A High Fat/High Sugar Diet Alters the Gastrointestinal Metabolome in a Sex Dependent Manner.

Ayland C Letsinger,Jorge Z Granados,J Timothy Lightfoot,Anjushree R Iyer,Rani Menon,Arul Jayaraman,Heather L Vellers

doi:10.3390/metabo10100421

Abstract

The gut metabolome offers insight for identifying the source of diet related pathology. As such, the purpose of this study was to characterize alterations of the gut metabolome in female and male C57BL/6J mice randomly assigned to a standard “chow” diet (CHOW) or a high fat/high sugar diet (HFHS; 45% fat and 20% fructose drinking solution) for nine weeks. Cecal metabolites were extracted and an untargeted analysis via LC-MS/MS was performed. Partial Least Sums Discriminate Analysis (PLS-DA) presented significant differences between the two diet groups in a sex-dependent manner. Mann–Whitney U-tests revealed 2443 and 1669 features to be significantly different between diet groups in the females and males, respectively. The majority of altered metabolites were depleted within the cecum of the HFHS fed mice. Metabolic pathways associated with galactose metabolism, leukotriene metabolism, and androgen and estrogen biosynthesis and metabolism were differentially altered with an HFHS diet between sexes. We concluded the immense metabolite depletion and elevation of adverse metabolites associated with the HFHS diet is suggestive of poor gut health. Further, the differential alterations between female and male mice suggests that sex plays an important role in determining the effect of diet on the metabolome and host health.

Highlights

Poor diet is considered the leading cause of preventable death in the United States [1] and directly contributes to low quality of life via cardiovascular disease, diabetes, obesity, and mental health disorders [2]
There was little separation between female and male mice reared on the chow” diet (CHOW) diet; the separation between female and male mice was more pronounced in high fat/high sugar diet (HFHS) fed mice (Figure 1)
The pattern of significant metabolite alteration in the HFHS fed mice was the opposite to that observed into the CHOW fed mice

Summary

Introduction

Poor diet is considered the leading cause of preventable death in the United States [1] and directly contributes to low quality of life via cardiovascular disease, diabetes, obesity, and mental health disorders [2]. Recent studies have shown that nutrients can have variable effects on health due to genetic and environmental interactions. Single nucleotide polymorphisms within APOA5, LIPC, and CETP gene regions have been associated with altered lipid profiles in response to the same diet [3]. The interactions can be sex dependent as females have greater incidence of irritable bowel syndrome [4] and Crohn’s disease [5], while men experience greater incidence of ulcerative colitis [5]. Causal links between specific nutrients and health are difficult to establish due to the physiological complexity, time, and cost required for longitudinal studies.

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Conclusion