# Transitory impact of subclinical Shigella infections on biomarkers of environmental enteropathy in children under 2 years

## TL;DR

This study found that subclinical Shigella infections in young children cause temporary increases in gut inflammation markers, but these effects do not last long enough to explain long-term growth issues.

## Contribution

The study is the first to show that the impact of subclinical Shigella infections on environmental enteropathy biomarkers is transient, not sustained.

## Key findings

- MPO concentrations increased during Shigella infection but returned to baseline within a month.
- NEO and AAT concentrations showed delayed decreases but not sustained elevation.
- The transient nature of biomarker changes suggests they are not reliable indicators of long-term growth effects.

## Abstract

Clinical and subclinical Shigella infections among children living in low- and middle-income countries (LMICs) have been associated with long-term adverse effects such as impaired linear growth. The mechanism for the impact of subclinical infections has been theorized to occur through contributions to environmental enteropathy (EE). While Shigella has previously been associated with biomarkers of EE at the time of infection, we evaluated whether this impact was sustained after infections, which would support EE being the mechanism for the effects of Shigella on growth. A prospective birth cohort study of 1,715 children living in 8 different LMICs was conducted. Over the course of 24 months, monthly non-diarrheal stool samples were analyzed for subclinical Shigella infections through quantitative PCR methods. EE was reflected by elevated concentrations of 3 fecal biomarkers: myeloperoxidase (MPO), neopterin (NEO), and alpha-1-antitrypsin (AAT). MPO concentrations were found to be significantly higher by 0.30 ln(nm/mL) (95% CI: 0.23, 0.37) in the initial month of Shigella detection among stools with subclinical Shigella infections. After the Shigella infection, MPO concentrations declined throughout the following 6 months, and concentrations were lower by 6 months post-infection [MPO 6-month difference: -0.16 ln(nm/mL) (95% CI: -0.26, -0.04)]. Subclinical Shigella infections had no effect on NEO concentration levels within the initial month of Shigella detection but did decrease post-infection. Subclinical Shigella infections had no effect on AAT concentration levels until 6 months post-infection [AAT difference: -0.13 ln(mg/g) (95% CI: -0.24, -0.03)]. These findings did not differ by antibiotic use around time of index infection. The impact of Shigella on biomarkers of EE was not sustained, suggesting the negative association between Shigella and growth could be explained by the accumulation of time-limited rather than persistent effects on inflammation.

We evaluated whether the impacts of Shigella on linear growth among children in low-resource settings were reflected in sustained effects of Shigella infections on biomarkers of environmental enteropathy. The effect of Shigella on environmental enteropathy biomarkers was in fact transient, with myeloperoxidase concentrations returning to baseline within one month following the index Shigella infection. Therefore, myeloperoxidase and other EE biomarkers unlikely to be good markers of the sustained impact of Shigella on EE and growth.