Importance of Sulfur-Containing Metabolites in Discriminating Fecal Extracts between Normal and Type‑2 Diabetic Mice

A metabolic disorder such as Type-2
Diabetes mellitus (T2DM) is
a complex disease induced by genetic, environmental, and nutritional
factors. The db/db mouse model, bearing a nonfunctional
leptin receptor, is widely used to investigate the pathophysiology
of T2DM. Fecal extracts of db/db and wild-type littermates
were studied to unravel a broad spectrum of new and relevant metabolites
related to T2DM as proxies of the interplay of gut microbiome and
murine metabolomes. The nontargeted metabolomics approach consists
of an integrated analytical concept of high-resolution mass spectrometry
FT-ICR-MS, followed by UPLC-TOF-MS/MS experiments. We demonstrate
that a metabolic disorder such as T2DM affects the gastrointestinal
tract environment, thereby influencing different metabolic pathways
and their respective metabolites in diabetic mice. Fatty acids, bile
acids concerning cholic and deoxycholic acid, and steroid metabolism
were highly discriminative comparing fecal meta-metabolomes of wt and db/db mice. Furthermore, sulfur-(S)-containing
metabolites including N-acyl taurines were altered
in diabetic mice, enabling us to focus on S-containing metabolites,
especially the sulfate and taurine conjugates of bile and fatty acids.
Different sulfate containing bile acids including sulfocholic acid,
oxocholic acid sulfate, taurocholic acid sulfate, and cyprinol sulfate
were significantly altered in diabetic mice. Moreover, we identified
12 new sulfate and taurine conjugates of hydroxylated fatty acids
with significant importance in T2DM metabolism in db/db mice.