Malnutrition and Gut Microbiota in Children.

Malnutrition continues to threaten the lives of millions across the world, with children being hardest hit. Although inadequate access to food and infectious disease are the primary causes of childhood malnutrition, the gut microbiota may also contribute. This review considers the evidence on the role of diet in modifying the gut microbiota, and how the microbiota impacts childhood malnutrition. It is widely understood that the gut microbiota of children is influenced by diet, which, in turn, can impact child nutritional status. Additionally, diarrhoea, a major contributor to malnutrition, is induced by pathogenic elements of the gut microbiota. Diarrhoea leads to malabsorption of essential nutrients and reduced energy availability resulting in weight loss, which can lead to malnutrition. Alterations in gut microbiota of severe acute malnourished (SAM) children include increased Proteobacteria and decreased Bacteroides levels. Additionally, the gut microbiota of SAM children exhibits lower relative diversity compared with healthy children. Thus, the data indicate a link between gut microbiota and malnutrition in children, suggesting that treatment of childhood malnutrition should include measures that support a healthy gut microbiota. This could be of particular relevance in sub-Saharan Africa and Asia where prevalence of malnutrition remains a major threat to the lives of millions.

A randomised controlled feasibility trial of a BabyWASH household playspace: The CAMPI study.

BACKGROUND: Water, sanitation and hygiene (WASH) interventions should support infant growth but trial results are inconsistent. Frequently, interventions do not consider behaviours or transmission pathways specific to age. A household playspace (HPS) is one intervention component which may block faecal-oral transmission. This study was a two-armed, parallel-group, randomised, controlled feasibility trial of a HPS in rural Ethiopia. It aimed to recommend proceeding to a definitive trial. Secondary outcomes included effects on infant health, injury prevention and women's time. METHODS: November 2019-January 2020 106 households were identified and assessed for eligibility. Recruited households (N = 100) were randomised (blinded prior to the trial start) to intervention or control (both n = 50). Outcomes included recruitment, attrition, adherence, and acceptability. Data were collected at baseline, two and four weeks. FINDINGS: Recruitment met a priori criteria (≥80%). There was no loss to follow-up, and no non-use, meeting adherence criteria (both ≤10%). Further, 48.0% (95% CI 33.7-62.6; n = 24) of households appropriately used and 56.0% (41.3-70.0; n = 28) cleaned the HPS over four weeks, partly meeting adherence criteria (≥50%). For acceptability, 41.0% (31.3-51.3; n = 41) of infants were in the HPS during random visits, failing criteria (≥50%). Further, the proportion of HPS use decreased during some activities, failing criteria (no decrease in use). A modified Barrier Analysis described good acceptability and multiple secondary benefits, including on women's time burden and infant injury prevention. INTERPRETATION: Despite failing some a priori criteria, the trial demonstrated mixed adherence and good acceptability among intervention households. A definitive trial to determine efficacy is warranted if recommended adjustments are made. FUNDING: People In Need; Czech Development Agency. TRIAL REGISTRATION: RIDIE-ID-5de0b6938afb8.

Multi-Nutrient Fortified Dairy-Based Drink Reduces Anaemia without Observed Adverse Effects on Gut Microbiota in Anaemic Malnourished Nigerian Toddlers: A Randomised Dose-Response Study.

Prevalence of anaemia among Nigerian toddlers is reported to be high, and may cause significant morbidity, affects brain development and function, and results in weakness and fatigue. Although, iron fortification can reduce anaemia, yet the effect on gut microbiota is unclear. This open-label randomised study in anaemic malnourished Nigerian toddlers aimed to decrease anaemia without affecting pathogenic gut bacteria using a multi-nutrient fortified dairy-based drink. The test product was provided daily in different amounts (200, 400 or 600 mL, supplying 2.24, 4.48 and 6.72 mg of elemental iron, respectively) for 6 months. Haemoglobin, ferritin, and C-reactive protein concentrations were measured to determine anaemia, iron deficiency (ID) and iron deficiency anaemia (IDA) prevalence. Faecal samples were collected to analyse gut microbiota composition. All three dosages reduced anaemia prevalence, to 47%, 27% and 18%, respectively. ID and IDA prevalence was low and did not significantly decrease over time. Regarding gut microbiota, Enterobacteriaceae decreased over time without differences between groups, whereas Bifidobacteriaceae and pathogenic E. coli were not affected. In conclusion, the multi-nutrient fortified dairy-based drink reduced anaemia in a dose-dependent way, without stimulating intestinal potential pathogenic bacteria, and thus appears to be safe and effective in treating anaemia in Nigerian toddlers.

Infrequent small bowel intestinal bacterial overgrowth in malnourished Zambian children.

There is evidence that children with malnutrition have an increased frequency of small intestinal bacterial overgrowth (SIBO) due to impaired gastric acidity, impaired intestinal motility, and dysbiosis. Children with malnutrition respond to antibiotic therapy but it is not clear if this effect is mediated by treatment of SIBO. We set out to determine the frequency of SIBO in children of varying nutritional status in a poor community in Lusaka, Zambia. Hydrogen breath testing, following a dose of 1g/kg oral glucose, was used to determine the presence of SIBO amongst the study participants. Forty nine children, 45 of whom had varying degrees of malnutrition, completed a full series of observations at 15, 30 and 60 minutes. Four children (8%) had a rise of 10ppm from baseline, consistent with SIBO. No correlation with nutritional status was observed. In this small study of Zambian children, SIBO was infrequent and unrelated to nutritional status.

The role of nutrition in pediatric oncology.

Introduction: Obesity compromises survival in children with cancer in high-income countries (HICs) and is accompanied often by sarcopenia. In low and middle-income countries (LMICs), where the great majority of children live, the prevalence of under-nutrition is as high as 95% in those with cancer. Nutritional support improves clinical outcomes, including survival.Areas covered: This narrative review describes the evolution of attention to nutrition in children with cancer and the increasing understanding of this relationship. An initial focus on obesity in children with acute leukemias in HICs has been matched more recently by a recognition of the negative effect of under-nutrition on survival in children with cancer in LMICs. These observations have stimulated explorations of underlying mechanisms, including dysbiosis of the gut microbiome, and structured nutritional interventions to redress adverse outcomes.Expert opinion: Studies of the gut microbiome and metabolome have yielded important information on the pathogenesis of malnutrition in children, providing new avenues for interventions. Combinations of plant products that are inexpensive and readily available in LMICs have been shown to 'mature' the microbiome and the corresponding plasma proteome in children with acute malnutrition, offering the prospect of cost-effective remedies that are tested in children with cancer.

The Gut Microbiome in Child Malnutrition.

Undernutrition affects almost 25% of all children under the age of 5 worldwide and underlies almost half of all child deaths. Child undernutrition is also associated with long-term growth deficits, in addition to reduced cognitive potential, reduced economic potential, and elevated chronic disease risk in later life. Dietary interventions alone are insufficient to comprehensively reduce the burden of child undernutrition and fail to address the persistent infectious burden of the disease. Although the role of infections is well recognized in the pathogenesis of undernutrition, an emerging body of evidence suggests that commensal microbial communities, known as the microbiome, also play an important role. The gut microbiome regulates energy harvesting from nutrients, growth hormone signaling, colonization resistance, and immune tolerance against pathogens, amongst other pathways critically associated with healthy child growth. Hence, disturbance of the normal gut microbial ecosystem via undernourished diets or unhygienic environments, especially in the early phases of life, may perturb these critical pathways associated with child growth, thereby contributing to child undernutrition. Here we discuss the emerging evidence for the role of the gut microbiome in child undernutrition and the potential for novel gut microbiota-targeted treatments to restore healthy child growth.

Animal Models of Undernutrition and Enteropathy as Tools for Assessment of Nutritional Intervention.

: Undernutrition is a major public health problem leading to 1 in 5 of all deaths in children under 5 years. Undernutrition leads to growth stunting and/or wasting and is often associated with environmental enteric dysfunction (EED). EED mechanisms leading to growth failure include intestinal hyperpermeability, villus blunting, malabsorption and gut inflammation. As non-invasive methods for investigating gut function in undernourished children are limited, pre-clinical models are relevant to elucidating the pathophysiological processes involved in undernutrition and EED, and to identifying novel therapeutic strategies. In many published models, undernutrition was induced using protein or micronutrient deficient diets, but these experimental models were not associated with EED. Enteropathy models mainly used gastrointestinal injury triggers. These models are presented in this review. We found only a few studies investigating the combination of undernutrition and enteropathy. This highlights the need for further developments to establish an experimental model reproducing the impact of undernutrition and enteropathy on growth, intestinal hyperpermeability and inflammation, that could be suitable for preclinical evaluation of innovative therapeutic intervention.

Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition.

Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.

A sparse covarying unit that describes healthy and impaired human gut microbiota development.

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of ecogroup population dynamics were recapitulated in gnotobiotic piglets as they transitioned from exclusive milk feeding to a fully weaned state consuming a representative Bangladeshi diet.

Effects of microbiota-directed foods in gnotobiotic animals and undernourished children.

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM.

Gut microbiota alterations and dietary modulation in childhood malnutrition - The role of short chain fatty acids.

The gut microbiome affects the health status of the host through different mechanisms and is associated with a wide variety of diseases. Both childhood undernutrition and obesity are linked to alterations in composition and functionality of the gut microbiome. One of the possible mechanisms underlying the interplay between microbiota and host metabolism is through appetite-regulating hormones (including leptin, ghrelin, glucagon-like peptide-1). Short chain fatty acids, the end product of bacterial fermentation of non-digestible carbohydrates, might be able to alter energy harvest and metabolism through enteroendocrine cell signaling, adipogenesis and insulin-like growth factor-1 production. Elucidating these mechanisms may lead to development of new modulation practices of the gut microbiota as a potential prevention and treatment strategy for childhood malnutrition. The present overview will briefly outline the gut microbiota development in the early life, gut microbiota alterations in childhood undernutrition and obesity, and whether this relationship is causal. Further we will discuss possible underlying mechanisms in relation to the gut-brain axis and short chain fatty acids, and the potential of probiotics, prebiotics and synbiotics for modulating the gut microbiota during childhood as a prevention and treatment strategy against undernutrition and obesity.

Gut microbiota dysbiosis is associated with malnutrition and reduced plasma amino acid levels: Lessons from genome-scale metabolic modeling.

Malnutrition is a severe non-communicable disease, which is prevalent in children from low-income countries. Recently, a number of metagenomics studies have illustrated associations between the altered gut microbiota and child malnutrition. However, these studies did not examine metabolic functions and interactions between individual species in the gut microbiota during health and malnutrition. Here, we applied genome-scale metabolic modeling to model the gut microbial species, which were selected from healthy and malnourished children from three countries. Our analysis showed reduced metabolite production capabilities in children from two low-income countries compared with a high-income country. Additionally, the models were also used to predict the community-level metabolic potentials of gut microbes and the patterns of pairwise interactions among species. Hereby we found that due to bacterial interactions there may be reduced production of certain amino acids in malnourished children compared with healthy children from the same communities. To gain insight into alterations in the metabolism of malnourished (stunted) children, we also performed targeted plasma metabolic profiling in the first 2 years of life of 25 healthy and 25 stunted children. Plasma metabolic profiling further revealed that stunted children had reduced plasma levels of essential amino acids compared to healthy controls. Our analyses provide a framework for future efforts towards further characterization of gut microbial metabolic capabilities and their contribution to malnutrition.

Severe acute malnutrition.

PURPOSE OF REVIEW: Advances in our understanding of the treatment of severe acute malnutrition (SAM) in a resource-limited environment are needed to improve outcome. RECENT FINDINGS: Ready-to-use therapeutic foods (RUTFs) made from local products and with reduced milk content lower costs and may be effective in older children. None of the therapeutic foods used to treat severely malnourished children correct long chain polyunsaturated fatty acid deficiencies.Routine short-term antibiotic (amoxicillin) treatment, in the context of adequate healthcare supervision, does not improve the recovery rate. Long-term antibiotic (cotrimoxazole) treatment also does not provide significant benefit to non-HIV-infected children.Increased pathogenic bacteria have been found in the intestinal microbiome of malnourished children and candidate organisms for use as probiotics have been identified. There is, however, no evidence to support the routine use of probiotics in these children. Although exocrine pancreatic function is reduced in malnourished children, routine pancreatic enzyme supplementation does not lead to accelerated recovery. SUMMARY: Alternative RUTF may provide a cheaper and more acceptable alternative to standard RUTF in the near future. Further research is needed to understand the implications of fatty acid deficiencies and dysbiosis that occur in malnourished children. Routine antibiotic administration in the appropriate setting is unnecessary.

