Increased Urinary Trimethylamine N-Oxide Following Cryptosporidium Infection and Protein Malnutrition Independent of Microbiome Effects.

David T Bolick,Jon R Swann,Jordi Mayneris-Perxachs,Glynis L Kolling,Jason A Papin,Greg L Medlock,Richard L Guerrant

doi:10.1093/infdis/jix234

Abstract

Cryptosporidium infections have been associated with growth stunting, even in the absence of diarrhea. Having previously detailed the effects of protein deficiency on both microbiome and metabolome in this model, we now describe the specific gut microbial and biochemical effects of Cryptosporidium infection. Protein-deficient mice were infected with Cryptosporidium parvum oocysts for 6-13 days and compared with uninfected controls. Following infection, there was an increase in the urinary excretion of choline- and amino-acid-derived metabolites. Conversely, infection reduced the excretion of the microbial-host cometabolite (3-hydroxyphenyl)propionate-sulfate and disrupted metabolites involved in the tricarboxylic acid (TCA) cycle. Correlation analysis of microbial and biochemical profiles resulted in associations between various microbiota members and TCA cycle metabolites, as well as some microbial-specific degradation products. However, no correlation was observed between the majority of the infection-associated metabolites and the fecal bacteria, suggesting that these biochemical perturbations are independent of concurrent changes in the relative abundance of members of the microbiota. We conclude that cryptosporidial infection in protein-deficient mice can mimic some metabolic changes seen in malnourished children and may help elucidate our understanding of long-term metabolic consequences of early childhood enteric infections.

Highlights

Cryptosporidiosis, a protozoan infection, is prevalent in malnourished populations, areas with limited access to clean water and sanitation, as well as immunocompromised individuals [2, 7,8,9,10,11,12,13]
We examined the effects of cryptosporidiosis on the fecal microbiome and urinary metabolic phenotypes of mice on the same protein-deficient diets
We have previously shown significant weight loss, colonization, fecal shedding of the parasite, and inflammation in mice maintained on a protein-deficient diet infected with C. parvum [15, 17, 18, 24]

Summary

Introduction

Cryptosporidiosis, a protozoan infection, is prevalent in malnourished populations, areas with limited access to clean water and sanitation, as well as immunocompromised individuals [2, 7,8,9,10,11,12,13]. Studies in children and rodents have indicated that undernutrition results in both compositional and functional modulations in the resident gut microbiota [19]. In a study examining the effect of various diets on the mouse microbiota and metabolome, we observed that mice fed a low-protein diet retained a fecal microbiota more similar in composition to newly weaned mice than those on any other diet [20,21,22]. We examined the effects of cryptosporidiosis on the fecal microbiome and urinary metabolic phenotypes of mice on the same protein-deficient diets. We disentangled the infection-specific metabolic alterations from those related to the diet. This approach reveals that several metabolic shifts after infection occur independent of changes in specific microbiota

Methods

Results

Conclusion