“This demonstrates that there is leakiness not only in inflammatory bowel disease, where we know about gut barrier dysfunction, but also in SLE and autoimmune hepatitis, where there is no overt inflammation in the gut,” says Dr. Kriegel. “We saw this based on markers for leakiness in the stool of autoimmune patients. Importantly, we also found E. gallinarum-specific DNA in liver biopsies taken from these patients.”
‘The overarching theme in my laboratory is the role of the microbiome in autoimmune diseases. These results work toward a better understanding of how the microbiome fits into the development & treatment of these diseases.’ —Dr. Kriegel
Can Bacteria Produce Pro-Inflammatory Pathways?
The researchers next addressed the issue of whether E. gallinarum could induce pro-inflammatory pathways in small intestine tissue during translocation. They also wanted to know if the bacterium could alter the gut barrier.
To do this, mice monocolonized with E. gallinarum were compared with mice monocolonized with two other gut bacteria. RNA expression profiling was used as one of the readouts.
The presence of E. gallinarum was shown to downregulate ileal molecules related to barrier function in the gut, the mucosal layer and antimicrobial defense. It was also noted that monocolonization with E. gallinarum upregulated those related to inflammation and induced systemic autoantibodies. One of the upregulated markers was Enpp3, a molecule known to increase key cells contributing to the type 1 interferon (IFN) signature in human SLE.
Another link to disease was found when a vaccine for E. gallinarum was introduced. Translocation in autoimmune-prone mice induced autoantibodies and caused mortality. Both were prevented by vaccination.
“An important part of the study is not only that we were able to associate E. gallinarum with autoimmune diseases,” says Dr. Kriegel. “We also did mechanistic work in the test tubes and animals that linked these bacteria to the pathways that are detrimental to patients with autoimmune disease.”
Gut Leakage & Human Disease
Turning to an analysis of gut leakage and effects on human disease, longitudinal analysis of stool from SLE patients revealed impaired gut barrier function with an increase in fecal albumin and calprotectin. The researchers then tested for E. gallinarum translocations in human livers of patients with SLE and autoimmune hepatitis (AIH).
Liver biopsies from three lupus patients were positive for E. gallinarum. Of the six control biopsies from healthy liver transplant donors, four were positive for other Enterococcus species, but not E. gallinarum.
