Uncovering the complexity of childhood undernutrition through strain-level analysis of the gut microbiome.

BACKGROUND: Undernutrition (UN) is a critical public health issue that threatens the lives of children under five in developing countries. While evidence indicates the crucial role of the gut microbiome (GM) in UN pathogenesis, the strain-level inspection and bacterial co-occurrence network investigation in the GM of UN children are lacking. RESULTS: This study examines the strain compositions of the GM in 61 undernutrition patients (UN group) and 36 healthy children (HC group) and explores the topological features of GM co-occurrence networks using a complex network strategy. The strain-level annotation reveals that the differentially enriched species between the UN and HC groups are due to discriminated strain compositions. For example, Prevotella copri is mainly composed of P. copri ASM1680343v1 and P. copri ASM345920v1 in the HC group, but it is composed of P. copri ASM346549v1 and P. copri ASM347465v1 in the UN group. In addition, the UN-risk model constructed at the strain level demonstrates higher accuracy (AUC = 0.810) than that at the species level (AUC = 0.743). With complex network analysis, we further discovered that the UN group had a more complex GM co-occurrence network, with more hub bacteria and a higher clustering coefficient but lower information transfer efficiencies. Moreover, the results at the strain level suggested the inaccurate and even false conclusions obtained from species level analysis. CONCLUSIONS: Overall, this study highlights the importance of examining the GM at the strain level and investigating bacterial co-occurrence networks to advance our knowledge of UN pathogenesis.

Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition.

Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting.

Do tribal children experience elevated risk of poor nutritional status in India? A multilevel analysis.

Economic progress in India over the past three decades has not been accompanied by a commensurate improvement in the nutritional status of children, and a disproportionate burden of undernutrition is still focused on socioeconomically disadvantaged populations in the poorest regions. This study examined the nutritional status of children under 3 years of age using data from the fourth round of Indian National Family Health Survey conducted in 2015-2016. Child undernutrition was assessed in a sample of 126,431 under-3 children using the anthropometric indices of stunting, underweight and wasting ('anthropometric failure') across 640 districts, 5489 primary sampling units and 35 states/UTs of India. Descriptive statistics were used to examine the regional pattern of childhood undernutrition. Multilevel logistic regression models were fitted to examine the adjusted effect of social group (tribal vs non-tribal) and economic, demographic and contextual factors on the risks of stunting, underweight and wasting accounting for the hierarchical nature of the data. Interaction effects were estimated to model the joint effects of socioeconomic position (household wealth, maternal education, urban/rural residence and geographical region) and social group (tribal vs non-tribal) with the likelihood of anthropometric failure among children. The burden of childhood undernutrition was found to vary starkly across social, economic, demographic and contextual factors. Interaction effects demonstrated that tribal children from economically poorer households, with less-educated mothers, residing in rural areas and living in the Central region of India had elevated odds of anthropometric deprivation than other tribal children. The one-size-fits-all approach to tackling undernutrition in tribal children may not be efficient and could be counterproductive.

Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation.

BACKGROUND: Environmental Enteropathy (EE), characterized by alterations in intestinal structure, function, and immune activation, is believed to be an important contributor to childhood undernutrition and its associated morbidities, including stunting. Half of all global deaths in children < 5 years are attributable to under-nutrition, making the study of EE an area of critical priority. METHODS: Community based intervention study, divided into two sub-studies, 1) Longitudinal analyses and 2) Biopsy studies for identification of EE features via omics analyses. Birth cohorts in Matiari, Pakistan established: moderately or severely malnourished (weight for height Z score (WHZ) < - 2) children, and well-nourished (WHZ > 0) children. Blood, urine, and fecal samples, for evaluation of potential biomarkers, will be collected at various time points from all participants (longitudinal analyses). Participants will receive appropriate educational and nutritional interventions; non-responders will undergo further evaluation to determine eligibility for further workup, including upper gastrointestinal endoscopy. Histopathological changes in duodenal biopsies will be compared with duodenal biopsies obtained from USA controls who have celiac disease, Crohn's disease, or who were found to have normal histopathology. RNA-Seq will be employed to characterize mucosal gene expression across groups. Duodenal biopsies, luminal aspirates from the duodenum, and fecal samples will be analyzed to define microbial community composition (omic analyses). The relationship between histopathology, mucosal gene expression, and community configuration will be assessed using a variety of bioinformatic tools to gain better understanding of disease pathogenesis and to identify mechanism-based biomarkers. Ethical review committees at all collaborating institutions have approved this study. All results will be made available to the scientific community. DISCUSSION: Operational and ethical constraints for safely obtaining intestinal biopsies from children in resource-poor settings have led to a paucity of human tissue-based investigations to understand and reverse EE in vulnerable populations. Furthermore, EE biomarkers have rarely been correlated with gold standard histopathological confirmation. The Study of Environmental Enteropathy and Malnutrition (SEEM) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology and accelerate progress towards the 2030 Sustainable Development Goals. TRIAL REGISTRATION: Retrospectively registered; clinicaltrials.gov ID NCT03588013 .

