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

PDMF@LGG successfully reduced plasma TMAO levels in atherosclerotic mice.

• PDMF@LGG is composed of polydopamine-coated Lacticaseibacillus rhamnosus GG (LGG) combined with nanoparticles based on a ROS-responsive polymeric prodrug of fluoromethylcholine (FMC).
• The system suppresses TMA production and absorption by targeting the gut microbiota-TMA-TMAO axis.
• Studies were conducted in male ApoE-/- mice, a standard atherosclerosis model.
• Plasma TMAO levels were measurably lowered compared to control groups.

PDMF@LGG alleviated atherosclerotic plaque formation in male ApoE-/- mice.

• Therapeutic effects were demonstrated specifically in male ApoE-/- mice.
• Plaque formation was reduced compared to untreated or control-treated animals.
• The treatment addresses atherosclerosis in patients without typical conventional risk factors, representing an unconventional therapeutic target.
• TMAO derived from gut microbes is described as 'a key unconventional contributor to the development of atherosclerosis.'

Polydopamine coating of LGG promoted retention of both probiotics and nanoparticles in the intestine.

• Polydopamine coating was applied to Lacticaseibacillus rhamnosus GG as part of the PDMF@LGG construct.
• Enhanced intestinal retention allowed persistent scavenging of elevated reactive oxygen species (ROS).
• Prolonged retention also facilitated sustained drug (FMC prodrug) release in the intestinal environment.
• The ROS-responsive polymeric prodrug releases fluoromethylcholine (FMC) upon encountering elevated ROS conditions.

PDMF@LGG regulated gut microbial composition and various metabolites in treated mice.

• Treatment with PDMF@LGG modulated the gut microbiota composition in ApoE-/- mice.
• Multiple metabolites were altered alongside changes in microbial composition.
• The intervention targeted the gut microbiota-TMA-TMAO axis, implicating microbial TMA production as a primary mechanism.
• ROS scavenging in the intestine is proposed as a contributing mechanism for modulating the gut microbial environment.

The FMC prodrug component of PDMF@LGG is ROS-responsive, enabling controlled drug release in the intestine.

• Fluoromethylcholine (FMC) was formulated as a polymeric prodrug that responds to reactive oxygen species.
• Elevated ROS in the atherosclerotic/dysbiotic gut environment triggers drug release.
• FMC functions as a choline analog that can interfere with TMA production by gut microbiota.
• This ROS-triggered release mechanism is designed to provide site-specific activity within the intestinal lumen.

PDMF@LGG broadens the range of treatable atherosclerosis by addressing TMAO-driven disease in patients without typical risk factors.

• The authors note that 'many patients are suffering from atherosclerosis without typical risk factors.'
• TMAO is identified as a 'key unconventional contributor to the development of atherosclerosis.'
• The strategy represents 'a potential candidate for atherosclerotic therapy caused by TMAO.'
• The approach is described as broadening 'the range of treatable atherosclerosis' beyond conventional risk factor management.