A common presentation of lupus involves the presence of antiphospholipid antibodies, which can lead to blood clots, miscarriages and other cardiovascular comorbidities. Why these antibodies develop remains mysterious — they can occur in people without lupus, as well — but new research suggests that the microbiome may play a role.
About 10 percent of all lupus patients have secondary antiphospholipid syndrome (APS), said Martin Kriegel, M.D., Ph.D, an assistant professor of immunobiology and medicine at the Yale School of Medicine. Dr. Kriegel and his colleagues conduct studies using lupus/antiphospholipid syndrome mouse models. They've found that wiping out the mouse gut microbiota with antibiotics prevents APS mortality. So does a special starch diet in another lupus model, he found.
"It's very preliminary," Dr. Kriegel warned. However, the alteration of the gut microbiome seems to alter immune markers in the lupus-prone mice, particularly interferon alpha.
"Experiments are going on right now to find out what the [microbial] cells produce and whether it's really important that interferon alpha is reduced," Dr. Kriegel said.
Dr. Kriegel's work is part of a larger push to understand the mechanisms by which the human microbiome alters the immune system. Researchers have found indications of microbial dysbiosis in type I diabetes and in the general gendered presentation of autoimmunity. In addition, CD103 dendritic cells in the gut, which induce T-regulatory cells, are affected by the microbiota.
Cross-reactivity is a well-known trigger for transient autoimmunity, Dr. Kriegel said, but conditions like lupus and APS are chronic. Perhaps, he and his colleagues thought, this chronic presentation indicates some kind of chronic cross-reactivity. For the source of this cross-reactivity, the researchers turned to the gut microbiota.
In early unpublished data presented at the 2015 Lupus Research Institute/Alliance for Lupus Research patient conference, Dr. Kriegel and his team found that when they treated their antiphospholipid syndrome mouse model with vancomycin or ampicillin, the clotting disorder disappeared.
"Remarkably, when we remove all microbes from the gut of these animals, we essentially have no disease anymore," Dr. Kriegel said at the conference. Auto-antibodies against beta-2-glycoprotein I were also reduced, he said. Surveys of human patients with antiphospholipid syndrome have found that some families of bacteria depleted by the antibiotics in antiphospholipid syndrome mice are enriched in the human gut. The researchers then focused their antibiotic regime on these specific bacteria using vancomycin and found the same preventative effect on antiphospholipid syndrome mortality.
Next, the researchers tried feeding another lupus mouse model specific diets to alter their microbial composition. They found that a starch diet altered the gut microbe community after a week, while long-term survival improved. The researchers are now trying to identify the microbes in the mice that change with diet and how they then alter immune function.
Dr. Kriegel and his colleagues aren't the only ones to try to control lupus with diet. Research from other labs has found that calorie restriction can stall the development of lupus in mouse models and can also stave off APS-like symptoms. In a mouse model of antiphospholipid syndrome, a diet enriched in n-3 polyunsaturated fatty acids prevented fetal loss and lowered titers of anti-beta-2-glycoprotein I, researchers reported in 2000. It's possible, Dr. Kriegel and colleagues wrote in the journal Lupus in 2015, that these diets worked by altering the gut microbiota, much like their starch diet does.
Transforming diet into treatment is difficult, Dr. Kriegel said, because it's very challenging to get people to eat according to a strict diet plan. However, the research may lead to supplement options or specific targeted treatments.
"I don't think one lupus treatment will fit all lupus patients," Dr. Kriegel said.
Nor are the pathways to autoimmunity simple. As noted in a paper published in 1993 in Immunology Today, non-obese diabetic (NOD) mice used as a model for type 1 diabetes are actually more prone to that autoimmune disorder when their guts are less populated. Even comparing the guts of the healthy to the sick may be misleading, Dr. Kriegel said: "Microbes present in both lupus patients and healthy controls may cause harm only in the lupus patients because of specific genetic factors."
"It's never just genes or environment, or 'only nature versus nurture,'" Dr. Kriegel said. "It's a combination of both."