Multiple Omics Study to Unravel the Mechanism of Parabacteroides Goldsteinii Mediated Anti-Obesogenic Effect in Obese Mice

The medicinal fungus Ophiocordyceps sinensis and its anamorph Hirsutella sinensis have a long history of use in traditional Chinese medicine for their immuno-modulatory properties. We previously examined the possibility that H. sinensis mycelium (HSM) and isolated fractions containing polysaccharides may prevent diet-induced obesity and type 2 diabetes by modulating the composition of the gut microbiota. High-fat diet (HFD)-fed mice were treated with HSM or fractions containing polysaccharides of different molecular weights. The effects of HSM and polysaccharides on the gut microbiota were assessed by horizontal fecal microbiota transplantation (FMT), antibiotic treatment and 16S rDNA-based microbiota analysis. Fraction H1 containing high-molecular weight polysaccharides (＞300 kDa) considerably reduced body weight gain (50–70% reduction) and metabolic disorders in HFD-fed mice. These effects were associated with increased expression of thermogenesis protein markers in adipose tissues, enhanced gut integrity, reduced intestinal and systemic inflammation, and improved insulin sensitivity and lipid metabolism. Gut microbiota analysis revealed that H1 polysaccharides selectively promoted the growth of P. goldsteinii, a commensal bacterium whose level was reduced in HFD-fed mice. FMT combined with antibiotic treatment showed that neomycin-sensitive gut bacteria negatively correlated with obesity traits and were required for H1’s anti-obesogenic effects. Notably, oral treatment of HFD-fed mice with live P. goldsteinii reduced obesity and was associated with increased adipose tissue thermogenesis, enhanced intestinal integrity and reduced levels of inflammation and insulin resistance. However, the possible mechanism of anti-obesogenic effect of P. goldsteinii is still uncharacterized. To uncover potential mechanism of anti-obesogenic effect in P. goldsteinii treatment, the advanced multi-omics platforms, including transcriptomics, metabolomics and metagenomic, will be used in this proposal and subdivided into four stages: (1) transcriptomics study: our preliminary results showed P. goldsteinii ameliorated endotoxin production, colonic inflammation status and further reversed gut permeability. In order to get more information, mRNA of whole proximal colon tissue will be examined by transcriptomics. We expect the expression of genes related to inflammatory, tight junction integrity and others will be affected after P. goldsteinii treatment in HFD mice. (2) metabolomics study: Previous studies indicated metabolites such as tryptophan-derived metabolites and short chain fatty acid (SCFA) inhibit inflammation status and gut permeability in obese mice. The serum metabolites will be screened by two platforms, high performance liquid chromatography (HPLC) mass spectrometry and Gas chromatography (GC) mass spectrometry. (3) metagenomics study: gut microbiota play an important role in obese mice. It is still uncertain whether P. goldsteinii may affect distribution of commensal microbes in gut. In order to known the possible functional modules of gut microbes, we replace shot-gun sequence with microbe-specific16S targeted sequence to examine functions in microbes. (4) Integration of big data to unravel the underlying mechanism: The data obtained from multi-omics will be integrated to uncover possible molecular mechanisms of the anti-obesity effect of P. goldsteinii. Results obtained from this proposal will present the underlying mechanism of the anti-obesity effect from P. goldsteinii to be developed as the next generation probiotic.

Project ID:PC10901-1631
External Project ID:MOST108-2320-B182-005-MY2