Role of parental education in reduction of prevalence of childhood undernutrition in Bangladesh.

OBJECTIVE: Despite progress, levels of malnutrition among children in Bangladesh are among the highest in the world and this is one of the major causes of death in children. The pace of reduction in the prevalence of undernutrition among children is still relatively low. The present study aimed to examine the association between parental education and childhood undernutrition among Bangladeshi children under 5 years of age when adjusting for potential risk factors. DESIGN: The data set was extracted from a nationally representative survey based on a cross-sectional study, the Bangladesh Demographic and Health Survey (BDHS) 2014. SETTING: The base survey was conducted using a two-stage stratified sample of households. In the first stage, 600 enumeration areas (EA) were selected with probability proportional to EA size (207 EA from urban areas, 393 EA from rural areas). SUBJECTS: A total of 7173 children under 5 years from 17 863 households were considered for the analysis. A modified Poisson regression model was implemented to the data for assessing the relationship between parental education and childhood undernutrition when demographic and socio-economic covariates for the child, parents, households and clustering were adjusted. RESULTS: Higher parental education level was associated with lower levels of stunting and underweight, but not with wasting. Maternal and paternal education were both significantly associated with the reduction in prevalence of childhood undernutrition in Bangladesh. CONCLUSIONS: Paternal education appears equally as important as maternal education in reducing undernutrition prevalence among children under 5 years in Bangladesh.

Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development.

The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2-3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this "microbial organ" and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain's default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children. Furthermore, we postulate that understanding the interrelationships between microbiota and brain metabolism in childhood undernutrition could provide insights about responses to injury seen in adults. We discuss approaches that can be used to test these hypotheses, their ramifications for optimizing nutritional recommendations that promote healthy brain development and function, and the potential societal implications of this area of investigation.

Systematic review of current efforts to quantify the impacts of climate change on undernutrition.

Malnutrition is a challenge to the health and productivity of populations and is viewed as one of the five largest adverse health impacts of climate change. Nonetheless, systematic evidence quantifying these impacts is currently limited. Our aim was to assess the scientific evidence base for the impact of climate change on childhood undernutrition (particularly stunting) in subsistence farmers in low- and middle-income countries. A systematic review was conducted to identify peer-reviewed and gray full-text documents in English with no limits for year of publication or study design. Fifteen manuscripts were reviewed. Few studies use primary data to investigate the proportion of stunting that can be attributed to climate/weather variability. Although scattered and limited, current evidence suggests a significant but variable link between weather variables, e.g., rainfall, extreme weather events (floods/droughts), seasonality, and temperature, and childhood stunting at the household level (12 of 15 studies, 80%). In addition, we note that agricultural, socioeconomic, and demographic factors at the household and individual levels also play substantial roles in mediating the nutritional impacts. Comparable interdisciplinary studies based on primary data at a household level are urgently required to guide effective adaptation, particularly for rural subsistence farmers. Systemization of data collection at the global level is indispensable and urgent. We need to assimilate data from long-term, high-quality agricultural, environmental, socioeconomic, health, and demographic surveillance systems and develop robust statistical methods to establish and validate causal links, quantify impacts, and make reliable predictions that can guide evidence-based health interventions in the future.

