Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine ...dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a prominent, colonization-discriminatory, taxon-specific metabolite. Guided by bioinformatic analyses of biochemically validated TIRs, we find that acute malnutrition is associated with decreased fecal levels of genes encoding TIRs known or predicted to generate v-cADPR-x, as well as decreased levels of the metabolite itself. These results underscore the need to consider microbiome TIR NADases when evaluating NAD metabolism in the human holobiont.
Display omitted
•Phylogenetically diverse human gut bacteria encode TIR-domain-containing proteins•In vitro assays of >150 human gut bacterial TIRs disclose diverse NADase activities•v-cADPR-x-TIR is prominently expressed in vivo by a model human gut microbiome•Microbiome TIR NADase content is altered in children with malnutrition
Weagley et al. characterize NAD metabolic activities of TIR domains in human gut bacterial proteins in vitro and in gnotobiotic mice. They show that TIR representation and activities differ in the developing microbiomes of age-matched healthy Bangladeshi infants and children versus those with malnutrition.
To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced ...bacterial strains cultured from the fecal microbiota of two 24-month-old Bangladeshi children: one healthy and the other underweight. The undernourished donor's bacterial collection contained an enterotoxigenic Bacteroides fragilis strain (ETBF), whereas the healthy donor's bacterial collection contained two nontoxigenic strains of B. fragilis (NTBF). Analyses of mice harboring either the unmanipulated culture collections or systematically manipulated versions revealed that ETBF was causally related to weight loss in the context of its native community but not when introduced into the healthy donor's community. This phenotype was transmissible from the dams to their offspring and was associated with derangements in host energy metabolism manifested by impaired tricarboxylic acid cycle activity and decreased acyl-coenzyme A utilization. NTBF reduced ETBF's expression of its enterotoxin and mitigated the effects of ETBF on the transcriptomes of other healthy donor community members. These results illustrate how intraspecific (ETBF-NTBF) and interspecific interactions influence the effects of harboring B. fragilis.
Chronic exposure to infectious agents results in environmental enteric dysfunction-a significant contributor to childhood stunting. Low plasma tryptophan (TRP), increased kynurenine (KYN), and ...KYN-TRP (KT) ratio are associated with infections and chronic immune activation. We postulated that both these conditions are interlinked, and therefore aimed to identify the association between KT ratio and the linear growth of Bangladeshi children. A total of 480 stunted and at risk of being stunted children aged 12-18 months were enrolled and provided nutrition intervention for 90 days. Plasma samples were assessed using liquid chromatography tandem mass spectrometry to measure TRP and KYN concentrations. Multivariable linear regression with generalized estimating equations was applied to analyze association between the KT ratio and linear growth. Tryptophan, KYN, and KT ratio were significantly higher in stunted children than in children at risk of being stunted both at baseline and at the end of nutrition intervention. Following intervention, the median (interquartile range IQR) KYN concentration was significantly reduced from 4.6 (3.6, 5.4) µmol/L to 3.9 (0.3, 7.6) µmol/L, and median (IQR) KT ratio decreased from 104 (80.9, 131) to 92.8 (6.6, 247) in stunted children. We also found KT ratio to be negatively associated (coefficient = -0.7; 95% CI = -1.13, -0.26; P-value = 0.002) with linear growth. In addition, KYN and KT ratio were positively correlated with fecal neopterin and plasma C-reactive protein, whereas TRP was negatively correlated with both of these biomarkers and alpha-1-acid glycoprotein. Our findings imply that KT ratio is associated in the pathophysiology of stunting as well as with biomarkers of inflammation in Bangladeshi children.
Breastfeeding is known to reduce the risk of enteropathogen infections, but protection from specific enteropathogens is not well characterized.
The aim was to estimate the association between full ...breastfeeding (days fed breast milk exclusively or with nonnutritive liquids) and enteropathogen detection.
A total of 2145 newborns were enrolled at 8 sites, of whom 1712 had breastfeeding and key enteropathogen data through 6 mo. We focused on 11 enteropathogens: adenovirus 40/41, norovirus, sapovirus, astrovirus, and rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter spp., and typical enteropathogenic E. coli as well as entero-aggregative E. coli, Shigella and Cryptosporidium. Logistic regression was used to estimate the risk of enteropathogen detection in stools and survival analysis was used to estimate the timing of first detection of an enteropathogen.
