May 15, 2019

One of the biggest questions in lupus is why the immune system tries to destroy patients’ own tissues. But in the last few years, researchers have learned that certain microbes living inside our bodies may trigger these attacks. Scientists supported by the Lupus Research Alliance (LRA) have made many of the key discoveries about how these microorganisms relate to lupus.

Dr. Gregg Silverman Found Bacteria that May Trigger Lupus
The microbes that live in our bodies are known as the microbiome. They live mostly in  the intestines. Earlier this year, LRA-funded researcher Dr. Gregg Silverman of the NYU School of Medicine in New York City and colleagues revealed that the balance of microbial species was out of whack in the intestines of patients with lupus [1]. One bacteria, Ruminococcus gnavus, was more than five times more abundant than in people who didn’t have the disease. Patients with lupus produce immune system molecules called antibodies that attack their own DNA. Dr. Silverman and his team found that these antibodies also attack molecules in the coating of Ruminococcus gnavus.  Among patients with lupus, patients with active lupus nephritis, or kidney inflammation, had the highest levels of these antibodies.  The bacterium may spur the immune system to target patient’s own tissues, especially their kidneys, either causing lupus or prompting disease flares.

“We are beginning to wonder if the shifts in the microbiome in Lupus patients contribute to disease flares,” noted Dr. Silverman.  “Treating the autoimmune disease may not be enough, and we need to explore how to make our inner communities healthy as well.”

Dr. Martin Kriegel Discovered a Microbe that Fools the Immune System
Last year, Novel Research Grant recipient Dr. Martin Alexander Kriegel of Yale University School of Medicine in New Haven, Connecticut, and colleagues also found that microbes fool the immune system. About half of patients with lupus produce antibodies against the protein Ro60 that occurs in human cells. Dr. Kriegel and his fellow researchers showed that several kinds of microbes that live in the body make proteins that are very similar to Ro60. The bacterial look-alike proteins may trigger the immune system to make antibodies that also damage cells carrying Ro60, such as those attacked in the skin of patients with lupus.

Lupus doesn’t usually cause intestinal symptoms, raising the question of how bacteria that normally live in the intestines could promote the disease. Last year, Dr. Kriegel and his team discovered a possible explanation. They found that in animal models of lupus, one type of bacterium called Enterococcus gallinarum moved from the intestines to the lymph nodes and liver, where it stimulated a response by the immune system and caused lupus symptoms [3]. Dr. Kriegel and his team also found that liver tissue from patients with lupus tested positive for the bacterium and that antibodies in the blood target it as well, suggesting that this microbe also contributes to lupus.

This year, Dr. Kriegel and his colleagues revealed that a type of dietary fiber may lessen the severity of lupus by stopping some bacteria from traveling out of the intestines. The researchers found that the bacterium, Lactobacillus reuteri, was more abundant than usual in the intestines of mouse models of lupus and the intestines of some lupus patients. In the mice, the microbes also travelled to other locations in the abdomen, including the spleen and liver. The bacteria worsened lupus symptoms in the mice. But feeding the animals resistant starch, a type of dietary fiber found in green bananas, beans, peas, whole grains and other foods, cut the number of bacteria that left the intestines and lessened the severity of lupus symptoms. Those results suggest it may be possible to treat or prevent lupus with diets that contain plenty of resistant starch.

“The support and in particular, the flexibility, by the LRA were crucial because our microbiome research took us in various directions we did not expect. The LRA did not restrict my lab in pursuing these unexpected findings, which I greatly appreciate,” Dr. Kriegel said.

Recent results like these have transformed scientists’ understanding, and the LRA is committed to accelerating research on the connection between microbes and lupus. The organization will host the first international conference on the subject. Attendees will discuss issues such as new directions in microbiome research, challenges faced by researchers, and potential applications for therapies.

References:

1) D. Azzouz et al. 2019. Annals of the Rheumatic Diseases February 19 (e-pub ahead of print).
2) T. M. Greiling et al. 2018. Science Translational Medicine 10: eaan2306.
3) S. Manfredo Vieira et al. 2018. Science 359: 1156-1161.
4) D.F. Zegarra-Ruiz et al. 2019. Cell Host & Microbe 25: 113-127.