Metabolic alterations in children with environmental enteric dysfunction

Richard D Semba, Michelle Shardell, Indi Trehan, Ruin Moaddel, Kenneth M Maleta, M Isabel Ordiz, Klaus Kraemer, Mohammed Khadeer, Luigi Ferrucci, Mark J Manary, Richard D Semba, Michelle Shardell, Indi Trehan, Ruin Moaddel, Kenneth M Maleta, M Isabel Ordiz, Klaus Kraemer, Mohammed Khadeer, Luigi Ferrucci, Mark J Manary

Abstract

Environmental enteric dysfunction, an asymptomatic condition characterized by inflammation of the small bowel mucosa, villous atrophy, malabsorption, and increased intestinal permeability, is a major contributor to childhood stunting in low-income countries. Here we report the relationship of increased intestinal permeability with serum metabolites in 315 children without acute malnutrition, aged 12-59 months, in rural Malawi. Increased gut permeability was associated with significant differences in circulating metabolites that included lower serum phosphatidylcholines, sphingomyelins, tryptophan, ornithine, and citrulline, and elevated serum glutamate, taurine, and serotonin. Our findings suggest that environmental enteric dysfunction is characterized by alterations in important metabolites involved in growth and differentiation and gut function and integrity.

Figures

Figure 1. Volcano plot showing the relationship…
Figure 1. Volcano plot showing the relationship of partial Spearman correlations between the gut permeability (L:M ratio) and serum metabolites, adjusted for age, gender, and village.
Horizontal line indicates significance at p-value of

Figure 2. Heat map and hierarchical clustering…

Figure 2. Heat map and hierarchical clustering of the 50 most significantly correlated metabolites with…

Figure 2. Heat map and hierarchical clustering of the 50 most significantly correlated metabolites with L:M ratio as continuous variable, after adjustment for age, gender, and village.
L:M ratio is categorized in deciles. Z-scores shown for metabolites. Abbreviations for lipid nomenclature are described in the methods section. Amino acid abbreviations: Trp (tryptophan), Orn (ornithine), Glu (glutamate), Cit (citrulline).

Figure 3. Scatterplots and fitted regression curves…

Figure 3. Scatterplots and fitted regression curves using non-linear cubic splines for serum metabolites with…

Figure 3. Scatterplots and fitted regression curves using non-linear cubic splines for serum metabolites with significant correlations with the L:M ratio.
Broken lines indicate 95% confidence intervals. Data were modeled using linear mixed effects models that include age and sex and village as a random intercept. Correlation coefficients are shown. Abbreviations for lipid nomenclature are described in the methods section. Amino acid abbreviations: Trp (tryptophan), Orn (ornithine), Glu (glutamate), Cit (citrulline).

Figure 4. Scatterplots and fitted regression curves…

Figure 4. Scatterplots and fitted regression curves using non-linear cubic splines for serotonin/tryptophan ratio and…

Figure 4. Scatterplots and fitted regression curves using non-linear cubic splines for serotonin/tryptophan ratio and kynurenine/tryptophan ratio with L:M ratio.
Broken lines indicate 95% confidence intervals. Data were modeled using linear mixed effects models that include age and sex and village as a random intercept. Correlation coefficients are shown.
Figure 2. Heat map and hierarchical clustering…
Figure 2. Heat map and hierarchical clustering of the 50 most significantly correlated metabolites with L:M ratio as continuous variable, after adjustment for age, gender, and village.
L:M ratio is categorized in deciles. Z-scores shown for metabolites. Abbreviations for lipid nomenclature are described in the methods section. Amino acid abbreviations: Trp (tryptophan), Orn (ornithine), Glu (glutamate), Cit (citrulline).
Figure 3. Scatterplots and fitted regression curves…
Figure 3. Scatterplots and fitted regression curves using non-linear cubic splines for serum metabolites with significant correlations with the L:M ratio.
Broken lines indicate 95% confidence intervals. Data were modeled using linear mixed effects models that include age and sex and village as a random intercept. Correlation coefficients are shown. Abbreviations for lipid nomenclature are described in the methods section. Amino acid abbreviations: Trp (tryptophan), Orn (ornithine), Glu (glutamate), Cit (citrulline).
Figure 4. Scatterplots and fitted regression curves…
Figure 4. Scatterplots and fitted regression curves using non-linear cubic splines for serotonin/tryptophan ratio and kynurenine/tryptophan ratio with L:M ratio.
Broken lines indicate 95% confidence intervals. Data were modeled using linear mixed effects models that include age and sex and village as a random intercept. Correlation coefficients are shown.

