Lupus Studies Point to Gut Microbes, Epigenetics

Janis C. Kelly

May 13, 2014

The complex network of genetic, environmental, and hormonal factors believed to contribute to systemic lupus erythematosus (SLE) is slowly being dissected, researchers report in a special issue of Lupus devoted to environmental causes of SLE. Several lines of research converged on the commensal bacteria in the gastrointestinal tract (the gut microbiota), which can be influenced by dietary and other external factors to alter immune response, and on environmental agents that inhibit epigenetic T-cell DNA methylation, which can trigger lupus flares in the genetically predisposed.

Christopher J. Edwards MD, MBBS, FRCP, and Karen H. Costenbader, MD, MPH, introduced the special issue with an editorial on epigenetics and the microbiome.

"Previously, we have been able just to list putative environmental factors that might be of importance and show the results of epidemiological studies. For the first time, we can now suggest how this actually works. It is still very complicated, but this work really shines a light on a complex area," Dr. Edwards told Medscape Medical News. Dr. Edwards is consultant rheumatologist and associate director of the National Institute for Health Research Wellcome Trust Clinical Research Facility, Southampton, United Kingdom.

Clue to How the Environment Acts Via the Genes to Produce Lupus

"We have thought for a long time that lupus and other autoimmune and inflammatory diseases like it are caused by both genetic and environmental factors and their interactions. Epigenetic modifications, influenced by the environment and controlling the expression of the genes, may explain how the environment acts via the genes to produce lupus,” Dr. Costenbader told Medscape Medical News. “We still don't know very much about exactly which factors are involved or how those interactions and the coordination of gene expression across the genome work, though," he added. Dr. Costenbader is associate professor of medicine, Harvard Medical School, and codirector of the Lupus Center at Brigham and Women's Hospital, Boston, Massachusetts.

Epigenetics refers to changes in gene expression resulting from changes in the structure of DNA that influence how available a gene is for transcription. Two key epigenetic processes are the addition of methyl groups to the DNA itself and the modification of histone proteins that bind to and help condense and package DNA.

The microbiome is the total population of bacteria and other microorganisms that reside in the gut. These bacteria aid in digestion, influence the host immune system, and produce epigenetic changes.

Animal studies described by S. M. Vieira, PhD, from the Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, and colleagues showed that the onset and severity of experimental lupus differed in germ-free and conventionally raised mice and that microbial triggers might contribute to SLE pathogenesis by altering expression of TLR7/9 and upsetting the effector/regulatory T cell equilibrium. The authors also suggest that sex-specific differences in commensals might play a role in female-biased autoimmune diseases such as SLE and antiphospholipid syndrome (APS).

"Our findings are still very preliminary and only based on animal models, but suggest that the gut microbiota is not only involved in APS but unexpectedly also in the pathogenesis of lupus. We are currently trying to figure out which components of the microbiota influence lupus nephritis and APS by depleting some, but not all, gut commensals,” senior author Martin A. Kriegel, MD, PhD, told Medscape Medical News. “Many details still remain to be determined, but the general finding that there is a connection between the microbiome and lupus is quite clear and suggests that novel therapeutic avenues could be developed in the future that are targeting not the host but one's microbiota. Since lupus has classically been considered to be a disease independent from the microbiota, it does change our basic understanding of the pathogenesis," he explained.

Dr. Kriegel is assistant professor of immunobiology and of medicine, Yale University School of Medicine. He said his group plans to report preliminary data from the lupus/APS gut commensals study at the American College of Rheumatology 2014 Annual Meeting in November.

In the clinical setting, Dr. Kriegel recommended that patients pay a little more attention to what effects various diets may have on their disease. "The long-standing anecdotal patient reports of certain diets worsening or improving flares might be more real than we thought. They should be studied more systematically, now that we know that almost any dietary component acts on the gut microbiota, [which] in turn has profound effects on the immune system," Dr. Kriegel said. He also warned that patients should not assume that the various "probiotic" products now available to consumers would have a beneficial effect in lupus. "Probiotics could theoretically even worsen a disease state, since it is possible that physiologic immune responses against benign commensals could fuel autoimmune responses via cross-reactivity (as we hypothesize) or other mechanisms," he said.

Dr. Kriegel concluded, "I think the best will be to wait until we have a better understanding of which commensals or commensal-derived products might be driving which autoimmune disease and then target those with a diet that is known to modulate these strains or products. Ideally, the field will also develop eventually novel types of antibiotics or vaccinations against certain commensals. Such approaches would allow us, in the future, to more specifically modulate the gut microbiota in autoimmunity."

Epigenetic processes help explain the complex interactions between genes and the environment. Dr. Edwards predicted this will help researchers understand the processes involved in the development of inflammatory diseases such as lupus and rheumatoid arthritis. "Without these, we will just continue to do more and more detailed genome-wide association studies...and produce longer lists of possible environmental factors. Epigenetics may help to understand not just the 'what' but the 'how,' " Dr. Edwards said. "It is early days, but there is very real hope and promise here for new therapies aimed at the heart of the gene–environment interaction."

Dr. Costenbader added a note of caution: Because epigenetic modifications control the expression of genes across the entire genome, researchers will also need to know more about the downstream effects of manipulating gene expression in lupus.

The authors, Dr. Edwards, and Dr. Costenbader have disclosed no relevant financial relationships.

Lupus. 2014;23:505-506, 518-526. Article abstract, Editorial extract

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