ObjectiveGut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice.MethodsGF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing.ResultsGF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard.ConclusionsIn conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

Background— The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow–derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction. Methods and Results— In a total of 58 patients (BMC group, n=30; placebo group, n=28), coronary flow reserve (CFR) in the infarct artery and a reference vessel was assessed by intracoronary Doppler at the time of study therapy (4.2±0.1 days after acute myocardial infarction) and at the 4-month follow-up. Initial CFR was reduced in the infarct artery compared with the reference vessel in both groups (BMC: 2.0±0.1 versus 2.9±0.2, P <0.05; placebo: 1.9±0.1 versus 2.8±0.2; P <0.05). At the 4-month follow-up, CFR in the infarct artery had slightly improved in the placebo group (+0.88±0.18; P <0.001 versus initial) but was markedly increased by 90% (+1.80±0.25; P =0.005 versus placebo) in BMC-treated patients, resulting in a normalization of CFR (3.8±0.2; P <0.001 versus initial and placebo at 4 months). In the infarct vessel, adenosine-induced minimal vascular resistance index declined slightly in the placebo group (from 1.77±0.12 to 1.52±0.15 mm Hg · s/cm; P <0.05) but considerably decreased by −29±6% in the BMC group (from 1.86±0.19 to 1.20±0.12 mm Hg · s/cm; P <0.05 versus initial and placebo at 4 months). Conclusions— Intracoronary BMC therapy after acute myocardial infarction restores microvascular function of the infarct-related artery, which is associated with a significant improvement in maximal vascular conductance capacity. These data provide clinical proof of concept that progenitor cell transplantation promotes vascular repair.