Time-constrained mother and expanding market: emerging model of under-nutrition in India.

BACKGROUND: Persistent high levels of under-nutrition in India despite economic growth continue to challenge political leadership and policy makers at the highest level. The present inductive enquiry was conducted to map the perceptions of mothers and other key stakeholders, to identify emerging drivers of childhood under-nutrition. METHODS: We conducted a multi-centric qualitative investigation in six empowered action group states of India. The study sample included 509 in-depth interviews with mothers of undernourished and normal nourished children, policy makers, district level managers, implementer and facilitators. Sixty six focus group discussions and 72 non-formal interactions were conducted in two rounds with primary caretakers of undernourished children, Anganwadi Workers and Auxiliary Nurse Midwives. RESULTS: Based on the perceptions of the mothers and other key stakeholders, a model evolved inductively showing core themes as drivers of under-nutrition. The most forceful emerging themes were: multitasking, time constrained mother with dwindling family support; fragile food security or seasonal food paucity; child targeted market with wide availability and consumption of ready-to-eat market food items; rising non-food expenditure, in the context of rising food prices; inadequate and inappropriate feeding; delayed recognition of under-nutrition and delayed care seeking; and inadequate responsiveness of health care system and Integrated Child Development Services (ICDS). The study emphasized that the persistence of child malnutrition in India is also tied closely to the high workload and consequent time constraint of mothers who are increasingly pursuing income generating activities and enrolled in paid labour force, without robust institutional support for childcare. CONCLUSION: The emerging framework needs to be further tested through mixed and multiple method research approaches to quantify the contribution of time limitation of the mother on the current burden of child under-nutrition.

A shared group of bacterial taxa in the duodenal microbiota of undernourished Pakistani children with environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length Z-score [WLZ]) failed to improve after a 2-month nutritional intervention underwent esophagogastroduodenoscopy (EGD). Paired duodenal luminal aspirates and duodenal mucosal biopsies were obtained from 43 children. Duodenal microbiota composition was characterized by sequencing bacterial 16S rRNA gene amplicons. Levels of bacterial taxa (amplicon sequence variants [ASVs]) were referenced to anthropometric indices, histopathologic severity in biopsies, expression of selected genes in the duodenal mucosa, and fecal levels of an immunoinflammatory biomarker (lipocalin-2). A "core" group of eight bacterial ASVs was present in the duodenal samples of 69% of participants. Streptococcus anginosus was the most prevalent, followed by Streptococcus sp., Gemella haemolysans, Streptococcus australis, Granulicatella elegans, Granulicatella adiacens, and Abiotrophia defectiva. At the time of EGD, none of the core taxa were significantly correlated with WLZ. Statistically significant correlations were documented between the abundances of Granulicatella elegans and Granulicatella adiacens and the expression of duodenal mucosal genes involved in immune responses (dual oxidase maturation factor 2, serum amyloid A, and granzyme H). These results suggest that a potential role for members of the oral microbiota in pathogenesis, notably Streptococcus, Gemella, and Granulicatella species, warrants further investigation.IMPORTANCEUndernutrition among women and children is a pressing global health problem. Environmental enteric dysfunction (EED) is a disease of the small intestine (SI) associated with impaired gut mucosal barrier function and reduced capacity for nutrient absorption. The cause of EED is ill-defined. One emerging hypothesis is that alterations in the SI microbiota contribute to EED. We performed a culture-independent analysis of the SI microbiota of a cohort of Pakistani children with undernutrition who had failed a standard nutritional intervention, underwent upper gastrointestinal tract endoscopy, and had histologic evidence of EED in their duodenal mucosal biopsies. The results revealed a shared group of bacterial taxa in their duodenums whose absolute abundances were correlated with levels of the expression of genes in the duodenal mucosa that are involved in inflammatory responses. A number of these bacterial taxa are more typically found in the oral microbiota, a finding that has potential physiologic and therapeutic implications.

Development and Acceptability of Shelf-Stable Microbiota Directed Complementary Food Formulations.