References

    1. Keusch G. T. et al.. Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences. Clin. Infect. Dis. 59 (suppl 4), S207–212 (2014).
    1. Crane R. J., Jones K. D. J. & Berkley J. A. Environmental enteric dysfunction: an overview. Food Nutr. Bull. 36, S76–87 (2015).
    1. Weisz A. J. et al.. Abnormal gut integrity is associated with reduced linear growth in rural Malawian children. J. Pediatr. Gastroenterol. Nutr. 55, 747–750 (2012).
    1. Lunn P. G., Northrop-Clewes C. A. & Downes R. M. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet 338, 907–910 (1991).
    1. Lunn P. G., Northrop-Clewes C. A. & Downes R. M. Recent developments in the nutritional management of diarrhoea. 2. Chronic diarrhoea and malnutrition in The Gambia: studies on intestinal permeability. Trans. R. Soc. Trop. Med. Hyg. 85, 8–11 (1991).
    1. George C. M. et al.. Fecal markers of environmental enteropathy are associated with animal exposure and caregiver hygiene in Bangladesh. Am. J. Trop. Med. Hyg. 93, 269–275 (2015).
    1. Campbell D. I. et al.. Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function. Pediatr. Res. 54, 306–311 (2003).
    1. Denno D. M. et al.. Use of the lactulose to mannitol ratio to evaluate childhood environmental enteric dysfunction: a systematic review. Clin. Infect. Dis. 59 (suppl 4), S213–219 (2014).
    1. Lord R. S. & Bralley J. A. (eds.) Laboratory Evaluations for Integrative and Functional Medicine. Metametrix Institute, Duluth, Georgia (2008).
    1. Schmerler D. et al.. Targeted metabolomics for discrimination of systemic inflammatory disorders in critically ill patients. J. Lipid Res. 53, 1369–1375 (2012).
    1. van der Laan M. J., Polley E. C. & Hubbard A. E. Super learner. Stat. Appl. Genet. Mol. Biol. 6, Article 25 (2007).
    1. Friedman J., Hastie T. & Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Software 33, 1–22 (2010).
    1. Friedman J. H. Greedy function approximation: a gradient boosting machine. Ann. Stat. 29, 1189–1232 (2001).
    1. Breiman L. Random forests. Machine Learning 45, 5–32 (2001).
    1. Milborrow S. Earth: Multivariate Adaptive Regression Spline Models, Package Version 4.4-3. Vienna, Austria: R Foundation for Statistical Computing (2015).
    1. Friedman J. H. Multivariate adaptive regression splines (with discussion) Ann. Stat. 19, 1–141 (1991).
    1. Fagone P. & Jackowski S. Phosphatidylcholine and the CDP-choline cycle. Biochim. Biophys. Acta 1831, 523–532 (2013).
    1. Cole L. K., Vance J. E. & Vance D. E. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim. Biophys. Acta 1821, 754–761 (2012).
    1. Goss V., Hunt A. N. & Postle A. D. Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim. Biophys. Acta 1831, 448–458 (2013).
    1. Stremmel W. et al.. Mucosal protection by phosphatidylcholine. Dig. Dis. 30 (suppl 3), 85–91 (2012).
    1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Panthothenic Acid, Biotin, and Choline. National Academy of Sciences. Washington, D.C. Food and Nutrition Board, Institute of Medicine National Academic Press, 390–422 (1998).
    1. Grzelczyk A. & Gendaszewska-Darmach E. Novel bioactive glycerol-based lysophospholipids: new data–new insight into their function. Biochimie 95, 667–679 (2013).
    1. Slotte J. P. Biological functions of sphingomyelins. Prog. Lipid Res. 2013, 52, 424–437 (2013).