Infants with 10% more days of full breastfeeding within the preceding 30 d of a stool sample were less likely to have the 3 E. coli and Campylobacter spp. detected in their stool (mean odds: 0.92–0.99) but equally likely (0.99–1.02) to have the viral pathogens detected in their stool. A 10% longer period of full breastfeeding from birth was associated with later first detection of the 3 E. coli, Campylobacter, adenovirus, astrovirus, and rotavirus (mean HRs of 0.52–0.75). The hazards declined and point estimates were not statistically significant at 3 mo.
In this large multicenter cohort study, full breastfeeding was associated with lower likelihood of detecting 4 important enteric pathogens in the first 6 mo of life. These results also show that full breastfeeding is related to delays in the first detection of some bacterial and viral pathogens in the stool. As several of these pathogens are risk factors for poor growth during childhood, this work underscores the importance of exclusive or full breastfeeding during the first 6 mo of life to optimize early health.
▪
Studies revealed that silencing of low-density lipoprotein receptor-related protein-1 (LRP1) expression can cause inhibition of adipogenesis in animal model and contribute to reduced body size. But ...there is no study that has explored the association of LRP1 with body mass index (BMI) of human adults. Therefore, the aim of this study was to investigate the relationship of LRP1 with undernutrition.
A total of 270 Bangladeshi slum-dwelling adults were enrolled as case control design. Their socio-economic, demographic, anthropometric and biomedical data were collected. Plasma LRP1, C-reactive protein (CRP), alpha-1 acid glycoprotein (AGP) and ferritin levels were measured by ELISA, haemoglobin by HemoCue and zinc by atomic absorption spectrometry.
The median (IQR) values of plasma LRP1 were 1673.1 (1382.5-1886.2) ng/mL in healthy participants and 707.7 (588.6-839.9) ng/mL in undernourished participants, respectively. A strong positive correlation (r = 0.70, p < 0.05) between LRP1 and BMI was found. Multivariable logistic regression analysis revealed a positive association between low plasma LRP1 (Adj. OR = 0.98, CI = 0.98, 0.99 and p < 0.05) and undernutrition.
The study found that increased level of LRP1 is associated with increased BMI, whereas lower level is associated with low BMI.
PURPOSE: Poor vitamin B12 (B12) status is associated with adverse outcomes in pregnancy and infancy. Little is known about effects of B12 supplementation on immune function. The present study aimed ...to evaluate effects of pre- and postnatal B12 supplementation on biomarkers of B12 status and vaccine-specific responses in mothers and infants. METHOD: In a blinded, placebo-controlled trial, Bangladeshi women (n = 68, age 18–35 years, hemoglobin <110 g/L, 11–14 weeks pregnant) were randomized to receive 250 μg/day B12 or a placebo throughout pregnancy and 3-month postpartum along with 60 mg iron + 400 μg folate. Women were immunized with pandemic influenza A (H1N1) vaccine at 26- to 28-week gestation. Blood from mothers (baseline, 72-h post-delivery, 3-month postpartum), newborns and infants (3-month) was analyzed for hemoglobin, B12, methylmalonic acid (MMA), total homocysteine (tHcy), ferritin and serum transferrin receptor, C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP). Vitamin B12 was also assessed in breast milk. H1N1-specific antibodies were determined in plasma and colostrum/breast milk. RESULTS: At baseline, 26 % women were B12 deficient (<150 pmol/L), 40 % had marginal status (150–220 pmol/L), 43 % had elevated MMA (>271 nmol/L), and 31 % had elevated tHcy (>10 μmol/L). Supplementation increased B12 in plasma, colostrums and breast milk (p < 0.05) and lowered MMA in neonates, mothers and infants at 3 months (p < 0.05). B12 supplementation significantly increased H1N1-specific IgA responses in plasma and colostrums in mothers and reduced proportion of infants with elevated AGP and CRP compared with placebo. CONCLUSION: Supplementation with 250 μg/day B12 during pregnancy and lactation substantially improved maternal, infant and breast milk B12 status. Maternal supplementation improved H1N1 vaccine-specific responses in mothers only and may alleviate inflammatory responses in infants.
