Defining the Metabolomic Signature of Systemic Lupus Erythematosus (SLE) and the Development of Novel Metabolite Therapies
Abstract
Lupus is an autoimmune disease. In healthy individuals, the role of the immune system is to fight infections and eliminate cancer cells. In patients with lupus, the immune system is malfunctioning and, rather than attacking infectious agents, it attacks the body and tissues such as the skin, kidneys, brain, heart, lungs, and joints. It is a difficult disease to diagnose because symptoms are not very specific. As a result, this is a very difficult disease to treat. Most treatments are very toxic and are often discontinued because patients fail to tolerate them. Patients with lupus have a poor quality of life and often need hospital care to manage complications. Therefore, lupus has high direct health costs but also significant indirect costs due to loss of work productivity. The frequency of the disease is highest in the United States and rising. Young to mid-age women are more affected than men and, more so, women of Asian and African ancestry. Nobody really knows why this is the case and what causes lupus. The ethnic difference is particularly surprising because in Africa lupus is less frequent. However, people in the United States and Africa eat very different foods. In Africa, populations eat a lot of grains, and their diet is rich in fiber. There is strong evidence that a diet rich in fiber is a healthier option and promotes a healthier gut. In addition, patients with lupus also experience gut disorders such as gut leakiness, which likely promotes inflammation. The human gut is colonized by trillions of microbes called the gut microbiome. There are good and bad microbes. Bad microbes can process digested foods, such as fat or meat, to generate toxic products, which then enter the bloodstream and drive body-wide inflammation and/or cardiovascular diseases. Good microbes in the gut do not make these toxic products but, instead, process fiber into small chemical products that are anti-inflammatory and have healing properties. We have tested the benefit of a diet rich in dietary fiber using different mouse models of lupus. We observed that a high-fiber diet was very effective at suppressing lupus in these models of the disease. We were curious as to what healing chemicals were released into the blood of the animals in response to high-fiber digestion. We identified one particular product more concentrated in the blood after a high-fiber diet. We gave a purified version of this product to the drinking water of lupus mice fed with normal food and showed that this product alone was able to treat lupus in these mice, similar to the high-fiber diet. Our observation is very important as it suggests that good microbes in the gut are factories producing natural medicines that can heal the body. It means that patients with lupus may have other therapeutic options than toxic drugs, or complicated diets involving fiber supplements, which may not work in a gut filled with bad microbes. What remains to be done is to understand how these natural chemicals stop lupus and prevent inflammation, which immune cells they bind to, and for what purpose. Our proposal uses years of experience in researching lupus and the immune system to carefully dissect the disease processes that are targeted by these natural healing products. Once we know how these fascinating products work, we can better design and formulate a new generation of nature-derived medicines, more effective and less toxic. Humans have lived for millions of years with microbes in their gut. This cooperation was intended to promote inner health and chemical balance. However, changes in lifestyle, and the evolution of food quality and quality over many decades have altered this chemical balance. This project will unravel the secrets of this ancient healing process and the use of modern and sophisticated scientific approaches will demonstrate how it works and what biology is involved, so we can harness it well for the development of new effective and better tolerated treatments
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810478
Entities
People
- Fabienne Mackay
Organizations
- United States Army
- University of Melbourne