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, Giardiainfected
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.