Inflammation, the kynurenines and mucosal injury during human experimental enterotoxigenic Escherichia coli infection

Enterotoxigenic Escherichia coli (ETEC) is an important cause of children’s and travelers’ diarrhea, especially in low- and middle-income countries. ETEC is a non-invasive gut pathogen, colonizing the small intestinal wall before secreting diarrhea-inducing enterotoxins. We sought to investigate the impact of ETEC infection on local and systemic host defenses by examining plasma markers of inflammation and mucosal injury, as well as kynurenine pathway metabolites.

Plasma from 21 volunteers experimentally infected with ETEC, were collected before and 1, 2, 3, and 7 days after ingesting the ETEC dose, grouped according to the level of intestinal ETEC proliferation: 14 volunteers experienced substantial proliferation (SP) and 7 had low proliferation (LP). Plasma markers of inflammation, kynurenine pathway metabolites, and related cofactors (vitamins B2 & B6) were quantified by using targeted mass spectrometry, while ELISA was used to quantify the mucosal injury markers Reg3a and iFABP.

We found increased concentrations of plasma C-reactive protein (CRP), serum amyloid A (SAA), neopterin, kynurenine/tryptophan ratio (KTR) and Reg3a in the SP group following dose ingestion. Vitamin B6 forms, pyridoxal 5'-phosphate and pyridoxal, and decreased over time in the SP group. CRP, SAA and the pyridoxic acid ratio correlated with ETEC proliferation levels.

The observed changes following experimental ETEC infection indicate that ETEC, despite causing a non-invasive infection, induced systemic inflammation and mucosal injury when proliferating substantially, even in cases without diarrheal symptoms. It is conceivable that ETEC infections, especially when repeated, contribute to the negative health impact on young children living in ETEC-endemic areas.