Sex- and mouse strain-related differences in body weight gain, composition of the gut microbiota, and levels of selected metabolites in response to a Western-style diet

Recent studies reveal an association between the mitochondrial Amidoxime Reducing Component (MTARC) 1 and 2 proteins and metabolism in Mtarc1/2-deficient mice that are resistant to diet-induced obesity; however, the impact of Mtarc1/2 knockout (KO) on the gut microbiota and metabolome has not been explored in the context of sex and diet. To compare the effects of a Western diet (WD) or a Novel Gubra Amylin NASH (GAN) diet on body weight gain, and on the composition of the gut microbiome and metabolome, between the background mouse strain and male and female Mtarc1- or Mtarc2-KO mice. Seventy-two 8-week-old male and female mice from each strain were fed a WD or a corresponding control normal diet (ND/WD), or a GAN diet or a corresponding control normal diet (ND/GAN), for 16 weeks. Fecal samples were collected at the beginning and end of the experiments, and 16 S rRNA-based microbiota profiling-based analysis was performed by sequencing the variable V3 and V4 regions of the bacterial 16 S rRNA gene. Mass spectrometry was used to measure short-chain fatty acids (SCFAs) and amino acids (AAs). Compared with a control ND, GAN feeding increased the body weight of all groups of mice, whereas the WD increased the body weight of all groups except Mtarc2-KO female mice. The most significant weight gain was observed for male and female C57BL6/NTac mice fed a WD or GAN. Differences in body weight were mirrored in the microbiota profiles. In each of the mouse strains tested, the number of differentially abundant taxa between the GAN- and ND/GAN-fed groups was greater than that between WD- and ND/WD-fed mice. Both the GAN and WD also altered the levels of SCFAs and AAs in feces in a manner dependent on the mouse strain and sex. Significant differences in body weight gain and changes in the composition of the gut microbiome and metabolome between the background mouse strain and Mtarc1-KO or Mtarc2-KO mice were further modified by sex and diet. Therefore, preclinical studies using animal models of obesity should ensure the selection of the appropriate mouse strain and sex, and be mindful of diet composition.