BACKGROUND: A randomized controlled trial in Bangladeshi children aged 12 to 18 months with moderate acute malnutrition found that dietary supplementation with the microbiota-directed complementary food (MDCF-2) significantly improved weight gain and repaired gut microbiota compared to the ready-to-use supplementary food. However, the MDCF-2 formulation was made daily from locally available ingredients and the need for a packaged, nutritionally compliant, and organoleptically acceptable MDCF-2 prototype was essential for future large-scale clinical studies. OBJECTIVE: The study aimed to develop and assess the acceptability of 3 alternative foil-packaged formulations of MDCF-2 in comparison to current MDCF-2. METHODS: Of the 3 packaged formulations, the Jumpstart version was provided in 2 sachets, the other 2 formulations were provided in a retort-stable foil pouch extended by sterilization, and microbiological growth was monitored over 10 months. The acceptability study included 40 children aged 8 to 12 months living in an urban slum in Dhaka, and the organoleptic properties were assessed using a 7-point hedonic scale. RESULTS: In the 100 g distributed over the 2 sessions, children consumed 82.5 ± 7.84 g (mean ± SD) of kitchen-prepared MDCF-2, 85.4 ± 7.15 g of the "Jumpstart" MDCF-2 formulation, 85.4 ± 8.70 g of the MDCF-2 with green banana powder, and 86.2 ± 4.26 g of the MDCF-2 with sweet potato formulation. The "Jumpstart" MDCF-2 and MDCF-2 with sweet potato achieved the highest overall acceptability scores on the hedonic scale; although none of the shelf-stable formulations were significantly different from the kitchen-prepared MDCF-2. CONCLUSIONS: Packaged, shelf-stable prototypes of MDCF-2 exhibited comparable acceptability among Bangladeshi children aged 8 to 12 months to the original freshly prepared formulation.

Plain language titleDevelopment and Acceptability of Shelf-Stable Microbiota-Directed Complementary FoodsPlain language summaryCountries around the world are making progress in fighting malnutrition, but it may be challenging to achieve the global nutrition targets for undernourished children by 2025 at the current rate. To address this problem, we need special types of food that can help children grow, develop properly, and sustain their growth. Children with moderate acute malnutrition have imbalanced gut bacteria. By providing them with the right nutrition, we can restore the healthy bacteria in their gut using a special food called microbiota-directed complementary food (MDCF). Currently, this food is made daily in the icddr, b established field kitchen, which follows standard production measures to control the quality of MDCF preparation, but we need to create stable prototypes that can be stored and used in different settings. This study was designed to develop shelf-stable new formulations in industrial settings and check their acceptability among children with moderate acute malnutrition. The shelf life of the food was extended using a sterilization method, and its microbiological safety was monitored for a year. The actual consumption and acceptability of these foods were evaluated and all these formulations were acceptable by the children and their mother. The children consumed all 4 food formulations in substantial quantities, with consumption rates exceeding 80% for each formulation. This study showed positive results in Bangladesh, but more research is needed to see if these formulations work well in other geographies and over longer periods.

Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition.

BACKGROUND: Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor health outcomes, and mothers who experience growth stunting in childhood are more likely to give birth to stunted children later in life. Based on these findings, we hypothesized that intergenerational colonization of mice with microbiota from human donors with undernutrition may recapitulate certain immune and growth changes observed in this disorder. RESULTS: To test this hypothesis, we developed a gnotobiotic murine model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational colonization with microbiota derived from children with growth stunting lead to less linear growth and the development of immune features of undernutrition and enteropathy, including intestinal villus blunting, lower liver IGF-1 and accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning lead to fewer host phenotypic changes between these distinct microbial communities. CONCLUSIONS: These results are broadly consistent with previous findings demonstrating that exposure of the immune system to microbial products during the weaning phase is a critical determinant of later life immune function. Overall, our results suggest intergenerational colonization with human microbiota samples is a useful approach with which to investigate microbiota-dependent changes in growth and immunity in early life. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Video Abstract.

A microbiota-directed complementary food intervention in 12-18-month-old Bangladeshi children improves linear growth.

