Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli

Abstract

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

The Intersection of Immune Responses, Microbiota, and Pathogenesis in Giardiasis

“…As nutrient malnourishment and Giardia infection in humans both likely contribute to decreased immune function [29], a recent report has examined the effects of protein malnourishment on murine Giardia infections. Mice fed a protein deficient diet presented with persistent infections, an alteration in the composition of duodenal microbes, and enhanced growth (weight) impairment when infected with Giardia [30]. Taken together, these reports suggest that Giardia have significant interactions with the intestinal microbiota, which may lead to changes in infection outcome and immunopathology.…”

“…However, this result must be further examined as the data was provided from 12 year-frozen samples and were taken from a study that was not designed to examine the intestinal microbiota composition [38]. The two latest studies identifying the taxa of duodenal microbiota during murine Giardia infections both use samples extracted from intestinal segments for sequencing rather than fecal samples [30, 37]. However, bacterial community analysis derived from fecal samples of non-antibiotic treated, infected mice were indistinguishable when compared to uninfected control mice [30].…”

“…The two latest studies identifying the taxa of duodenal microbiota during murine Giardia infections both use samples extracted from intestinal segments for sequencing rather than fecal samples [30, 37]. However, bacterial community analysis derived from fecal samples of non-antibiotic treated, infected mice were indistinguishable when compared to uninfected control mice [30]. Accordingly, if possible, future microbial studies should use samples isolated from intestinal segments rather than fecal samples to provide accurate results.…”

Immunological interaction between Giardia cyst extract and experimental toxoplasmosis

“…Others demonstrated increased expression of the anti‐inflammatory molecules due to inhibition of genes associated with inflammatory responses . Interestingly, Giardia alters the inflammatory markers in the intestine when presents alone and they are strongly increased in co‐infection with other pathogens . Some observations showed that Giardia infections could protect against other diarrhoeal diseases because of its immunomodulatory role.…”

“…68 Interestingly, Giardia alters the inflammatory markers in the intestine when presents alone and they are strongly increased in co-infection with other pathogens. 69 Some observations showed that Giardia infections could protect against other diarrhoeal diseases because of its immunomodulatory role. Research has demonstrated that, in some cases of Giardia infections, attenuation of pro-inflammatory leucocytes recruitment and decreased NO production occur.…”