Obesity has emerged as one of the major global socioeconomic healthcare burdens at present. Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB) has been largely utilised to treat individual suffering from morbid obesity. In the current study, a hyperinsulinemic obese Zucker rat model was employed to study two different weight loss approaches, RYGB and caloric restriction. To understand the host metabolic-microbial cross-talk, the two major analytical platforms including nuclear magnetic resonance (NMR) spectroscopy and 16S rRNA gene Illumina MiSeq sequencing were used in companion with multivariate statistical analysis to extract useful information from data with high complexity. The aim of this study was to 1) characterise the genotype-associated metabolic and microbial fingerprints; 2) investigate the dynamic changes in biofluids from RYGB-treated or caloric restriction-treated obese Zucker rats; 3) investigate genotype-related, RYGBinduced or caloric restriction-induced metabolic profiles and microbial shifts of the luminal contents; and 4) investigate the statistical correlation between metabolites and gut microbiota following either of the weight loss treatment. Metabolic observations of portal vein and peripheral blood plasma profiles in both obese and lean Zucker rats indicated the phenotype-independent absorption of short-chain fatty acids (SCFAs), choline and trimethylamine (TMA). However, phenotype-specific urinary host-microbial co-metabolites were revealed, suggesting distinct gut microbial metabolic activities in lean and obese Zucker rats. Furthermore, metabolic alterations induced by the RYGB surgery included the enhanced production of neuroactive metabolites, branchedchain amino acid (BCAA) catabolism, aromatic amino acid metabolism with lower lipogenesis and SCFA production. Even though caloric restriction demonstrated some health benefit-related biochemical and microbial markers, its effectiveness as a resolution for metabolic syndrome, especially type-2 diabetes mellitus has not been observed in this study in spite of the significant weight reduction.