BACKGROUND: Globally, stunting affects ∼150 million children under five, while wasting affects nearly 50 million. Current interventions have had limited effectiveness in ameliorating long-term sequelae of undernutrition including stunting, cognitive deficits and immune dysfunction. Disrupted development of the gut microbiota has been linked to the pathogenesis of undernutrition, providing potentially new treatment approaches. METHODS: 124 Bangladeshi children with moderate acute malnutrition (MAM) enrolled (at 12-18 months) in a previously reported 3-month RCT of a microbiota-directed complementary food (MDCF-2) were followed for two years. Weight and length were monitored by anthropometry, the abundances of bacterial strains were assessed by quantifying metagenome-assembled genomes (MAGs) in serially collected fecal samples and levels of growth-associated proteins were measured in plasma. FINDINGS: Children who had received MDCF-2 were significantly less stunted during follow-up than those who received a standard ready-to-use supplementary food (RUSF) [linear mixed-effects model, ßtreatment group x study week (95% CI) = 0.002 (0.001, 0.003); P = 0.004]. They also had elevated fecal abundances of Agathobacter faecis, Blautia massiliensis, Lachnospira and Dialister, plus increased levels of a group of 37 plasma proteins (linear model; FDR-adjusted P < 0.1), including IGF-1, neurotrophin receptor NTRK2 and multiple proteins linked to musculoskeletal and CNS development, that persisted for 6-months post-intervention. INTERPRETATION: MDCF-2 treatment of Bangladeshi children with MAM, which produced significant improvements in wasting during intervention, also reduced stunting during follow-up. These results suggest that the effectiveness of supplementary foods for undernutrition may be improved by including ingredients that sponsor healthy microbiota-host co-development. FUNDING: This work was supported by the BMGF (Grants OPP1134649/INV-000247).

Globally elevated levels of histone H3 lysine 9 trimethylation in early infancy are associated with poor growth trajectory in Bangladeshi children.

BACKGROUND: Stunting is a global health problem affecting hundreds of millions of children worldwide and contributing to 45% of deaths in children under the age of five. Current therapeutic interventions have limited efficacy. Understanding the epigenetic changes underlying stunting will elucidate molecular mechanisms and likely lead to new therapies. RESULTS: We profiled the repressive mark histone H3 lysine 9 trimethylation (H3K9me3) genome-wide in peripheral blood mononuclear cells (PBMCs) from 18-week-old infants (n = 15) and mothers (n = 14) enrolled in the PROVIDE study established in an urban slum in Bangladesh. We associated H3K9me3 levels within individual loci as well as genome-wide with anthropometric measurements and other biomarkers of stunting and performed functional annotation of differentially affected regions. Despite the relatively small number of samples from this vulnerable population, we observed globally elevated H3K9me3 levels were associated with poor linear growth between birth and one year of age. A large proportion of the differentially methylated genes code for proteins targeting viral mRNA and highly significant regions were enriched in transposon elements with potential regulatory roles in immune system activation and cytokine production. Maternal data show a similar trend with child's anthropometry; however, these trends lack statistical significance to infer an intergenerational relationship. CONCLUSIONS: We speculate that high H3K9me3 levels may result in poor linear growth by repressing genes involved in immune system activation. Importantly, changes to H3K9me3 were detectable before the overt manifestation of stunting and therefore may be valuable as new biomarkers of stunting.

Changes in Retinol Binding Protein 4 Level in Undernourished Children After a Nutrition Intervention Are Positively Associated With Mother's Weight but Negatively With Mother's Height, Intake of Whole Milk, and Markers of Systemic Inflammation: Results From a Community-Based Intervention Study.

