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Recovery from cholera is characterized by a pattern of accumulation of bacterial taxa that shows similarities to the pattern of maturation of the gut microbiota in healthy children, raising the possibility that some of these taxa may be useful for ‘repair’ of the gut microbiota in individuals whose gut communities have been ‘wounded’ through a variety of insults. Gut microbes aid recovery from cholera Cholera and other diarrhoeal diseases caused by bacterial pathogens affect millions of people worldwide each year. Understanding how the gut microbiota affects diarrhoeal disease, in particular that associated with Vibrio cholera infection, is therefore an important goal. Jeffrey Gordon and colleagues carried out a time-series metagnomic analysis of the gut microbiota during acute and recovery phases of the disease in a cohort of Bangladeshi adults. They find that the recovery phase is characterized by a pattern of accumulation of bacterial taxa that mirrors the assembly pattern of normal microbiota of healthy children. In a mouse model they show that the abundance of one species, Ruminococcus obeum increased upon infection by V. cholerae and that R. obeum restricts colonization by V. cholerae in a quorum sensing dependent manner. These findings suggest that mining the gut microbiota of suitable populations for isolates that use autoinducers or other mechanisms to limit V. cholera colonization could provide a means of restoring the gut microbiota in cholera sufferers. Given the global burden of diarrhoeal diseases 1 , it is important to understand how members of the gut microbiota affect the risk for, course of, and recovery from disease in children and adults. The acute, voluminous diarrhoea caused by Vibrio cholerae represents a dramatic example of enteropathogen invasion and gut microbial community disruption. Here we conduct a detailed time-series metagenomic study of faecal microbiota collected during the acute diarrhoeal and recovery phases of cholera in a cohort of Bangladeshi adults living in an area with a high burden of disease 2 . We find that recovery is characterized by a pattern of accumulation of bacterial taxa that shows similarities to the pattern of assembly/maturation of the gut microbiota in healthy Bangladeshi children 3 . To define the underlying mechanisms, we introduce into gnotobiotic mice an artificial community composed of human gut bacterial species that directly correlate with recovery from cholera in adults and are indicative of normal microbiota maturation in healthy Bangladeshi children 3 . One of the species, Ruminococcus obeum , exhibits consistent increases in its relative abundance upon V. cholerae infection of the mice. Follow-up analyses, including mono- and co-colonization studies, establish that R. obeum restricts V. cholerae colonization, that R. obeum luxS (autoinducer-2 (AI-2) synthase) expression and AI-2 production increase significantly with V. cholerae invasion, and that R. obeum AI-2 causes quorum-sensing-mediated repression of several V. cholerae colonization factors. Co-colonization with V. cholerae mutants discloses that R. obeum AI-2 reduces Vibrio colonization/pathogenicity through a novel pathway that does not depend on the V. cholerae AI-2 sensor, LuxP. The approach described can be used to mine the gut microbiota of Bangladeshi or other populations for members that use autoinducers and/or other mechanisms to limit colonization with V. cholerae , or conceivably other enteropathogens.

Bacterial species whose representation defines healthy postnatal assembly of the gut microbiota in Bangladeshi children during their first 2 years are identified, and a model is constructed to compare healthy children to those with severe acute malnutrition (SAM); results show that SAM is associated with microbiota immaturity that is only partially ameliorated by existing nutritional interventions. Gut microbiota response to malnutrition Childhood malnutrition is a major health problem in many low-income countries, and although mortality can be reduced by therapeutic food interventions, it is difficult to achieve complete restoration of healthy growth in cases of severe acute malnutrition. Here Jeffrey Gordon and colleagues identify a group of 24 bacterial species whose proportional representation in the microbiota defines how a healthy microbiota assembles over the course of the first two postnatal years in a cohort of healthy children in Bangladesh. They define a 'relative microbiota maturity index' and 'microbiota-for-age Z -score' that allow comparison across individuals and use these indices to demonstrate that severe malnutrition is associated with significant relative microbiota immaturity that is only partially ameliorated by two widely used nutritional interventions. This work suggests that more prolonged food-based interventions and/or addition of gut microbes may be needed to achieve durable repair of microbiota immaturity in childhood malnutrition and improved clinical outcomes. Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem 1 , 2 . The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth. These age-discriminatory bacterial species were incorporated into a model that computes a ‘relative microbiota maturity index’ and ‘microbiota-for-age Z -score’ that compare postnatal assembly (defined here as maturation) of a child’s faecal microbiota relative to healthy children of similar chronologic age. The model was applied to twins and triplets (to test for associations of these indices with genetic and environmental factors, including diarrhoea), children with SAM enrolled in a randomized trial of two food interventions, and children with moderate acute malnutrition. Our results indicate that SAM is associated with significant relative microbiota immaturity that is only partially ameliorated following two widely used nutritional interventions. Immaturity is also evident in less severe forms of malnutrition and correlates with anthropometric measurements. Microbiota maturity indices provide a microbial measure of human postnatal development, a way of classifying malnourished states, and a parameter for judging therapeutic efficacy. More prolonged interventions with existing or new therapeutic foods and/or addition of gut microbes may be needed to achieve enduring repair of gut microbiota immaturity in childhood malnutrition and improve clinical outcomes.

Duodenal and plasma biomarkers of environmental enteric dysfunction that were identified through analyses of duodenal biopsy samples and the plasma of growth-stunted children were found to induce enteropathy of the small intestine in gnotobiotic mice.

Our current understanding of the composition and stability of the human distal gut microbiota is based largely on studies of infants and adults living in developed countries. In contrast, little is known about the gut microbiota and its variation over time in older children and adolescents, especially in developing countries. We compared the diversity, composition, and temporal stability of the fecal microbiota of healthy children, ages 9 to 14 years, living in an urban slum in Bangladesh with that of children of the same age range in an upper-middle class suburban community in the United States. We analyzed >8,000 near full-length 16S rRNA gene sequences and over 845,000 pyrosequencing reads of the 16S rRNA V1-V3 region. The distal gut of Bangladeshi children harbored significantly greater bacterial diversity than that of U.S. children, including novel lineages from several bacterial phyla. Bangladeshi and U.S. children had distinct fecal bacterial community membership and structure; the microbiota of Bangladeshi children was enriched in Prevotella, Butyrivibrio, and Oscillospira and depleted in Bacteroides relative to U.S. children (although similar to Bangladeshi adults). Furthermore, community membership and structure in Bangladeshi children was significantly less stable month-to-month than U.S. children. Together, these results suggest that differing environmental or genetic factors may shape the microbiota of healthy children in the two countries. Further investigation is necessary to understand the mechanisms and factors that underlie these differences, and to incorporate these findings into new strategies for the prevention and treatment of childhood and adolescent diseases.

Detection and quantification of enteropathogens in stool specimens is useful for diagnosing the cause of diarrhea but is technically challenging. Here we evaluate several important determinants of quantification: specimen collection, nucleic acid extraction, and extraction and amplification efficiency. First, we evaluate the molecular detection and quantification of pathogens in rectal swabs versus stool, using paired flocked rectal swabs and whole stool collected from 129 children hospitalized with diarrhea in Tanzania. Swabs generally yielded a higher quantification cycle (Cq) (average 29.7, standard deviation 3.5 vs. 25.3 ± 2.9 from stool, P<0.001) but were still able to detect 80% of pathogens with a Cq < 30 in stool. Second, a simplified total nucleic acid (TNA) extraction procedure was compared to separate DNA and RNA extractions and showed 92% (318/344) sensitivity and 98% (951/968) specificity, with no difference in Cq value for the positive results (ΔCq(DNA+RNA-TNA) = -0.01 ± 1.17, P = 0.972, N = 318). Third, we devised a quantification scheme that adjusts pathogen quantity to the specimen's extraction and amplification efficiency, and show that this better estimates the quantity of spiked specimens than the raw target Cq. In sum, these methods for enteropathogen quantification, stool sample collection, and nucleic acid extraction will be useful for laboratories studying enteric disease.

Background Stunting affects more than 161 million children worldwide and can compromise cognitive development beginning early in childhood. There is a paucity of research using neuroimaging tools in conjunction with sensitive behavioral assays in low-income settings, which has hindered researchers’ ability to explain how stunting impacts brain and behavioral development. We employed high-density EEG to examine associations among children’s physical growth, brain functional connectivity (FC), and cognitive development. Methods We recruited participants from an urban impoverished neighborhood in Dhaka, Bangladesh. One infant cohort consisted of 92 infants whose height (length) was measured at 3, 4.5, and 6 months; EEG data were collected at 6 months; and cognitive outcomes were assessed using the Mullen Scales of Early Learning at 27 months. A second, older cohort consisted of 118 children whose height was measured at 24, 30, and 36 months; EEG data were collected at 36 months; and Intelligence Quotient (IQ) scores were assessed at 48 months. Height-for-age (HAZ) z -scores were calculated based on the World Health Organization standard. EEG FC in different frequency bands was calculated in the cortical source space. Linear regression and longitudinal path analysis were conducted to test the associations between variables, as well as the indirect effect of child growth on cognitive outcomes via brain FC. Results In the older cohort, we found that HAZ was negatively related to brain FC in the theta and beta frequency bands, which in turn was negatively related to children’s IQ score at 48 months. Longitudinal path analysis showed an indirect effect of HAZ on children’s IQ via brain FC in both the theta and beta bands. There were no associations between HAZ and brain FC or cognitive outcomes in the infant cohort. Conclusions The association observed between child growth and brain FC may reflect a broad deleterious effect of malnutrition on children’s brain development. The mediation effect of FC on the relation between child growth and later IQ provides the first evidence suggesting that brain FC may serve as a neural pathway by which biological adversity impacts cognitive development.

