faltering (stunting) who failed a nutritional intervention underwent endoscopy to obtain duodenal biopsies and aspirates. Levels of 4077 plasma proteins and 2619 duodenal proteins were quantified in 80 children with histopathologic evidence of EED, and the abundances of bacterial strains in their duodenal microbiota were determined using culture-independent methods. Young germ-free mice, fed a Bangladeshi diet, were colonized with bacterial strains cultured from the duodenal aspirates. RESULTS The absolute abundances of a shared group of 14 bacterial strains recovered from the duodenums of children with EED and not typically classified as enteropathogens were negatively correlated with linear growth (length-for-age Z-score;β=-0.38±0.12(SEM);ρ=-0.49;p=0.003), and positively correlated with duodenal proteins involved in immunoinflammatory responses. Representation of these 14 duodenal taxa was significantly different in fecal microbiota from EED versus healthy children (p<0.001;PERMANOVA). Gnotobiotic mice colonized with cultured EED-donor duodenal strains develop a small intestinal enteropathy. CONCLUSIONS These results provide evidence of a causal relationship between components of the small intestinal microbiota, enteropathy and stunting and offer a rationale for developing therapeutics that target what must no longer remain terra incognita-the small intestinal microbiota. ClinicalTrials.gov identifier: NCT02812615
Disrupted development of the gut microbiota is a contributing cause of childhood malnutrition. Bifidobacterium longum subspecies infantis is a prominent early colonizer of the infant gut that consumes human milk oligosaccharides (HMOs). We found that the absolute abundance of Bifidobacterium infantis is lower in 3- to 24-month-old Bangladeshi infants with severe acute malnutrition (SAM) compared to their healthy age-matched counterparts. A single-blind, placebo-controlled trial (SYNERGIE) was conducted in 2- to 6-month-old Bangladeshi infants with SAM. A commercial U.S. donor–derived B. infantis strain (EVC001) was administered daily with or without the HMO lacto- N -neotetraose for 28 days. This intervention increased fecal B. infantis abundance in infants with SAM, although to levels still 10- to 100-fold lower than in untreated healthy controls. EVC001 treatment promoted weight gain that was associated with reduced intestinal inflammation markers in infants with SAM. We cultured fecal B. infantis strains from Bangladeshi infants and colonized gnotobiotic mice with these cultured strains. The gnotobiotic mice were fed a diet representative of that consumed by 6-month-old Bangladeshi infants, with or without HMO supplementation. One B. infantis strain, Bg_2D9, expressing two gene clusters involved in uptake and utilization of N -glycans and plant-derived polysaccharides, exhibited superior fitness over EVC001. The fitness advantage of Bg_2D9 was confirmed in a gnotobiotic mouse model of mother-to-infant gut microbiota transmission where dams received a pretreatment fecal community from a SAM infant in the SYNERGIE trial. Whether Bg_2D9 is superior to EVC001 for treating malnourished infants who consume a diet with limited breastmilk requires further clinical testing.
BackgroundMany epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association.MethodsWe used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer subtypes.ResultsA total of 14,778 article citations were identified, of which 80 met inclusion criteria. Pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types.ConclusionsSome children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy.
The study objective was to estimate the prevalence of selected sexually transmitted infections (STIs) and associated factors among Dhaka slum dwellers. Blood and urine specimens were collected from 1534 men and women. Participants in this cross-sectional study responded to a questionnaire, providing socioeconomic data, symptomatology and treatment-seeking behaviour. Specimens were tested for syphilis, hepatitis B (HBsAg), Neisseria gonorrhoeae, Chlamydia trachomatis, and HIV. Serologic evidence of syphilis infection was found in 6.0% of respondents, HBsAg in 3.8%. Prevalence rates of gonorrhoea and chlamydia were 1.7% and <1%, respectively. No HIV infections were found. Men were more than twice as likely as women to be infected with syphilis or HBsAg carriers. Behaviours facilitating STI transmission were common among men. Syphilis infection is prevalent enough to warrant the initiation of screening programmes in this population. The prevalence rate of hepatitis B carriage suggests that this population would benefit from universal vaccination against hepatitis B.
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