BACKGROUND: The changes of plasma retinol binding protein 4 (RBP4) level after a nutrition intervention can indicate the metabolic changes associated with the delivered intervention. OBJECTIVE: We investigated the changes in plasma RBP4 level among 12- to 18-month-old children after a nutrition intervention and measured its association with subcutaneous adiposity, maternal characteristics, and inflammation. METHODS: Data of 520 undernourished children (250 of them had length-for-age Z score [LAZ] <-1 to -2 and 270 had LAZ score <-2) were collected from the Bangladesh Environmental Enteric Dysfunction study conducted in Dhaka, Bangladesh. Multivariable linear regression and generalized estimation equations (GEE) modeling techniques were used to measure the association. RESULTS: At baseline, median RBP4 level was 19.9 mg/L (interquartile range [IQR]: 7.96), and at the end of the intervention, it was 20.6 mg/L (IQR: 9.06). Percentage changes in plasma RBP4 level were not significantly associated (P > .05) with the percentage changes in child's height, weight, and subcutaneous adiposity. But maternal height (regression coefficient, ß = -1.62, P = .002) and milk intake (ß = -0.05, P = .01) were negatively and maternal weight was positively associated (ß = 0.56, P = .03) with the changes in RBP4 levels. The GEE models revealed negative association of RBP4 levels with C-reactive protein (CRP; ß = -0.14, P < .05) and α-1-acid glycoprotein (AGP; ß = -0.03, P < .05). CONCLUSION: Children whose mothers were taller experienced less increase in plasma RBP4 level, and children whose mothers had a higher weight experienced more increase in the RBP4 level from baseline. We have also found that CRP and AGP levels and intake of whole milk were negatively associated with the plasma RBP4 level.

Combined Prebiotic and Microbial Intervention Improves Oral Cholera Vaccination Responses in a Mouse Model of Childhood Undernutrition.

Undernourished children in low-income countries often exhibit poor responses to oral vaccination. Perturbed microbiota development is linked to undernutrition, but whether and how microbiota changes affect vaccine responsiveness remains unclear. Here, we show that gnotobiotic mice colonized with microbiota from undernourished Bangladeshi children and fed a Bangladeshi diet exhibited microbiota-dependent differences in mucosal IgA responses to oral vaccination with cholera toxin (CT). Supplementation with a nutraceutical consisting of spirulina, amaranth, flaxseed, and micronutrients augmented CT-IgA production. Mice initially colonized with a microbiota associated with poor CT responses exhibited improved immunogenicity upon invasion of bacterial taxa from cagemates colonized with a more "responsive" microbiota. Additionally, a consortium of five cultured bacterial invaders conferred augmented CT-IgA responses in mice fed the supplemented diet and colonized with the "hypo-responsive" community. These results provide preclinical proof-of-concept that diet and microbiota influence mucosal immune responses to CT vaccination and identify a candidate synbiotic formulation.

Intestinal Bacteroides sp. Imbalance Associated With the Occurrence of Childhood Undernutrition in China.

Undernutrition (UN) is a worldwide concern affecting morbidity and mortality among children, but the safety and long-term efficacy of its current treatments remain controversial. Recent evidence showing the roles of the gut microbiome (GM) in nutrient absorption indicates its usefulness in alternative interventions to treat UN safely with sustainable amelioration. To enhance our understanding of the GM and childhood undernutrition, we deep sequenced the gut metagenomes of 65 children with moderate or severe undernutrition (UN group) and 61 healthy children (HC group) to identify associated taxa and genes using a two-stage validation scheme. At stage I, 54 UN patients and 51 healthy children were enrolled for the discovery of GM markers in UN children. The accuracy of the markers was then tested in an additional 11 UN patients and 10 healthy children at stage II. Compared to the HC group, the UN group had lower richness in microbial genes (P = 0.005, FDR = 0.005) and species (P = 0.002, FDR = 0.002). The distributions of bacterial genes enable the identification of 16 gene markers with which to discriminate UN patients with high accuracy [averaged areas under the receiver operating curve (AUC) = 0.87], including three Bacteroides uniformis genes that are responsible for the synthesis of iron transporters. We also identified four species markers that enable the UN patients to be confidently discriminated from the HC children (averaged AUC = 0.91), namely Bacteroides ovatus, Bacteroides uniformis, Bacteroides uniformis, and Bacteroides vulgatus. In addition, metabolic comparison showed significantly decreased isobutyric acid (P = 0.005, FDR = 0.017) and increased isovaleric acid (P = 0.006, FDR = 0.017) in UN patients. We also identified notable correlations between microbial species and short-chain fatty acids (SCFAs) and several nutritional indicators, including acetic acid and iron (r = 0.436, P = 0.029), butyric acid and iron (r = 0.422, P = 0.036), butyric acid and lymphocyte (r = -0.309, P = 0.011), and acetic acid and total protein (r = -0.303, P = 0.043). Taken together, the distinct features of gut microbiota in UN patients highlight the taxonomic and functional shift during the development of UN and provide a solid theoretical basis for intervention in childhood undernutrition through gut microbes.

