Vascular Endothelial Dysfunction Induced by a Western‐Style Diet Can Be Transferred via Fecal Microbiota Transplant in Mice

Consumption of a Western‐style diet (WD; high fat and sugar, low fiber) is associated with vascular endothelial dysfunction, which increases risk of cardiovascular and metabolic diseases. Endothelial dysfunction is largely mediated by reduced nitric oxide (NO) bioavailability, caused by increased superoxide‐driven oxidative stress and inflammation. WD is also associated with adverse changes to the gut microbiome—a potential link between WD and vascular dysfunction and a promising target for therapeutic intervention. PURPOSE To determine if WD‐induced vascular dysfunction can be transferred solely via the gut microbiome using fecal microbiota transplants (FMT). METHODS Young male C57BL/6 mice were fed either control (CON) or WD chow beginning at 3 mo of age. Starting at age 3–5 mo, mice were administered FMTs (feces collected pre‐treatment), via oral gavage, from either their own cohort (i.e., sham condition: CON+CON, N=5; WD+WD, N=12) or from the other cohort of mice (CON+WD, N=5; WD+CON, N=12) for 8–16 weeks. Endothelium‐dependent dilation (EDD; ex vivo carotid artery dilation to increasing doses of acetylcholine) and associated mechanisms were assessed following the intervention. RESULTS Body mass at sacrifice was higher in WD (35.9±0.3 g) vs. CON‐fed mice (CON: 33.4±1.0 g, p<0.01) but was not affected by FMT (both p>0.14). WD‐related impairments in peak EDD (CON+CON: 98.5±1% vs. WD‐WD: 83.3±1%, p<0.01) were attenuated by FMT from CON‐fed mice (WD+CON: 90.6±0.4%; p=0.02 vs. WD+WD), whereas FMT from WD‐fed mice induced a similar impairment in peak EDD (CON+WD: 86.0±2%) to WD chow alone. These changes were NO‐mediated, as addition of the endothelial NO synthase inhibitor L‐NAME abolished differences in peak EDD (CON+CON: 26±3% vs. CON+WD: 26±3%, p=0.91; WD‐WD: 32±1%, vs. WD+CON: 26±2%, p=0.44). FMT did not alter smooth muscle sensitivity to NO, assessed as dilation with the NO donor sodium nitroprusside (both cohorts p>0.17), or aortic superoxide production (electron paramagnetic resonance spectroscopy; both p>0.34). As endothelial function can also be influenced by systemic inflammation, we cultured visceral white adipose tissue for 24 h and measured pro‐inflammatory cytokine production in culture media. In preliminary results (N=4–10/group), FMT from WD‐fed mice increased adipose tissue release of interleukin (IL)‐1β (CON+CON: 60±28 vs. CON+WD: 163±68 pg/ml per 1g of tissue), interferon (IFN)□ (CON+CON: 19±4 vs. CON+WD: 65±25 pg/ml/g), and tumor necrosis factor (TNF)□ (CON+CON: 548±80 vs. CON+WD: 693±27 pg/ml/g) to higher levels than WD‐fed mice (WD+WD: mice, IL‐1β: 89±8 pg/ml/g, IFN□: 43±6 pg/ml/g). However, FMT from CON‐fed mice did not consistently affect adipose inflammation in WD‐fed mice. CONCLUSIONS Our data indicate that WD‐induced vascular endothelial dysfunction: 1) can be transferred by FMT via alterations in NO bioavailability and possibly systemic inflammation; and 2) can be ameliorated by FMT from healthy mice. The gut microbiome may be a promising target for the treatment of WD‐induced vascular dysfunction and cardiovascular diseases. Support or Funding Information R01 HL134887, F32 HL140875