Using ketone bodies in the fight against lymphedema

12 July 2019

The administration of ketone bodies, an alternative energy source, stimulates the growth of lymph vessels and has substantial beneficial effects in conditions affecting the lymphatic system. These spectacular positive effects were found by the group of professor Peter Carmeliet (VIB-KU Leuven Center for Cancer Biology). The team has developed a dietary metabolic approach which will soon be tested in a clinical Phase II trial to treat lymphedema, a condition for which currently no cure exists. The first patients are already enrolled in the study, which is led by dr. Sarah Thomis, vascular surgeon and head of the center for lymphedema in UZ Leuven in collaboration with the Clinical Nutrition Unit, UZ Leuven.

A network of lymph vessels

The lymphatic system consists of a network of lymph vessels that drain tissue fluid (lymph) back to the blood vascular system. Abnormalities in the lymphatic system are associated with the development of several human conditions, including lymphedema (tissue swelling due to failing lymph drainage). Prof. Peter Carmeliet’s group previously discovered that a molecule called acetyl-CoA is essential for the regulation and growth of lymphatic vessels. The production of acetyl-CoA depends on the availability of substances such as glucose, fatty acids, and acetate. However, it can also be made from ketone bodies. 

In this study, the team found that supplementing with ketone bodies to increase the availability of acetyl-CoA, induces lymphatic vessel growth and improves their function in pathological conditions, such as lymphedema. This research has unveiled an entirely innovative therapeutic avenue (changes in diet) to promote the formation of new lymphatic vessels and drainage of lymph fluid in lymphedema. 

A keto diet for mice and human cells

To study the role of keto bodies in the lymphatic system, the scientists used two model systems: human cells and mice. First, the pathway that transformed ketone bodies into acetyl-CoA was blocked in human lymphatic cells by stopping a key molecule in this pathway from working. Result? The lymph cells grew and spread less. Then, the researchers added ketone bodies to the cells. The opposite happened. The cells grew and spread with fervor.   

But how would lymphatic cells react in living creatures? To find out, the scientists put mice on a keto diet. 

Dr. Melissa García-Caballero, postdoctoral researcher (VIB-KU Leuven), provides some details: "We then studied the impact of the ketone bodies in the lymph system of mice. In adult mice, elevation of ketone body levels in the lymph by feeding a high-fat, low-carbohydrate ketogenic diet, or by administration of ketone bodies, increased the growth and recovery of the lymph system in a mouse version of lymphedema.  The ketogenic diet improved lymphatic growth and function, reduced infiltration of immune cells attacking the lymph system, and decreased fluid buildup in the tail."

A potential tool for lymphedema and cancer recovery

Lymphedema can occur by itself, but it is also a common post-cancer complication. Among cancer patients, 1 in 6 who undergo treatment for breast cancer, melanoma, genito-urinary or gynaecological tumors that involves lymph node removal or radiotherapy will develop secondary lymphedema.

Prof. Peter Carmeliet (VIB-KU Leuven) explains how their findings can aid patients: "These exciting data suggest that a ketogenic diet could be a novel therapeutic opportunity to stimulate lymph vessel formation, for instance to treat lymphedema. Despite its medical importance, lymphedema is currently incurable, and no approved pharmacological treatment is available, only symptom-controlling physical therapy. The novelty and relevance of our findings triggered great interest from clinicians and has allowed the initiation of a clinical Phase II trial to test a ketogenic diet in lymphedema patients. This is the first diet-based treatment and it represents a milestone in the treatment of lymphedema.”

Dr. Sarah Thomis (UZ Leuven) coordinates the clinical study: “Together with our dietitian, we have developed our own recipes that lead to a high ketone body production and which are relatively easy to adhere to. The diet consists for more than 90% of fat, with very low levels of carbohydrates and proteins, which will mimic the metabolic effects of a fasting period. Because it can have side effects, it is not recommended to start a ketogenic diet without guidance of an experienced dietitian and doctor.”

The clinical team is still looking for participants. “We are currently recruiting patients who have developed secondary lymphedema in the arm after breast cancer treatment. They will be asked to follow the ketogenic diet for 24 weeks and then switch to a modified diet. We will measure changes in the edema volume and in the lymphatic transport. Given the promising findings in the mouse experiments by professor Carmeliet, we are hopeful to see positive effects of a ketogenic diet also in patients", concludes dr. Thomis.


Publication

Funding
This work is supported by: fellowships from LE&RN/FDRS, by the VIB TechWatch program, long-term structural Methusalem funding by the Flemish Government, grants from the Research Foundation Flanders (FWO-Vlaanderen), Foundation against Cancer (2016-078), Fund for Translation Biomedical research (FTBO-KU Leuven) and European Research Council (ERC) Advanced Research Grant (EU-ERC269073 and 743074).”
 
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