Frequent enteric infections in children may be an important cause of
growth faltering; however, we do not fully understand the mechanisms by
which pathogen infections and the physiological responses to these
infections result in poorer growth. Commonly used protein fecal biomarkers
(anti-alpha trypsin, neopterin, and myeloperoxidase) provide broad
immunological information on an inflammatory response; however, they do
not provide information on non-immune processes (e.g., gut integrity) that
may be important indicators of chronic end states such as environmental
enteric dysfunction (EED). To explore how additional biomarkers will
better inform which physiological pathways (both immune and non-immune)
are impacted by pathogen exposure we added to the traditional panel of 3
protein fecal biomarkers 4 novel fecal mRNA transcript biomarkers (sucrase
isomaltase, caudal homeobox 1, S100A8, and mucin 12) and analyzed stool
samples from infants living in informal settlements in Addis Ababa,
Ethiopia. To test how this expanded biomarker panel captures distinct
pathogen exposure processes we used two different scoring systems. First,
we used a theory-based approach to assign each biomarker to specific
physiological attributes based on prior understanding of each biomarker.
Second, we used data reduction methods to categorize biomarkers and then
assign physiological attributes to those categories. We used linear models
to examine the association between the derived biomarker scores (based on
mRNA and protein levels) and stool pathogen gene counts to determine
pathogen-specific effects on gut physiology and immune responses.
Inflammation scores were positively associated with Shigella and
enteropathogenic E. coli (EPEC) infection, while gut integrity scores were
negatively associated with Shigella, EPEC, and shigatoxigenic E. coli
(STEC) infection. Our expanded panel of biomarkers hold promise as tools
to measure systemic outcomes of enteric pathogen infection. mRNA
biomarkers complement established protein biomarkers by providing
important cell-specific physiological and immunological consequences of
pathogen carriage that can lead to chronic end states such as EED.