Translocation of Enterococcus gallinarum, a gut bacterium, drives a mouse model of systemic lupus erythematosus, according to a recent study.
E. gallinarum was also found in the livers of human patients with lupus and autoimmune hepatitis (AIH), but not in controls without autoimmune disease, suggesting that the findings in mice may translate to humans (Science. 2018;359:1156-61.)
In health, several mechanisms prevent intestinal bacteria and their byproducts from entering systemic circulation. Foremost is the gut barrier, followed by the liver and mesenteric lymph nodes. Increased gut permeability is common in patients with inflammatory bowel disease and has been reported in other autoimmune conditions, including rheumatoid arthritis and ankylosing spondylitis
The gut bacterium E. gallinarum (blue) travels from the gut to the liver (and lymph nodes, not shown) to stimulate liver and immune cells that leads to inflammation and autoimmune reactions. Liver inflammation leads to autoimmune hepatitis. Autoantibodies generated systemically lead to lupus kidney disease and lupus-related autoimmune clotting called antiphospholipid syndrome. An oral antibiotic or a vaccine into the muscle that is directed against E. gallinarum prevent autoimmune diseases to occur.
Credit: Martin Kriegel
When barrier mechanisms fail, bacterial byproducts can enter systemic circulation, an event that is known to cause inflammation. Although research has suggested a causative relationship between this inflammatory process and the development or persistence of autoimmune disease, details have remained elusive.
“The establishment of causal pathways between bacteria and disease is no easy feat,” wrote James Rosenbaum, MD, and Gregg Silverman, MD, in an editorial in the New England Journal of Medicine (2018;378:2236-37).
The authors noted that the sheer complexity of the human microbiome is one major obstacle for researchers; gut bacteria number in the trillions. As a further hindrance, some varieties cannot be cultured.
Despite these challenges, Silvio Manfredo Vieira, PhD, and colleagues of Yale University, New Haven, Conn., were able to show a causative link between E. gallinarum and lupus in mice.
The investigators first observed that treating a mouse model of lupus with antibiotics (ampicillin or vancomycin) reduced levels of autoantigen antibodies, lessened disease severity, and extended survival. This suggested that gram-positive bacteria were playing a role in disease pathogenesis.
Confocal image of the small intestine of animals colonized only with E. gallinarum. Compared to germ-free animals without any bacteria, the pore-forming molecule Claudin-2 is upregulated.
Credit: Manfredo Vieira et al., Science (2018)
Lupus-prone mice had changes in the gut epithelium that increased bowel permeability, thereby allowing E. gallinarum to spread to the liver, mesenteric veins, and gut-draining lymph nodes. When the same mice were treated with antibiotics, intestinal permeability decreased in correlation with E. gallinarum titers. These findings confirmed that E. gallinarum was escaping the intestines and entering circulation, and that the process could be mitigated with antibiotics.
Vaccination also could control the disease process. In lupus-prone mice, an E. gallinarum–specific vaccine reduced serum autoantibody levels and prolonged survival. In vaccinated mice, E. gallinarum could not be cultured from internal organs.
Further investigation showed that E. gallinarum had unique properties, compared with other bacteria. When E. gallinarum was used to monocolonize the small intestines of healthy mice, gut permeability increased, as did production of antibodies to double-stranded DNA. In contrast, monocolonization with other types of bacteria did not increase gut permeability or autoantibody production. Such autoantibodies characterize lupus, suggesting that E. gallinarum could be a unique driver of autoimmune disease.
“E. gallinarum has some properties that distinguish it from several other intestinal bacteria,” Dr. Rosenbaum and Dr. Silverman noted in their editorial. “The bacterium induces an increase in levels of plasmacytoid dendritic cells, a source of interferon-alpha, which has been implicated in lupus pathogenesis. E. gallinarum also induces cultured liver cells to produce more interferon-alpha and to synthesize beta-2 glycoprotein 1, a protein targeted by antibodies in the antiphospholipid antibody syndrome [another autoimmune disease].”
In a series of experiments, Dr. Vieira and colleagues found that E. gallinarum may play a similar role in human autoimmune disease.
First, they analyzed stool samples and found that patients with lupus had increased intestinal permeability, compared with healthy controls.
Next, polymerase chain reaction was used to look for E. gallinarum in the livers of patients with lupus and autoimmune hepatitis with lupuslike characteristics (the presence of antinuclear antibodies and anti-dsDNA IgG). The majority of patients with autoimmune disease, but none of the controls, tested positive for E. gallinarum.
Confocal image of the small intestine of animals colonized only with E. gallinarum. Compared to germ-free animals without any bacteria, the barrier-tightening molecule Claudin-5 is downregulated.
Credit: Manfredo Vieira et al., Science (2018)
Finally, the researchers reported that when human hepatocytes were cultured with E. gallinarum, they produced interferon-alpha and beta-2 glycoprotein 1. These results mirror those found in mice, providing evidence that E. gallinarum drives the pathogenesis of autoimmune disease in people.
“Although the work by Manfredo Vieira et al. is intriguing,” Dr. Rosenbaum and Dr. Silverman wrote, “much more research needs to be done.”
Many questions remain unanswered, including the mechanism by which E. gallinarum induces autoimmune disease, whether other bacteria have similar capabilities, and if E. gallinarum plays a role in lupus patients without liver disease.
Still, the current findings hold potential for new methods of controlling, or even preventing, autoimmune disease in people, thereby avoiding risks inherent to immune suppression.
“If the complexity of host tissue – microbiota interactions is considered in chronic autoimmunity,” the researchers concluded, “it may offer new therapeutic avenues for these debilitating and potentially lethal diseases.”
Will Pass is a freelance reporter with MDedge News.