Neonatal Mouse Gut Metabolites Influence Cryptosporidium parvum Infection in Intestinal Epithelial Cells

Abstract

The protozoan parasite <i>Cryptosporidium</i> sp. is a leading cause of diarrheal disease in those with compromised or underdeveloped immune systems, particularly infants and toddlers in resource-poor localities. As an enteric pathogen, <i>Cryptosporidium</i> sp. invades the apical surface of intestinal epithelial cells, where it resides in close proximity to metabolites in the intestinal lumen. However, the effect of gut metabolites on susceptibility to <i>Cryptosporidium</i> infection remains largely unstudied. Here, we first identified which gut metabolites are prevalent in neonatal mice when they are most susceptible to <i>Cryptosporidium parvum</i> infection and then tested the isolated effects of these metabolites on <i>C. parvum</i> invasion and growth in intestinal epithelial cells. Our findings demonstrate that medium or long-chain saturated fatty acids inhibit <i>C. parvum</i> growth, perhaps by negatively affecting the streamlined metabolism in <i>C. parvum</i>, which is unable to synthesize fatty acids. Conversely, long-chain unsaturated fatty acids enhanced <i>C. parvum</i> invasion, possibly by modulating membrane fluidity. Hence, gut metabolites, either from diet or produced by the microbiota, influence <i>C. parvum</i> growth <i>in vitro</i> and may also contribute to the early susceptibility to cryptosporidiosis seen in young animals.<b>IMPORTANCE</b><i>Cryptosporidium</i> sp. occupies a unique intracellular niche that exposes the parasite to both host cell contents and the intestinal lumen, including metabolites from the diet and produced by the microbiota. Both dietary and microbial products change over the course of early development and could contribute to the changes seen in susceptibility to cryptosporidiosis in humans and mice. Consistent with this model, we show that the immature gut metabolome influenced the growth of <i>Cryptosporidium parvum</i><i>in vitro</i> Interestingly, metabolites that significantly altered parasite growth were fatty acids, a class of molecules that <i>Cryptosporidium</i> sp. is unable to synthesize <i>de novo</i> The enhancing effects of polyunsaturated fatty acids and the inhibitory effects of saturated fatty acids presented in this study may provide a framework for future studies into this enteric parasite's interactions with exogenous fatty acids during the initial stages of infection.