Serum anti-flagellin and anti-lipopolysaccharide immunoglobulins as predictors of linear growth faltering in Pakistani infants at risk for environmental enteric dysfunction

Background: Environmental Enteric Dysfunction (EED) in children from low-income countries has been linked to linear growth declines. There is a critical need to identify sensitive and early EED biomarkers.Objective: Determine whether levels of antibodies against bacterial components flagellin (flic) and lipopolysaccharide (LPS) predict poor growth.Design/Methods: In a prospective birth cohort of 380 children in rural Pakistan blood and stool samples were obtained at ages 6 and 9 months. Linear mixed effects models were used to examine longitudinal associations between quartiles of anti-flic and anti-LPS antibodies and changes in LAZ, WAZ and WLZ scores. Spearman\u27s correlations were measured between anti-flic and anti-LPS immunoglobulins with measures of systemic/enteric inflammation and intestinal regeneration.Results: Anti-LPS IgA correlated significantly with CRP, AGP and Reg1 serum at 6mo and with MPO at 9mo. In multivariate analysis at 6mo of age, higher anti-LPS IgA levels predicted greater declines in LAZ scores over subsequent 18mo (comparing highest to lowest quartile, β (SE) change in LAZ score/year = -0.313 (0.125), p-value = 0.013). Anti-flic Ig A in the two highest quartiles measured at 9mo of age had declines in LAZ of -0.269 (0.126), p = 0.033; and -0.306 (0.129), p = 0.018 respectively, during the subsequent 18mo of life, compared to those in the lowest quartile of anti-flic IgA.Conclusions and Relevance: Elevated anti-flic IgA and anti-LPS IgA antibodies at 6 and 9mo, predict declines in linear growth. Systemic and enteric inflammation correlated with anti-LPS IgA provides mechanistic considerations for potential future interventions

Additional file 1 of Physiology education in China: the current situation and changes over the past 3 decades

Supplementary Material 1

Patient, tumor, and treatment data in derivation and validation sets.

<p>N/A, data not available.</p><p>Patient, tumor, and treatment data in derivation and validation sets.</p

Characteristics and reported findings for the genes comprising the 13-gene prognostic signature.

<p>SNP, single-nucleotide polymorphism; ER, estrogen receptor; AA, African American; SCC, squamous cell carcinoma; AML, acute myeloid leukemia; MM, multiple myeloma; VHL, von Hippel-Lindau; NSCLC, non-small cell lung carcinoma; NK, natural killer; B-CLL, B-cell chronic lymphocytic leukemia.</p><p>Characteristics and reported findings for the genes comprising the 13-gene prognostic signature.</p

Top 20 KEGG pathways significantly enriched (p<0.05) for upregulation in high risk patients relative to low risk patients.

<p>*Pathways that include genes from the prognostic signature are shown.</p><p>FDR, False Discovery Rate; KEGG, Kyoto Encyclopedia for Genes and Genomes.</p><p>Top 20 KEGG pathways significantly enriched (p<0.05) for upregulation in high risk patients relative to low risk patients.</p

A 13-gene expression signature combined with lymph node status accurately predicts patient survival.

<p>Kaplan-Meier overall survival of (<b>A</b>) a validation set of 101 patients with localized, resected PDAC according to 13-gene prognostic score combined with pathologic lymph node status at the time of surgery, and (<b>B</b>) the same 101 patients grouped according to either high-risk 13-gene prognostic score alone or low-risk 13-gene prognostic score plus pathologic nodal status at time of surgery.</p

Application of a 13-gene prognostic signature for patients with PDAC.

<p>(<b>A</b>) Kaplan-Meier overall survival of patients comprising the UVA-15 derivation set grouped by short survival time (n = 7, survival range: 2.0–9.0 mo; median: 6.1 mo) and long survival time (n = 8, survival range: 10.6–32.8 mo; median: 13.7 mo; log-rank p<0.001). (<b>B</b>) Expression of 13-genes in the 15-tumor derivation set of patients with PDAC reveals clustering into high- (purple bar) and low-risk (yellow bar) populations. (<b>C</b>) Application of the 13-gene signature to an independent validation set of 101 patients with localized and resected PDAC reveals clustering into high- (purple bar) and low-risk (yellow bar) groups based on gene expression. (<b>D</b>) Kaplan-Meier overall survival of the independent validation set according to high- and low-risk groups as determined by 13-gene signature (log-rank p = 0.001).</p

Infant and Maternal Characteristics at six and nine months^*.

<p>Infant and Maternal Characteristics at six and nine months^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193768#t001fn002" target="_blank">*</a>}.</p

The association of anti-flagellin and anti-lipopolysaccharide immunoglobulin concentrations at 6 and 9 months with annual Z score changes for length using linear mixed effects models.

<p>The association of anti-flagellin and anti-lipopolysaccharide immunoglobulin concentrations at 6 and 9 months with annual Z score changes for length using linear mixed effects models.</p

Overall model schema.

<p>After resection, human pancreatic ductal adenocarcinomas are orthotopically implanted into the pancreases of immunocompromised mice and propagated in subsequent generations. Tumors undergo genetic and proteomic assessment. Clinical and pathologic data are collected for each individual human tumor.</p