Nano-engineered probiotic treats atherosclerosis via inhibiting intestinal microbiota-TMA-TMAO axis

Considerable numbers of patient are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complication but is lack of practical treatment. Thereinto, trimethylamine N-oxide (TMAO), originated from enteric microorganism, emerges as an unconventional and crucial factor causing atherosclerosis. Here we demonstrate a strategy to inhibit TMAO through intestinal microbiota-trimethylamine (TMA)-TMAO axis for atherosclerotic treatment. The therapy is performed by an oral-treated nano-engineered probiotic PDMF@LGG, where the probiotic Lacticaseibacillus rhamnosus GG (LGG) is armed with polydopamine coating and conjugated with PMF nanoparticles based on a ROS-responsive polymeric prodrug of fluoromethylcholine (FMC). PDMF@LGG can durably colonize the intestinal canal due to sticky polydopamine coating and the protection of PMF against ROS-induced injury. The ROS trigger the delivery of FMC from nanoparticles, which can inhibit TMA production in enteric microorganisms. Meanwhile, LGG can strengthen the tight junctions of intestinal epithelium and reduce TMA entering the blood. The in vivo study suggests that PDMF@LGG reduces plasma TMAO and suppresses atherosclerotic progression. Furthermore, the microbiomics and metabolomics show that PDMF@LGG also regulates gut microbial composition and various metabolites, assisting in the therapeutic outcome. Together, PDMF@LGG offers a potential candidate for atherosclerotic therapy caused by TMAO and broadens the range of treatable atherosclerosis.