Microbes for life; investigating the effects of oral administration of Lactobacillus mucosae DPC 6426 on cardiometabolic parameters

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O'Donovan, Aoife
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University College Cork
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Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors, including obesity, dyslipidaemia, hypertension and insulin resistance, with a range of secondary conditions such as non-alcoholic fatty liver disease (NAFLD) and heart failure and has been identified as one of the major global health challenges of the 21st century. This thesis outlines the role the gut microbiome has in the progression of the associated risk factors and alternative therapeutic approaches for cardiovascular disease prevention. In Chapter 1, the importance of the gut microbiome and use of clinical scale models are discussed with a view towards identifying key gut microbiota which are associated with the risk factors for cardiovascular disease development, and how different pre-clinical animal models can assist in understanding the underlying mechanisms of disease, test procedures and develop appropriate therapeutic interventions that will yield the highest reproducible results. In Chapter 2, a method was developed in order to optimise cultivation and freeze-drying of Lactobacillus mucosae DPC 6426, an exopolysaccharide (EPS)-producing lactic acid bacteria (LAB), previously shown to reduce serum cholesterol in the apoE model of lipid driven atherosclerosis [1] at a minimum concentration of 109 CFU/g in order to achieve a minimum concentration of 1010 CFU/g following freeze-drying and subsequent storage at -30°C. In Chapter 3, the efficacy of oral supplementation with Lactobacillus mucosae DPC 6426 at a minimum concentration of 109 CFU/g on reducing cholesterol levels in mildly hypercholesterolaemic (≥5mmol/L and <7.5mml/L) adults over a 12-week period was investigated. Results indicated that supplementation with Lb. mucosae DPC 6426 had no significant effects on the serum lipid profiles (total cholesterol, LDL- cholesterol, HDL-cholesterol and triglycerides). Additionally, there were no significant changes observed in the gut microbiota diversity between the placebo group and probiotic group. These results suggest that a minimum concentration of 109 CFU/g may be insufficient to have a significant effect on serum lipid profiles and gut microbiota diversity, prompting future investigations to be carried out. In Chapter 4, a porcine model of diet- and mineralocorticoid-induced metabolic syndrome (MetS) and heart failure with preserved ejection fraction (HF-pEF) was developed, in which this model closely mimicked the cardiovascular, metabolic, gut microbiome and metataxonomic phenotype observed in human studies. Following feeding of a high fat diet (HFD) for a period of 12 weeks, all animals developed obesity, hyperlipidaemia, insulin resistance, hypertension, fatty liver disease, structural cardiovascular changes and also a reduction in α-diversity and specific microbiota changes, in particular increased abundances of pro-inflammatory bacteria, Fusobacteriaceae, Enterobacteriaceae, and Veillonellaceae at family level and Fusobacterium, Methanosphaera, and Acidaminococcus at genus level, and a reduction in short-chain fatty acid-producing bacteria Lachnospiraceae, Rikenellaceae and Akkermansia in the porcine gut. In Chapter 5, using the previously established porcine model of MetS, the efficacy of daily oral supplementation of Lb. mucosae DPC 6426 and fibre, singly, or in combination, on the gut microbiome composition was investigated. Animals were fed a high fat, sugar and salt diet over 12 weeks combined with either Lb. mucosae DPC 6426 (1010 CFU/g/day) and fibre, alone, or in combination. All animals developed obesity, however the percentage of weight gained was reduced from week 6 and was significantly decreased at week 12 in animals supplemented with Lb. mucosae DPC 6426 and fibre compared to animals receiving Lb. mucosae DPC 6426 and fibre, singly, or no dietary supplementation. Overall results of this study have indicated that supplementation with fibre alone and in combination with Lb. mucosae DPC 6426 has a significant effect on the composition of the gut microbiota. Furthermore, results have indicated that fibre acts in combination with Lb. mucosae DPC 6426 to increase existing anti-inflammatory gut microbiota, suggesting that supplementation of a combination of Lb. mucosae DPC 6426 and fibre could provide a new, novel therapeutic approach in the treatment of the gut microbiota compositions alterations associated with MetS. In conclusion, this thesis has shown that the use of larger pre-clinical animal models are paramount in order to translate reproducible results from a pre-clinical animal model to a human clinical setting, with regards to understanding the underlying mechanisms of disease, in particular Mets, and the potential advantages of using novel gut microbiota targeted therapeutics, such as probiotics and combination therapies, on MetS-associated risk factors.
Metabolic syndrome , Gut microbiota , Probiotics
O'Donovan, A. N. 2021. Microbes for life; investigating the effects of oral administration of Lactobacillus mucosae DPC 6426 on cardiometabolic parameters. PhD Thesis, University College Cork.