Characterizing the Biochemical Response to <i>Schistosoma mansoni</i> Infection and Treatment with Praziquantel in Preschool and School Aged Children

Schistosomiasis is a widespread chronic neglected tropical disease prevalent mostly in children in under-resourced rural areas. Its pathological effects have been clinically characterized, yet the molecular-level effects are understudied. In this study, the biochemical effects of <i>Schistosoma mansoni</i> infection and praziquantel treatment were studied in 130 preschool aged and 159 school aged infected children and 11 noninfected children in Azaguié, Côte d’Ivoire. Urine samples were collected prior to receiving 20, 40, or 60 mg/kg of praziquantel or a placebo, as well as 24 h post-treatment, and at the 3-week follow up. Urinary metabolic phenotypes were measured using ¹H NMR spectroscopy, and metabolic variation associated with <i>S. mansoni</i> infection and praziquantel administration was identified using multivariate statistical techniques. Discriminatory metabolic signatures were detected between heavily infected and noninfected children at baseline as well as according to the dose of praziquantel administered 24 h post treatment. These signatures were primarily associated with the metabolic activity of the gut microbiota, gut health and growth biomarkers and energy and liver metabolism. These analyses provide insights into the metabolic phenotype of schistosomiasis and treatment with praziquantel in two important demographics

Box plots of the unweighted UniFrac distances.

<p>Box plots showing the median, lower and upper quartiles of the unweighted UniFrac distances at each time point comparing the effect of genotype and cage on the community structure. Whiskers were calculated using the Tukey method; filled circles represent outliers. A lower UniFrac distance indicates greater similarity between two microbial communities (Student's <i>t</i> test: ns = not significant; asterisks indicate significant differences: ****P<0.0001).</p

Mean relative abundances of bacteria for each genotype at week 14 (n = 6 per genotype).

<p>A: Phylum level; key: see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone-0100916-g002" target="_blank">Figure 2</a> legend. B: Family level; key: see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone-0100916-g002" target="_blank">Figure 2</a> legend. Mean relative abundances of each phylum and family for each genotype at each time point (weeks 5, 7, 10 and 14) are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone.0100916.s015" target="_blank">Figure S15</a> (phylum) and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone.0100916.s016" target="_blank">S16</a> (family).</p

Relative abundances of bacteria across all 68 animal samples ordered by time point.

<p>A: Phylum-level; key: ‘Others’ composed of TM7 and <i>Verrucomicrobia</i>. B: Family-level; key: ‘Others’ composed of the families: <i>Alcaligenaceae, Anaeroplasmataceae, Bacillaceae, Clostridiaceae, Enterobacteriaceae, Erysipelotrichaceae, Eubacteriaceae, Halomonadaceae, IncertaeSedis XIII, IncertaeSedis XIV, Lactobacillaceae, Peptococcaceae, Pseudomonadaceae</i> and <i>Sphingomonadaceae</i>. Plot labels: O = obese, L = homozygous lean, H = heterozygous lean; number indicates cage number 1–6.</p

Relative abundances of bacteria for all animals grouped according to cage, at weeks 5 and 14.

<p>A: Phylum-level; key: see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone-0100916-g002" target="_blank">Figure 2</a> legend. B: Family-level; key: see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone-0100916-g002" target="_blank">Figure 2</a> legend. Data for weeks 7 and 10 are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone.0100916.s009" target="_blank">Figure S9</a> (phylum) and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone.0100916.s010" target="_blank">S10</a> (family). Key: O = obese, L = homozygous lean, H = heterozygous lean.</p

Non-Metric Multidimensional Scaling (NMDS) based on the unweighted UniFrac distances between the faecal samples.

<p>A: Samples are coloured by cage (1, red; 2, yellow; 3, green; 4, cyan; 5, dark blue; 6, purple). B: Samples are coloured by the age of the animals at sample collection; the genotype of the animals is shown for week 5. All time points coloured according to genotype are shown in supplementary information (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100916#pone.0100916.s001" target="_blank">Figure S1</a>).</p

Additional file 1: Table S1. of Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse

Blood parameters. Values from minimum of six male mice. (DOCX 13 kb

Additional file 3: Figure S2. of Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse

Effect of high fat diet on Gastrocnemius lipid content. All values are fraction of total lipid content. ANOVA; (*) P<0.05 vs. WT ND; WT HF; (**) P<0.05 vs. Mstn-/- ND. N=6 male mice per group

Fecal MPO, Fecal alpha-1-antitrypsin (A1AT), and plasma LPS, FABP and SAA each predicts subsequent growth impairment.

<p>a: For MPO, <i>p</i> = 0.028; n = 266 when correcting for age and gender, and independent of breastfeeding status (that showed no correlation in these 6-26m old children) and of age. b: For A1AT, n = 237; <i>p</i> = 0.042; and A1AT also correlates with “catchup WAZ” as well, <i>p</i> = 0.035 after correcting for age and gender. c: For urine L/M, higher values correlated (controlling for age and gender) with impaired growth (delta HAZ) (<i>r</i> = -0.173; <i>p</i> = 0.009; n = 230). d: For plasma LPS (ie lower LUM), higher values correlated with impaired growth (delta HAZ) (<i>r</i> = 0.151; <i>p</i> = 0.017; n = 251). e: For plasma FABP, higher values correlated with impaired growth (delta HAZ) (r = -0.134; <i>p</i> = 0.042; n = 231). f: For plasma SAA, higher values correlated with impaired growth (delta HAZ) (r = -0.132; p = 0.046; n = 231).</p

Demographic information for study participants (Children and caregivers; n = 375 at study start, except where otherwise noted).

<p>Demographic information for study participants (Children and caregivers; n = 375 at study start, except where otherwise noted).</p