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

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.

Fig 1. Association of Shigella infections with EE biomarker concentration over time.

Each plot shows EE biomarker natural log concentration differences and 95% confidence intervals comparing non-diarrheal stool samples with and without Shigella detection at month 0. Concentrations were measured monthly from the index Shigella-positive detection through 6-months post-detection.

Fig 2. Associations between Shigella infections and EE biomarker concentrations from time of index subclinical Shigella detection through 6-months post-detection, stratified by antibiotic use within the 15 days before or after Shigella infection.

Each panel shows the respective EE biomarker natural log concentration differences comparing non-diarrheal stool samples with and without Shigella detection at month 0. Concentrations were measured monthly from the index Shigella-positive detection through 6-months post-detection. The black line represents no antibiotic use, and the red line represents antibiotic use within the 15-days before or after month 0.