Levels and trends of childhood undernutrition by wealth and education according to a Composite Index of Anthropometric Failure: evidence from 146 Demographic and Health Surveys from 39 countries.

BACKGROUND: Governments have endorsed global targets to reduce childhood undernutrition as part of the Sustainable Development Goals. Understanding the socioeconomic differences in childhood undernutrition has the potential to be helpful for targeting policy to reach these goals. METHODS: We specify a logistic regression model with the Composite Index of Anthropometric Failure (CIAF) as the outcome and indicator variables for wealth quartiles, maternal education categories and a set of covariates as explanatory variables. Wealth and education variables are interacted with a period indicator for 1990-2000 compared with 2001-2014 to observe differences over time. Based on these regressions we calculate predicted CIAF prevalence by wealth and education categories and over time. RESULTS: The sample included 146 surveys from 39 low-income and lower-middle-income countries with an overall sample size of 533 217 children. CIAF prevalence was 47.5% in 1990-2000, and it declined to 42.6% in 2001-2014. In 1990-2000 the CIAF prevalence of children with mothers with less than primary education was 31 percentage points higher than for mothers with secondary or higher education. This difference slightly decreased to 27 percentage points in 2001-2014. The difference in predicted CIAF prevalence of children from the highest and lowest wealth quartiles was 21 percentage points and did not change over time. CONCLUSIONS: We find evidence for persistent and even increasing socioeconomic inequalities in childhood undernutrition, which underlines the importance of previous calls for equity-driven approaches targeting the most vulnerable to reduce childhood malnutrition.

Association between household unavailability of iodized salt and child growth: evidence from 89 demographic and health surveys.

BACKGROUND: Although a strong biological basis exists for a role of iodine in somatic growth failure in childhood, this relation has not been previously studied on a large scale to our knowledge. OBJECTIVE: We investigated if a general association exists between the household unavailability of iodized salt and child growth across countries. DESIGN: We used 89 nationally representative, repeated, cross-sectional and mutually comparable demographic and health surveys that were conducted between 1994 and 2012 across 46 low- and middle-income countries. We analyzed the data for the outcome variables of stunting (low height-for-age), underweight (low weight-for-age), wasting (low weight-for-height), and low birth weight in children aged between 0 and 59 mo at the time of the interview with the use of logistic regression models. Our samples consisted of 390,328 children for the stunting analysis, 397,080 children for the underweight analysis, 384,163 children for the wasting analysis, and 187,744 children for the low-birth-weight analysis. Models were adjusted for individual, maternal, and household covariates and fixed effects on the level of the primary sampling unit. RESULTS: In the fully adjusted models, the unavailability of iodized salt was associated with 3% higher odds of being stunted (95% CI of ORs: 1.00, 1.06; P = 0.04), 5% higher odds of being underweight (95% CI: 1.02, 1.09; P < 0.01), and 9% higher odds of low birth weight (95% CI: 1.02, 1.17; P = 0.01). When India was excluded from the sample, the association was only statistically significant (P = 0.05) for low birth weight. CONCLUSION: Although we did not establish causality in our analysis, the findings might indicate that the causal effect of iodized salt on child growth, if it exists, is most profound in utero and is not universally effective across all countries with respect to longer-run child-growth outcomes such as stunting and underweight.

