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    • br Methods br Results The demographic

    2018-11-14


    Methods
    Results The demographic characteristics of the 400 children are shown in Table 1. Three hundred twenty-three (80.7%) children had EED. Children with EED were significantly younger, more likely to have a living father, reside in a home without a metal roof (an indicator of lower socioeconomic status), and less likely to use water from a clean source than children without EED. There were significant differences in prevalence of EED among the six villages. There were no significant differences in gender, anthropometric measurements, or number of siblings between children with and without EED. The relationship of gut permeability, as assessed by the L:M ratio, with serum metabolites is summarized in a volcano plot in Fig. 2. There were 77 metabolites that purchase ST 2825 were significantly associated with gut permeability. Twenty-one metabolites were negatively associated with gut permeability, including six metabolites related to dietary polyphenols, citrulline, ornithine, tryptophan, and indolelactate (Table 2). Fifty-six metabolites were positively associated with gut permeability, including 9 acylcarnitines, deoxycarnitine, 3 intermediates of β-oxidation of fatty acids, 4 metabolites from ω-oxidation of fatty acids, 4 odd-chain fatty acids, trimethylamine-N-oxide, cystathionine, and homocitrulline (Table 3). The age-, sex-, and village-adjusted Spearman correlations between gut permeability and serum metabolites are presented in Supplementary Table 1. Serotonin was positively associated with gut permeability but was of marginal significance (p=0.0098, q=0.050007). Serum metabolites in children with and without EED were compared in Supplementary Table 2. When multiple machine-learning classification algorithms were used to assess the ability of the 77 metabolites significantly correlated with the L:M ratio to classify EED status (EED vs. no EED), six algorithms had positive weights: LASSO (Friedman et al., 2010), ridge regression (Friedman et al., 2010), generalized boosted models (Friedman, 2001), random forests (Breiman, 2001), multivariate adaptive regression splines (Friedman, 1991) implemented using the polymars() function in R software version 3.20, and Bayes generalized linear models. A receiver operating characteristic curve (ROC) is shown in Supplementary Appendix Fig. 1. (Supplementary Appendix Fig. 1). The Super Learner cross-validated area under the ROC curve was 0.710 (95% confidence interval 0.643, 0.777). The final cross-validated Super Learner model was well calibrated showing little evidence of lack of fit (Hosmer-Lemeshow p-value=0.91) (Supplementary Appendix Table 1). These findings show that the 77 serum metabolites that were significantly associated with gut permeability have a modest ability to discriminate between children with and without EED.
    Discussion The present study shows that increased gut permeability is associated with elevated serum concentrations of nine acylcarnitines, three intermediate metabolites associated with blocked β-oxidation of fatty acids, and four metabolites related to upregulation of ω-oxidation of fatty acids, a serum metabolite profile that is consistent with secondary carnitine deficiency and defective fatty acid oxidation (Stanley, 2004; Tein, 2013). Carnitine is a conditionally essential nutrient that plays a vital role in fatty acid metabolism and energy production. This study shows that secondary carnitine deficiency is associated with EED. In healthy humans consuming a normal diet, ~75% of carnitine is from food and the remaining ~25% is synthesized by the body (Kendler, 1986). The richest dietary sources of carnitine are animal source foods, such as red meat, chicken, fish, and dairy products. Plant foods only contain negligible amounts of carnitine (Demarquoy et al., 2004). Carnitine is synthesized in the body from two essential amino acids, lysine and methionine. Lysine provides the carbon backbone and nitrogen atom of carnitine, while methionine provides the methyl groups. Cofactors necessary for this synthesis include niacin, pyridoxine, ascorbic acid, and ferrous iron. In many parts of the developing world, including rural Malawi, animal source foods are rarely consumed (Dror and Allen, 2011), and lysine is a limiting essential amino acid in the maize-based diet (Nuss and Tanumihardjo, 2011). A limitation of dietary lysine could theoretically increase the risk of carnitine deficiency, however serum lysine was not significantly associated with gut permeability. Experimental animal models show that lysine deficiency leads to impaired carnitine synthesis and fatty acid abnormalities (Tanphaichitr and Broquist, 1973; Khan and Bamji, 1979). In addition to its role in fatty acid metabolism, carnitine may play an important role in normal gut function. Enterocytes synthesize carnitine from lysine and methionine (Shekhawat et al., 2013). Mice with loss of functional mutations in OCTN2 show villous atrophy and inflammation in the small intestine (Shekhawat et al., 2007; Sonne et al., 2012).