This study aimed to explore the association between the GDP of various countries and the progress of COVID-19 vaccinations; to explore how the global pattern holds in the continents, and investigate the spatial distribution pattern of COVID-19 vaccination progress for all countries. We have used consolidated data on COVID-19 vaccination and GDP from Our World in Data, an open-access data source. Data analysis and visualization were performed in R-Studio. There was a strong linear association between per capita income and the proportion of people vaccinated in countries with populations of one million or more. GDP per capita accounts for a 50% variation in the vaccination rate across the nations. Our assessments revealed that the global pattern holds in every continent. Rich European and North-American countries are most protected against COVID-19. Less developed African countries barely initiated a vaccination program. There is a significant disparity among Asian countries. The security of wealthier nations (vaccinated their citizens) cannot be guaranteed unless adequate vaccination covers the less affluent countries. Therefore, the global community should undertake initiatives to speed up the COVID-19 vaccination program in all countries of the world, irrespective of their wealth.

Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Usually this test involves a time consuming procedure of about 5 hour's urine collection, which makes the test incompatible to some extent. As the results are expressed as the ratio of lactulose and mannitol recovered in urine within certain time, it may be possible to get similar result despite the reduced urine collection time of 2 hours. Moreover, different laboratories do the test by different methods, which make the results incomparable between laboratories. Here, we are also trying to find the correlation between results from most commonly used methods: HPAE-PAD and LC-MSMS. The lactulose: mannitol (LM) test was performed in a cohort of Bangladeshi infants considered at-risk for environmental enteropathy. 208 urine specimens from 104 (52 male and 52 female) infants were collected at 2 and 5 hours after LM solution administration and were tested for lactulose and mannitol by two different methods, one HPAE-PAD platform and another LC-MSMS platform. Median age of the children was 15.0 months (range 6.9 to 25.8 months) and their mean weight-for-age z-score was -0.92. A higher percentage of lactulose and mannitol recovery was found in 5 hours urine collection than in the corresponding 2 hours by both HPAE-PAD and LC-MSMS method, but when results were expressed as lactulose to mannitol ratio (LMR) there was no significant difference between 2 and 5 hours urine collection in both HPAE-PAD (P = 0.138) and LC-MSMS (P = 0.099) method. LMR based on 2 hours urine collection correlated well with LMR based on traditional 5 hours urine collection (Spearman's correlation coefficient 0.578 and 0.604 respectively for HPAE-PAD and LC-MSMS). In future, LM test to assess intestinal permeability in children can be simplified by shortening the urine collection time from 5 hours to 2 hours.

Diarrhea is one of the most common illnesses among children worldwide. In low- and middle-income countries with limited health care resources, it can be deadly. Diarrhea can be caused by infections with viruses or bacteria. Antibiotics can treat bacterial infections, but they are not effective against viral infections. It can often be difficult to determine the cause of diarrhea. As a result, many clinicians just prescribe antibiotics. However, since diarrhea in young children is often due to viral infections, prescribing unnecessary antibiotics can cause children to have side effects without any benefit. Excessive use of antibiotics also contributes to the development of bacteria that are resistant to antibiotics, making infections harder to treat. Scientists are working to develop mobile health tools or ‘apps’ that may help clinicians identify the cause of diarrhea. Using computer algorithms to analyze information about the patient and seasonal infection patterns, the apps predict whether a bacterial or viral infection is the likely culprit. These tools may be particularly useful in low- or middle-income country settings, where clinicians have limited access to testing for bacteria or viruses. Garbern, Nelson et al. previously built an app to help distinguish cases of viral diarrhea in children in Mali and Bangladesh. Now, the researchers have put their app to the test in the real-world in a new group of patients to verify it works. In the experiments, nurses in Mali and Bangladesh used the app to predict whether a child with diarrhea had a viral or non-viral infection. The children’s stool was then tested for viral or bacterial DNA to confirm whether the prediction was correct. The experiments showed the app accurately identified viral cases of diarrhea. The experiments also showed that customizing the app to local conditions may further improve its accuracy. For example, a version of the app that factored in seasonal virus transmission performed the best in Bangladesh, while a version that factored in data from recent patients in the past few weeks performed the best in Mali. Garbern and Nelson et al. are now testing whether their app could help reduce unnecessary use of antibiotics in children with diarrhea. If it does, it may help minimize antibiotic resistance and ensure more children get appropriate diarrhea care.