| Elevated serum cholesterol, particularly in the low-density lipoprotein (LDL) fraction, is a major independent risk factor for atherosclerosis and coronary artery disease. Current evidence from a variety of human and animal trials suggests a cholesterol lowering effect of specific strains of probiotic lactic acid bacteria; however the results are frequently inconclusive and supportive mechanistic data is scarce. A need therefore exists for low-cost and effective new technologies to meet the present demands and future challenges of probiotics for use in hypercholesterolemia.;The Bio F1B golden Syrian hamster was selected, after species and diet based studies, as a model of hyperlipidemia and cholesterol and bile acid metabolism. Using this model, orally delivered microencapsulated genetically engineered L. plantarum 80 strain significantly lowered total and LDL cholesterol, and improved the atherogenic profile associated with hypercholesterolemia. The effectiveness of the formulation was shown to be dependent on dose and frequency of administration. Furthermore, heart histological samples confirmed a protective effect. Microencapsulated bile salt hydrolase active L. reuteri, chosen among naturally occurring candidate strains, was shown to also lower serum lipids at equivalent dosage, albeit with a significant lag effect towards LDL cholesterol. Treated groups showed increased fecal bile salt excretion along with a significant shift in biliary lipid components compared to control animals, likely due to an up-regulation of hepatic bile acid synthesis from cholesterol.;This work demonstrates the potential effectiveness of this approach as a means of preventing or treating hypercholesterolemia in humans. Furthermore, safety studies indicate that side effects often associated with currently used pharmacologics are largely avoided.;In this thesis, microcapsule formulations for the entrapment of genetically engineered and non-genetically engineered lactic acid bacteria with elevated bile salt hydrolase activity were designed and developed. Strain specific microencapsulation techniques were used to produce spherical microcapsules with narrow size distribution and high cell loading. By enhancing the micro-environment of the encased strains, a high number of viable cells were delivered to the intestine with protection from acid, bile and mechanical stresses. Furthermore, enzymatic activity towards conjugated bile salt substrates was maintained, with significant preference for glyco-conjugates, when administered through a dynamic model simulating human gastrointestinal (GI) transit. |
