Stunting Is Preceded by Intestinal Mucosal Damage and Microbiome Changes and Is Associated with Systemic Inflammation in a Cohort of Peruvian Infants

Abstract

Stunting, defined as height-for-age Z score equal to or lower than -2, is associated with increased childhood mortality, cognitive impairment, and chronic diseases. The aim of the study was to investigate the relationship between linear growth, intestinal damage, and systemic inflammation in infants at risk of stunting. We followed up 78 infants aged 5-12 months living in rural areas of Peru for 6 months. Blood samples for biomarkers of intestinal damage (intestinal fatty-acid-binding protein [I-FABP] and zonulin) and systemic inflammation (interleukin-1β, interleukin-6, tumor necrosis factor α [TNF-α], soluble CD14, and lipopolysaccharide-binding protein [LBP]) and fecal samples for microbiome analysis were collected at baseline and closure of the study. The children's growth and health status were monitored through biweekly home visits by trained staff. Twenty-one percent of the children became stunted: compared with non-stunted children, they had worse nutritional parameters and higher levels of serum I-FABP at baseline. The likelihood of becoming stunted was strongly associated with an increase in sCD14 over time; LBP and TNF-α showed a trend toward increase in stunted children but not in controls. The fecal microbiota composition of stunted children had an increased beta diversity compared with that of healthy controls throughout the study. The relative abundance of Ruminococcus 1 and 2, Clostridium sensu stricto, and Collinsella increased in children becoming stunted but not in controls, whereas Providencia abundance decreased. In conclusion, stunting in our population was preceded by an increase in markers of enterocyte turnover and differences in the fecal microbiota and was associated with increasing levels of systemic inflammation markers.

Figure 1.

Changes in anthropometric measures during follow-up. (A) Median changes in weight-for-age, length-for-age, and weight-for-length Z scores during follow-up (75 children) and (B) median change in length-for-age Z score: stunted children (16 children) vs. non-stunted (59 children). **P < 0.001, Mann–Whitney U-test.

Figure 2.

Monthly changes in length-for-age Z (LAZ) score, stunted children (N = 16) vs. non-stunted (N = 59) children. The children who developed stunting at the end of the follow-up had a lower LAZ score at enrollment and at each time point during the follow-up (each point indicates the median value per group; error bars indicate 95% CI). At the end of the follow-up, the median decrease in LAZ score was −1.1 for children meeting the criteria for stunting vs. −0.29 for non-stunted children (P = 0.01).

Figure 3.

Proportional changes in blood levels of seven serum biomarkers during the 6-month follow-up, stunted children (N = 16) vs. non-stunted (N = 59) children. Graphs A–F report medians with the 25th–75th percentile (Mann–Whitney U-test). Graph H shows the correlation between changes in sCD14 and LBP over time (Spearman rank correlation).

Figure 4.

Correlation between intestinal fatty-acid–binding protein (I-FABP) levels and change in length-for-age Z scores (LAZ) in stunted children (16) vs. non-stunted children (59). The concentration of serum I-FABP was inversely correlated with changes in LAZ scores among stunted children, whereas it seemed to have a weak positive correlation with LAZ score change in children who did not become stunted. r = Spearman correlation coefficient.

Figure 5.

Bray–Curtis diversity comparisons among fecal microbiome samples collected at baseline and end of follow-up, stunted children vs. non-stunted children. P-values are calculated using t-test.