    1. Slotte J. P. Molecular properties of various structurally defined sphingomyelins—correlation of structure with function. Prog. Lipid Res. 52, 206–219 (2013).
    1. Beyersdorf N. & Müller N. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation. Biol. Chem. 396, 749–758 (2015).
    1. Kinney H. C. et al.. Myelination in the developing human brain: biochemical correlates. Neurochem. Res. 19, 983–996 (1994).
    1. Le Floc’h N., Otten. W. & Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41, 1195–1205 (2011).
    1. Imbesi R., Mazzone V. & Castrogiovanni P. Is tryptophan ‘more’ essential than other essential aminoacids in development? A morphologic study. Anat. Histol. Embryol. 38, 361–369 (2009).
    1. El-Merahbi R., Löffler M., Mayer A. & Sumara G. The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett. 589, 1728–1734 (2015).
    1. Keszthelyi D., Troost F. J. & Masclee A. A. M. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol. Motil. 21, 1239–1249 (2009).
    1. Mawe G. M. & Hoffman J. M. Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 10, 473–486 (2013).
    1. Burrin D. G. & Stoll B. Metabolic fate and function of dietary glutamate in the gut. Am. J. Clin. Nutr. 90 (suppl), 850S–856S (2009).
    1. Brosnan M.E. & Brosnan J. T. Hepatic glutamate metabolism: a tale of 2 hepatocytes. Am. J. Clin. Nutr. 90 (suppl), 857S–861S (2009).
    1. Blachier F., Boutry C., Bos C. & Tomé D. Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines. Am. J. Clin. Nutr. 90 (suppl), 814S–821S (2009).
    1. De Luca A., Pierno S. & Camerino D. C. Taurine: the appeal of a safe amino acid for skeletal muscle disorders. J. Transl. Med. 13, 243 (2015).
    1. Lambert I. H., Kristensen D. M., Holm J.B. & Mortensen O. H. Physiological role of taurine–from organism to organelle. Acta. Physiol. (Oxf.) 213, 191–212 (2015).
    1. Jianfeng G. et al.. Serum citrulline is a simple quantitative marker for small intestinal enterocytes mass and absorption function in short bowel patients. J. Surg. Res. 127, 177–182 (2005).
    1. Crenn P., Messing B. & Cynober L. Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin. Nutr. 27, 328–339 (2008).
    1. Marini J. C. Arginine and ornithine are the main precursors for citrulline synthesis in mice. J. Nutr. 142, 572–580 (2012).
    1. Lee G. O. et al.. Lactulose: mannitol diagnostic test by HPLC and LC-MSMS platforms: considerations for field studies of intestinal barrier function and environmental enteropathy. J. Pediatr. Gastroenterol. Nutr. 59, 544–550 (2014).
    1. Storey J. D. A direct approach to false discovery rates. J. Roy. Stat. Soc. Ser. B. 64, 479–498 (2002).
    1. Storey J. D., Taylor J. E. & Siegmund D. Strong control, conservative point estimation, and simultaneous conservative consistency of false discovery rates: a unified approach. J. Roy. Stat. Soc. Ser. B. 66, 187–205 (2004).
    1. Rachakonda V. et al.. Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways. PLoS One 9, e113860 (2014).
    1. Polley E. C. & van der Laan M. J. SuperLearner: Super Learner Prediction, Package Version 2.0-15. Vienna, Austria: R Foundation for Statistical Computing [] (Accessed November 25, 2015) (2015).

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera