HUMAN MILK OLIGOSACCHARIDES AND CARDIOVASCULAR DISEASE

Cardiovascular diseases (CVDs) are the leading cause of death globally. The majority of CVD-related deaths are caused by atherosclerosis, a chronic inflammatory disorder. Atherosclerosis is characterized by a thickening and narrowing of arteries caused by accumulation of lipids (cholesterol), inflammatory cells like macrophages and fibrous elements. Ultimately, this narrowing reduces blood flow to critical levels in many vital organs which can cause stroke and heart attacks. One therapeutic approach aims to stop the infiltration of macrophages into arteries and thereby reduce the chronic inflammation. However, available therapeutics that target inflammation often show adverse effects, require injections and are very expensive. We have taken a rather unusual drug discovery approach and looked at what is already working well in `Mother Nature`. Human breast milk contains an arsenal of bioactive components that are beneficial for the baby and are, per definition, safe for oral consumption. Therefore, we hypothesize that specific human milk components also benefit adults with CVD. Human milk oligosaccharides (HMOs) are complex sugar molecules that represent the third most abundant component of human breast milk. HMOs are known immune system modulators, and our extensive preliminary data identified one specific HMO that effectively reduced the activation of macrophages. Macrophages represent immune cells that are highly relevant for chronic inflammation and atherosclerosis in the context of CVD. We aim to investigate the effects of this specific HMO in more detail. First, we investigate how it mediates its anti-inflammatory effects on macrophages. Then, we also study whether we can translate the results obtained in tissue culture into beneficial effects in a mouse model of atherosclerosis. Obesity is one of the major risk factors for CVDs and also for type 2 diabetes. Therefore, in the last stage of the project back in Austria it will be tested whether HMOs also influence the development of obesity and obesity-related diseases. Our ultimate goal is to develop safe and effective therapeutics for CVD and obesity that are based on the natural template human milk and the anti-inflammatory properties of one of its main components. New technologies make individual HMOs like the one we study not only available, but also commercially viable. Therefore, this project will be an important contribution to HMO research especially in an adult context which was not studied before.

Cardiovascular diseases (CVDs) are the leading cause of death globally. The majority of CVD - related deaths are caused by atherosclerosis, a chronic inflammatory disorder. Atherosclerosis is characterized by a thickening and narrowing of arteries caused by accumulation of lipids (cholesterol), inflammatory cells like macrophages and fibrous elements. Ultimately, this narrowing reduces blood flow to critical levels which can cause stroke and heart attacks. One therapeutic approach aims to stop chronic inflammation. However, available therapeutics that target inflammation often show adverse effects, require injections and are ver y expensive. We have taken a rather unusual drug discovery approach and looked at what is already working well in `Mother Nature`. Human breast milk contains an arsenal of bioactive components that are beneficial for the baby and are, per definition, safe for oral consumption. Therefore, we tested whether specific human milk components also benefit adults with CVD. Human milk oligosaccharides (HMOs) are complex sugar molecules of human breast milk. Some of them are known to have anti-inflammatory properties. We identified one specific HMO that effectively reduced the activation of macrophages. Macrophages contribute to chronic inflammation and atherosclerosis in the context of CVD. In the study, performed at University of California in San Diego, we investigated the effects of this specific HMO in more detail. First, we investigated how it mediates its anti-inflammatory effects on macrophages. Then, we also studied its beneficial effects in a mouse model of atherosclerosis which successfully reduced the development of the disease. Obesity is one of the major risk factors for CVDs and also for type 2 diabetes. Therefore, in the last stage of the project back in Austria at Medical University of Graz, we tested whether HMOs also influence the development of diabetes. This project is an important contribution to HMO research especially in an adult context which was not studied before. The successful outcome of this study is the basis for our ultimate goal which is to develop safe and effective therapeutics for CVDs.