Biomarkers of environmental enteric dysfunction are differently associated with recovery and growth among children with moderate acute malnutrition in Sierra Leone

Abstract

Background Environmental enteric dysfunction (EED) may influence growth during and recovery from moderate acute malnutrition (MAM), however, biomarkers to assess these relations have yet to be identified. Objectives The objectives of this study were to: 1) develop a score for EED based on host fecal mRNA transcripts, 2) compare biomarkers of EED with each other, and 3) examine associations between the EED biomarkers and recovery from MAM and growth outcomes. Methods In a cohort of 520 Sierra Leonean MAM children, biomarkers of EED included the lactulose: mannitol (L: M) test, 15 host fecal mRNA transcripts, and host fecal proteins [α-1-antitrypsin (AAT), myeloperoxidase (MPO), neopterin (NEO)]. Anthropometry data were also collected and z scores were computed for length-for-age (LAZ) and weight-for-length (WLZ). Recovery from MAM was defined as midupper arm circumference ≥12.5 cm. Factor analysis was used to identify EED scores using the mRNA transcripts, and mixed effects regression was conducted to test for associations. Results The 15 host fecal mRNA transcripts were clustered into 3 scores: gut inflammation (GI) score, gut structure (GS) score, and gut defense (GD) score. We found agreement between certain inflammation markers (GI score and MPO), and permeability markers (GS score and AAT; AAT and the L: M excretion ratio). Antimicrobial gut defense (GD score) was inversely associated with percent lactulose excreted, a measure of intestinal permeability. LAZ (β: –0.08; 95% CI: –0.14, –0.02) and WLZ (β: –0.03; 95% CI: –0.06, –0.01) were negatively associated with GI score. A high GD score (β: 0.36; 95% CI: 0.08, 0.64) and low AAT (β: –1.35; 95% CI: –2.35, –0.36) were associated with recovery from MAM. Conclusions Scores derived from host fecal mRNA transcript variably correlated with the L: M test and host fecal proteins. Markers of intestinal inflammation, permeability, and defense were associated with growth outcomes and recovery from MAM.

Host Fecal mRNAs Predicted Environmental Enteric Dysfunction among Children with Moderate Acute Malnutrition in Sierra Leone

“…In a separate analysis, our group showed that EED biomarkers developed using factor analysis on the same 15 host fecal mRNA transcripts resulted in three scores measuring intestinal inflammation, permeability, and antimicrobial defense. 18 However, those scores were not associated with the L:M test markers. This may be because the factor analysis-based scores separately identified a particular domain of EED, whereas these eight transcripts together likely capture several domains of EED.…”

“…Previously, we showed that the mRNA transcripts were variably correlated with the L:M test variables. 18 Table 5 presents the relationship between recovery from MAM, study arm, and EED at enrollment using unadjusted and adjusted logistic regression models. There was no association between study arm and recovery from MAM even after controlling for EED at enrollment using %L, %M, LMER, or LM ratio in unadjusted models ( P testparm = 0.155, 0.204, 0.160, and 0.165, respectively) and models adjusted for age, sex, and transfer from SAM ( P testparm = 0.328, 0.349, 0.357, and 0.371 respectively).…”

“…Details of sample collection have been described previously. 18 At the PHU, a 20-mL dose comprising 5 g of lactulose (McKesson, San Francisco, CA) and 1 g of mannitol (Sigma Aldrich, St. Louis, MO) was orally given to each participant, using a medicine cup or syringe, after an 8-hour overnight fast. Water was allowed as often as desired by the child before and after being dosed with the sugar solution.…”

“…The function of each has been described previously along with their correlation with the L:M test variables. 18 The copies of the mRNA transcripts were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Samples with GAPDH < 25 copies could not be used to assay the mRNA transcript and were treated as zero.…”

Exposure to multiple mycotoxins, environmental enteric dysfunction and child growth: Results from the AflaCohort Study in Banke, Nepal

“…Lastly, while urinary L:M ratio tests are commonly used to identify gut dysfunction, this test has many limitations. Researchers have identified a need for additional field‐appropriate biomarkers of EED that can measure different characteristics of EED (Denno et al, 2014; Singh et al, 2021).…”