Centros de recuperación nutricional: 1984-2011 / Nutritional Recovery Centers: 1984-2011

Los centros de recuperación nutricional (CRN) fueron creados por el Dr. José María Bengoa en Venezuela. En el presente estudio se realizó una revisión sistemática cualitativa, de 1984 al 2011, que permitió analizar las modalidades de funcionamiento de los diferentes CRN en el mundo, mediante indicadores de: criterios de admisión, parámetros utilizados en estos centros, así como las modalidades de tratamiento, tiempo de estancia y criterios de alta. Se encontraron diecisiete artículos que describen algunos o todos estos indicadores. El uso de los CRN se encontró en cuatro países de África (Etiopía, Kenia, Malawi y Nigeria), cuatro de América (Bolivia, Brasil, Chile y Nicaragua) y dos en Asia (India y Nepal). Los resultados reflejan la importancia de los CRN en el tratamiento de la desnutrición, sobre todo si se acompaña con la educación de las madres sobre la alimentación, prácticas higiénicas, etc., para un mejor cuidado en el hogar. Nuevas evidencias en el tratamiento de la desnutrición han motivado la evolución de los centros, pero aún así, sus limitaciones persisten. No obstante, las ventajas de su uso son excepcionales. Se propone, de acuerdo con los diferentes tipos de centros, y en base a las deficiencias o limitaciones observadas en su conceptualización y designación, redefinir las NRC bajo el concepto de Centros Globales de Nutrición (GloNuCen) basados en la comunidad y la personalización nutricional, los cuales podrían ser centros fijos en el caso de hospitales y servicios ambulatorios, e instalaciones móviles para situaciones de emergencia que, si duran con el tiempo, puedan convertirse en centros fijos(AU)

The Nutritional Recovery Centers (NRC) were created by Dr. Jose María Bengoa in Venezuela. In the present study a qualitative systematic review was carried out, from 1984 to 2011, allowing us to analyze the operating modalities of the different CRNs in the world, by means of indicators of: admission criteria, parameters used in these centers, as well as their treatment modalities, time of stay and discharge criteria. Seventeen articles have been found that describe some or all of these indicators. The use of NRCs was found in four African countries (Ethiopia, Kenya, Malawi and Nigeria), four in America (Bolivia, Brazil, Chile and Nicaragua) and two in Asia (India and Nepal). The results reflect the importance of NRC in the treatment of malnutrition, especially if it is reinforced with mothers' education about food, hygiene practices, etc., for better home care. New evidence in the treatment of malnutrition has motivated the evolution of the centers, but still, their limitations persist. Nonetheless, the advantages of their use are exceptional. It is proposed, according to the different types of centers, and based on the deficiencies or limitations observed in their conceptualization and designation, to redefine the NRCs under the concept of Global Nutrition Centers (GloNuCen) based on the community and nutritional customization, which could be fixed centers in the case of hospitals and outpatient services, and mobile facilities for emergency situations that, if they last over time, could turn into fixed centers(AU)

Dyslipidaemia and undernutrition in children from impoverished areas of Maceió, state of Alagoas, Brazil.

Chronic undernutrition causes reduced growth and endocrine adaptations in order to maintain basic life processes. In the present study, the biochemical profiles of chronically undernourished children were determined in order to test the hypothesis that chronic undernutrition also causes changes in lipid profile in pre-school children. The study population comprised 80 children aged between 12 and 71 months, including 60 with moderate undernutrition [height-for-age Z (HAZ) scores ≤ -2 and > -3] and 20 with severe undernutrition (HAZ scores ≤ -3). Socioeconomic, demographic and environmental data were obtained by application of a questionnaire, and anthropometric measurements and information relating to sex, age and feeding habits were collected by a trained nutritionist. Blood samples were analysed for haemoglobin, vitamin A, insulin-like growth factor 1 (IGF-1) and serum lipids, while cortisol was assayed in the saliva. Faecal samples were submitted to parasitological investigation. Analysis of variance and χ² methods were employed in order to select the variables that participated in the multivariate logistic regression analysis. The study population was socioeconomically homogeneous, while the lack of a treated water supply was clearly associated with the degree of malnutrition. Most children were parasitised and anaemia was significantly more prevalent among the severely undernourished. Levels of IGF-1 decreased significantly with increasing severity of undernutrition. Lipid analysis revealed that almost all of the children had dyslipidemia, while low levels of high-density lipoprotein were associated with the degree of undernutrition. It is concluded that chronic malnutrition causes endocrine changes that give rise to alterations in the metabolic profile of pre-school children.