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      Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study12

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          Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear.

          Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM.

          Design: Intestinal pathogens ( n = 15), cytokines ( n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6–59 mo ( n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling.

          Results: Fatal subjects ( n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443–535 mg/kg feces) compared with 698 mg/kg feces (1438–244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112–22 ng/mL) compared with 2036 ng/mL (5800–149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831–131 ng/mL) compared with 3174 ng/mL (5819–357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation.

          Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at as ISRCTN13916953.

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          Most cited references 38

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          Maternal and child undernutrition and overweight in low-income and middle-income countries.

          Maternal and child malnutrition in low-income and middle-income countries encompasses both undernutrition and a growing problem with overweight and obesity. Low body-mass index, indicative of maternal undernutrition, has declined somewhat in the past two decades but continues to be prevalent in Asia and Africa. Prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions. Prevalence of stunting of linear growth of children younger than 5 years has decreased during the past two decades, but is higher in south Asia and sub-Saharan Africa than elsewhere and globally affected at least 165 million children in 2011; wasting affected at least 52 million children. Deficiencies of vitamin A and zinc result in deaths; deficiencies of iodine and iron, together with stunting, can contribute to children not reaching their developmental potential. Maternal undernutrition contributes to fetal growth restriction, which increases the risk of neonatal deaths and, for survivors, of stunting by 2 years of age. Suboptimum breastfeeding results in an increased risk for mortality in the first 2 years of life. We estimate that undernutrition in the aggregate--including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding--is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011. Maternal overweight and obesity result in increased maternal morbidity and infant mortality. Childhood overweight is becoming an increasingly important contributor to adult obesity, diabetes, and non-communicable diseases. The high present and future disease burden caused by malnutrition in women of reproductive age, pregnancy, and children in the first 2 years of life should lead to interventions focused on these groups. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation

            Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T (Treg) cells expressing transcription factor Foxp3 play a key role in limiting inflammatory responses in the intestine 1 . Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory Th17 cells 2-6 , the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we hypothesized that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We found that a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg cell numbers upon provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells as the observed phenomenon was dependent upon intronic enhancer CNS1, essential for extrathymic, but dispensable for thymic Treg cell differentiation 1, 7 . In addition to butyrate, de novo Treg cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of HDAC inhibition, but not acetate, lacking this activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
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              The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.

              Short-chain fatty acids (SCFAs), the end products of fermentation of dietary fibers by the anaerobic intestinal microbiota, have been shown to exert multiple beneficial effects on mammalian energy metabolism. The mechanisms underlying these effects are the subject of intensive research and encompass the complex interplay between diet, gut microbiota, and host energy metabolism. This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism. There are interesting leads on the underlying molecular mechanisms, but there are also many apparently contradictory results. A coherent understanding of the multilevel network in which SCFAs exert their effects is hampered by the lack of quantitative data on actual fluxes of SCFAs and metabolic processes regulated by SCFAs. In this review we address questions that, when answered, will bring us a great step forward in elucidating the role of SCFAs in mammalian energy metabolism.

                Author and article information

                [3 ]Division of Gastroenterology, Hepatology, and Nutrition,
                [4 ]Physiology and Experimental Medicine, Peter Gilgan Centre for Research and Learning,
                [5 ]Microbiology Department, and
                [6 ]Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada;
                [7 ]Department of Paediatrics and Child Health, College of Medicine, University of Malawi, Blantyre, Malawi;
                [8 ]Global Child Health Group, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, Netherlands;
                [9 ]University of Groningen, University Medical Center Groningen, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Groningen, Netherlands;
                [10 ]Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands;
                [11 ]Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi Nuffield Department of Clinical Medicine, Oxford University, Oxford, United Kingdom; and
                [12 ]Childhood Acute Illness and Nutrition Network (CHAIN)
                Author notes
                [* ]To whom correspondence should be addressed. E-mail: robert.bandsma@ .

                Internal Principal Investigator Support provided by The Hospital for Sick Children, Toronto. Luminex assay was performed by the Analytical Facility for Bioactive Molecules of The Centre for the Study of Complex Childhood Diseases, The Hospital for Sick Children, Toronto, Canada. JAB and RHJB were supported by the Bill & Melinda Gates Foundation as part of the CHAIN study of childhood acute illness and nutrition [CHAIN grant no. OPP1131320]. This is an open access article distributed under the CC-BY license (


                Supplemental Figure 1, Supplemental Tables 1–6, and Supplemental Methods are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at

                Am J Clin Nutr
                Am. J. Clin. Nutr
                The American Journal of Clinical Nutrition
                American Society for Nutrition
                November 2016
                21 September 2016
                21 September 2016
                : 104
                : 5
                : 1441-1449

                This is an open access article distributed under the CC-BY license (

                Pages: 9
                International Nutrition


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