Evidence is accumulating that perturbed postnatal development of the gut microbiome contributes to childhood malnutrition
. Here we analyse biospecimens from a randomized, controlled trial of a ...microbiome-directed complementary food (MDCF-2) that produced superior rates of weight gain compared with a calorically more dense conventional ready-to-use supplementary food in 12-18-month-old Bangladeshi children with moderate acute malnutrition
. We reconstructed 1,000 bacterial genomes (metagenome-assembled genomes (MAGs)) from the faecal microbiomes of trial participants, identified 75 MAGs of which the abundances were positively associated with ponderal growth (change in weight-for-length Z score (WLZ)), characterized changes in MAG gene expression as a function of treatment type and WLZ response, and quantified carbohydrate structures in MDCF-2 and faeces. The results reveal that two Prevotella copri MAGs that are positively associated with WLZ are the principal contributors to MDCF-2-induced expression of metabolic pathways involved in utilizing the component glycans of MDCF-2. The predicted specificities of carbohydrate-active enzymes expressed by their polysaccharide-utilization loci are correlated with (1) the in vitro growth of Bangladeshi P. copri strains, possessing varying degrees of polysaccharide-utilization loci and genomic conservation with these MAGs, in defined medium containing different purified glycans representative of those in MDCF-2, and (2) the levels of faecal carbohydrate structures in the trial participants. These associations suggest that identifying bioactive glycan structures in MDCFs metabolized by growth-associated bacterial taxa will help to guide recommendations about their use in children with acute malnutrition and enable the development of additional formulations.
In the clinical setting, small intestinal bacterial overgrowth (SIBO) is a frequent, but under-diagnosed entity. SIBO is linked to various gastrointestinal (GI) and non-GI disorders with potentially ...significant morbidity. The optimal management of SIBO is undefined while there is a lack of published consensus guidelines. Against this background, under the auspices of the Indian Neurogastroenterology and Motility Association (INMA), formerly known as the Indian Motility and Functional Diseases Association (IMFDA), experts from the Asian-Pacific region with extensive research and clinical experience in the field of gut dysbiosis including SIBO developed this evidence-based practice guideline for the management of SIBO utilizing a modified Delphi process based upon 37 consensus statements, involving an electronic voting process as well as face-to-face meetings and review of relevant supporting literature. These statements include 6 statements on definition and epidemiology; 11 on etiopathogenesis and pathophysiology; 5 on clinical manifestations, differential diagnosis, and predictors; and 15 on investigations and treatment. When the proportion of those who voted either to accept completely or with minor reservations was 80% or higher, the statement was regarded as accepted. The members of the consensus team consider that this guideline would be valuable to inform clinical practice, teaching, and research on SIBO in the Asian-Pacific region as well as in other countries.
Reliable and validated tools for measuring appetite of children in South Asia are not available. This study aimed to develop and validate a tool for assessing appetite level of under-five children.
...Based on literature review and findings from focus group discussions (FGDs), an initial 27-item interview-based tool, the “Early Childhood Appetite and Satiety Tool (ECAST)” was developed in Bangladesh. Fourteen FGDs were carried out in rural and urban settings and constructs for inclusion were derived from the themes and coding of FGDs and appetite assessment tools used in Western contexts. For structural validation, the ECAST-27-was administered on 150 mothers/primary caregivers of children aged 6–59 months, living in urban and rural areas. To validate the association with other variables, the ECAST was administered on mothers of children aged 12–24 months in the community (N = 50), and two groups of wasted, hospitalized children (Weight-for-length, Z score <-2SD) group1: twenty acutely ill children aged 6–59 months; group 2: twenty children in nutritional rehabilitation aged 18–24 months. Reliability of ECAST was estimated using Cronbach's alpha and Pearson's correlation coefficient.
Kaiser-Meyer-Olkin = 0.73 and the Bartlett's test of sphericity, χ2(253) = 755.791, p < 0.001 indicated that the raw data were suitable. Given the convergence of the Scree plot, Kaiser's criterion and dropping of cross loading items, a 16-item ECAST was produced with three sub scales: Appetite cue; Food responsiveness and Emotion and preference, which were internally valid and had good test-retest reliability (Cronbach's alpha 0.6 and test-retest reliability 0.797). Total ECAST scores of wasted children with good appetite were significantly higher from those with poor appetite (p = 0.004 and 0.001 for two wasted groups respectively).
Results suggest that ECAST may provide a useful measure to assess the appetite level of under-five children.
PDF