Coinfection of intestinal schistosomiasis and malaria and association with haemoglobin levels and nutritional status in school children in Mara region, Northwestern Tanzania: a cross-sectional exploratory study.

BACKGROUND: Schistosomiasis represents a major public health problem in Tanzania despite ongoing national control efforts. This study examined whether intestinal schistosomiasis is associated with malaria and assessed the contribution of intestinal schistosomiasis and malaria on anaemia and undernutrition in school children in Mara region, North-western Tanzania. METHODS: Stool samples were collected from each of 928 school children randomly selected from 5 schools and examined for intestinal schistosomiasis using the Kato Katz method. Finger prick blood samples were collected and examined for malaria parasites and haemoglobin concentrations using the Giemsa stain and Haemocue methods, respectively. Nutritional status was assessed by taking anthropometric measurements. RESULTS: The overall prevalence and infection intensity of S. mansoni was 85.6% (794/928) and 192 (100-278), respectively. The prevalence of malaria was 27.4% (254/928) with significant differences among villages (χ 2  = 96.11, p < 0.001). The prevalence of anaemia was 42.3% (392/928) with significant differences among villages (χ 2  = 39.61, p < 0.001). The prevalence of stunting, thinness and underweight was 21, 6.8 and 1.3%, respectively. Stunting varied significantly by sex (χ 2  = 267.8, p < 0.001), age group (χ 2  = 96.4, p < 0.001) and by village (χ 2  = 20.5, p < 0.001). Out of the 825 infected children, 217 (26.4%) had multiple parasite infections (two to three parasites). The prevalence of co-infections occurred more frequently in boys than in girls (χ 2  = 21.65, p = 0.010). Mean haemoglobin concentrations for co-infected children was significantly lower than that of children not co-infected (115.2 vs 119.6; t = 0.01, p = 0.002). Co-infected children were more likely to be stunted than children who were not co-infected (χ 2  = 11.6, p = 0.003). On multivariate analysis, age group, village of residence and severe anaemia were significant predictors of stunting after adjusting for sex and infection status. CONCLUSIONS: Intestinal schistosomiasis and malaria are prevalent in Mara region. Coinfections of these parasites as well as chronic undernutrition were also common. We recommend Mara region to be included in national schistosomiasis control programmes.

Association between enteropathogens and malnutrition in children aged 6-23 mo in Bangladesh: a case-control study.

Background: Early exposure to enteropathogens has been associated with malnutrition in children in low-resource settings. However, the contribution of individual enteropathogens remains poorly defined. Molecular diagnostics offer an increase in sensitivity for detecting enteropathogens but have not been comprehensively applied to studies of malnutrition.Objective: We sought to identify enteropathogens associated with malnutrition in Bangladesh.Design: Malnourished children [weight-for-age z score (WAZ) <-2] aged 6-23 mo in Dhaka, Bangladesh, and identified by active community surveillance were enrolled as cases, and normal-weight children (WAZ >-1) of the same age and from the same community were enrolled as controls. Stools were collected at enrollment and, for cases, after a 5-mo nutritional intervention. Enrollment and follow-up stools were tested by quantitative polymerase chain reaction for 32 enteropathogens with the use of a custom-developed TaqMan Array Card.Results: Enteropathogen testing was performed on 486 cases and 442 controls upon enrollment and 365 cases at follow-up. At enrollment, the detection of enteroaggregative Escherichia coli (OR: 1.39; 95% CI: 1.05, 1.83), Campylobacter spp. (OR: 1.46; 95% CI: 1.11, 1.91), heat-labile enterotoxin-producing E. coli (OR: 1.55; 95% CI: 1.04, 2.33), Shigella/enteroinvasive E. coli (OR: 1.65; 95% CI: 1.10, 2.46), norovirus genogroup I (OR: 1.66; 95% CI: 1.23, 2.25), and Giardia (OR: 1.73; 95% CI: 1.20, 2.49) were associated with malnourished cases, and the total burden of these pathogens remained associated with malnutrition after adjusting for sociodemographic factors. The number of these pathogens at follow-up was negatively associated with the change in WAZ during the intervention (-0.10 change in WAZ per pathogen detected; 95% CI: -0.14, -0.06), whereas the number at enrollment was positively associated with the change in WAZ (0.05 change in WAZ per pathogen detected; 95% CI: 0.00, 0.10).Conclusions: A subset of enteropathogens was associated with malnutrition in this setting. Broad interventions designed to reduce the burden of infection with these pathogens are needed. This trial was registered at clinicaltrials.gov as NCT02441426.

