GEN Exclusives

More »

GEN News Highlights

More »
March 9, 2018

Leaky Gut Lets Bacteria Slip Away and Stir Up Autoimmunity

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. [Manfredo Vieira et al, Science Science (2018)]

  • If the gut barrier weakens, a bacterium called Enterococcus gallinarum can leak out of the intestines, colonize the liver and other organs, and trigger a lupus-like autoimmune reaction, reports a team of Yale scientists. These scientists also discovered that the autoimmune reaction can be suppressed with an antibiotic or vaccine.

    These new findings appeared March 9 in the journal Science, in an article entitled “Translocation of a Gut Pathobiont Drives Autoimmunity in Mice and Humans.” This article describes how the Yale scientists began with a key observation: E. gallinarum can translocate from the gut into the organs of mice with a genetic predisposition to lupus-like autoimmunity. Subsequent work revealed that when E. gallinarum escapes, it can colonize the liver and other systemic tissues. The scientists detected the molecular signatures of gut barrier disintegration and pathogenic T helper cells in the gut, liver, and lymphoid organs.

    The Yale team did not confine its work to mouse models. “E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients,” the scientists noted. “Cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans.”

  • A summary of the role of the microbiome in autoimmune diseases, as well as the findings of the study by Manfredo Vieira et al. Gut bacteria can travel outside the gut into tissues, thereby triggering autoimmune responses that lead to tissue damage and organ failures. Antibiotics or commensal-targeted vaccination prevent autoimmune processes and damage to occur. The same gut bacterium as in the animal model was found in human liver tissues taken from patients with autoimmune hepatitis and lupus. Human liver cell studies together with the gut bacterium resembled similar changes as seen in the animals. [Martin Kriegel]
  • Essentially, the Yale team detected the suspect bacterium in livers of patients with autoimmune disease. (The presence of other types of bacteria in these organs did not induce such autoimmunity.) The scientists also confirmed that the mechanism of inflammation in the mouse model was the same as that observed in cultured liver cells of healthy people.

    Through further experiments, the research team found that they could suppress autoimmunity in mice with an antibiotic or a vaccine aimed at E. gallinarum. With either approach, the researchers were able to suppress growth of the bacterium in the tissues and blunt its effects on the immune system.

    "When we blocked the pathway leading to inflammation, we could reverse the effect of this bug on autoimmunity," said Martin Kriegel, M.D., the senior author of the Science paper.

    "The vaccine against E. gallinarum was a specific approach, as vaccinations against other bacteria we investigated did not prevent mortality and autoimmunity," he noted. The vaccine was delivered through injection in muscle to avoid targeting other bacteria that reside in the gut.

    In a related Perspective article in Science (“Intestinal Barriers Protect against Disease”), Sandra Citi, M.D., Ph.D., a cell biologist at the University of Geneva, highlighted the Yale study and a related one, providing more context on the mechanisms behind a leaky gut barrier and potential therapies to improve it.

    In a different study (“Hyperglycemia Drives Intestinal Barrier Dysfunction and Risk for Enteric Infection”), also published in Science, and also evaluating the gut barrier, Christoph Thaiss, Ph.D., and colleagues at the Weizmann Institute of Science and elsewhere find that high blood sugar levels, as seen in diabetes and obesity, are associated with intestinal barrier dysfunction and susceptibility to infection in mice. Preliminary data supports this finding in humans as well, the authors reported. Together, these studies highlight the importance of a healthy gut barrier in preventing disease.

    In particular, the Yale study emphasizes the relevance of the gut barrier to systemic lupus and autoimmune liver disease. "Treatment with an antibiotic and other approaches such as vaccination are promising ways to improve the lives of patients with autoimmune disease," Dr. Kriegel concluded.

Related content