Determinant Variables, Enteric Pathogen Burden, Gut Function and Immune-related Inflammatory Biomarkers Associated With Childhood Malnutrition: A Prospective Case-Control Study in Northeastern Brazil.

Malnutrition results in serious consequences for growth and cognitive development in children. We studied select child and maternal biologic factors, socioeconomic factors, enteric pathogenic burden and gut function biomarkers in 402 children 6-24 months of age in Northeastern Brazil. In this prospective case-control study, not being fed colostrum [odds ratio (OR): 3.29, 95% confidence interval (CI): 1.73-6.26], maternal age ≥18 years (OR: 1.88, 95% CI: 1.10-3.22) and no electric fan (OR: 2.46, 95% CI: 1.22-4.96) or bicycle (OR: 1.80, 95% CI: 1.10-2.95) in the household were positively associated, and higher birth weight (OR: 0.27, 95% CI: 0.19-0.38), larger head circumference (OR: 0.74, 95% CI: 0.66-0.82) and shortness of breath in the last 2 weeks (OR: 0.49, 95% CI: 0.27-0.90) were negatively associated with malnutrition. Subclinical enteric pathogen infections were common, and enteroaggregative Escherichia coli infections were more prevalent in malnourished children (P = 0.045). Biomarkers such as the lactulose-mannitol test, myeloperoxidase, neopterin and calprotectin were highly elevated in both malnourished and nourished children. Nourished children had a better systemic immune response than the malnourished children, as detected by elevated serum amyloid A-1 and soluble cluster of differentiation protein 14 biomarkers (P < 0.001). Serum amyloid A-1 and soluble cluster of differentiation protein 14 were also associated with better nutritional Z scores. Neonatal, maternal and socioeconomic factors were associated with malnutrition in children. There was a substantial subclinical enteric pathogen burden, particularly with enteroaggregative E. coli, in malnourished children.

Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition.

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.

Global challenges in acute diarrhea.

PURPOSE OF REVIEW: Childhood diarrhea is the most common cause of morbidity and mortality, especially in the low and middle-income countries. The burden of child mortality because of diarrhea has declined, but still a lot is desired not only to reduce diarrhea-specific mortality but reduce the overall incidence, and hence the morbidity associated with childhood diarrhea. RECENT FINDINGS: A recent Lancet series on diarrhea suggests that amplification of the current interventions can eliminate virtually all preventable diarrhea deaths. A refocused attention and strategy and collective effort from the multilateral entities to promote water sanitation and hygiene, rotavirus vaccination, nutrition, and improved case management can bridge gaps and tackle the existing undue burden of deaths because of diarrhea. SUMMARY: Investment toward preventing and controlling childhood diarrhea should be a priority, especially when the existing solution is plausible for implementation at scale and in underprivileged settings.

Childhood malnutrition and the intestinal microbiome.

Malnutrition contributes to almost half of all deaths in children under the age of 5 y, particularly those who live in resource-constrained areas. Those who survive frequently suffer from long-term sequelae including growth failure and neurodevelopmental impairment. Malnutrition is part of a vicious cycle of impaired immunity, recurrent infections, and worsening malnutrition. Recently, alterations in the gut microbiome have also been strongly implicated in childhood malnutrition. It has been suggested that malnutrition may delay the normal development of the gut microbiota in early childhood or force it toward an altered composition that lacks the required functions for healthy growth and/or increases the risk for intestinal inflammation. This review addresses our current understanding of the beneficial contributions of gut microbiota to human nutrition (and conversely the potential role of changes in that community to malnutrition), the process of acquiring an intestinal microbiome, potential influences of malnutrition on the developing microbiota, and the evidence directly linking alterations in the intestinal microbiome to childhood malnutrition. We review recent studies on the association between alterations in the intestinal microbiome and early childhood malnutrition and discuss them in the context of implications for intervention or prevention of the devastation caused by malnutrition.