A study suggests that a harmless strain of Escherichia coli called Nissle 1917 primes the small intestine to defend itself against another strain that causes potentially fatal infections.
Most strains of the bacterium E. coli are benign, but some can cause severe illness, including stomach cramps, vomiting, and diarrhea. The bacteria can spread via contaminated food and water or through contact with an animal or person who has the infection.
Other strains can cause urinary tract infections, respiratory illness, and pneumonia.
Some of the most dangerous E. coli strains produce a toxin called Shiga. In the United States, the Centers for Disease Control and Prevention (CDC) estimate that these strains are responsible for 265,000 infections annually.
They note that a strain called E. coli O157 causes about 36% of these infections. E. coli O157 can infect people of all ages, but infections can be particularly severe, and even fatal, in younger children.
Antibiotics are unsuitable for treating these infections because they can provoke the bacteria to produce more Shiga toxin, which can trigger a potentially fatal kidney condition called hemolytic uremic syndrome.
“Right now, there is no cure for an E. coli infection,” says Alison Weiss, Ph.D., a professor at the University of Cincinnati College of Medicine, OH. “We can give individuals fluids, but [the infection] can be really deadly, and it would be really nice for us to figure out how to cure it.”
Weiss and her colleague Suman Pradhan, Ph.D., wondered whether a probiotic could prevent infections, based on observations dating back to the early 20th century.
For more than 100 years, doctors have used a “friendly” E. coli strain called Nissle to prevent and treat infectious diarrhea.
Alfred Nissle, a German physician and researcher, first isolated the strain from the feces of a soldier during the First World War.
In 1917, Dr. Nissle noticed that in contrast to his fellow soldiers, the man did not develop diarrhea during an outbreak of the highly contagious bacterial infection shigellosis.
More than a century later, the strain of E. coli that was named after Nissle is the active component of a probiotic called Mutaflor that doctors in Europe, Canada, and Australia use to treat infectious diarrhea, chronic constipation, and inflammatory bowel disease.
Research in mice in 2009 suggested that Nissle could also protect people against infection with E. coli O157.
However, Weiss and Pradhan were concerned that this strain could have adapted to cause disease in humans, while leading to only mild symptoms, if any, in mice.
Studies in mice may, therefore, be a poor indicator of how good Nissle is at protecting people.
To get a better idea, the researchers used human pluripotent stem cells to create human intestinal organoids, which are tiny living models of the small intestine.
Pluripotent stem cells are universal progenitor cells that, under the right conditions, can differentiate into any tissue in the body.
This ability meant that the researchers were able to ensure that the organoids contained all the major cell types that are present in the lining of the human intestine.
As in a real intestine, each organoid comprised a space or lumen that a single layer of cells (an epithelium) enclosed.
When the researchers injected E. coli O157:H7 into the lumen of the organoid, within hours, the bacteria had destroyed the epithelium. A closely related strain called uropathogenic E. coli CFT073 had the same effect.
In contrast, when the researchers injected Nissle into the organoids, the bacteria did not appear to harm the epithelium.
More importantly, when they injected the pathogenic strains into these Nissle-containing organoids, the bacteria were no longer able to damage the epithelium.
Rather than outcompeting the pathogens, Nissle seems to prime the epithelium to defend itself against them.
“Nissle did not kill pathogenic E. coli but rather ramps up your intestinal responses and prepares you for possible pathogens attacking the intestine,” says Weiss. “We don’t know how it does this, but our study confirms its effectiveness in human cells. Our hope is to figure out how this is happening.”
The study’s findings appear online in mBio, which is the journal of the American Society for Microbiology.
The researchers believe that human intestinal organoids provide a more reliable test of the safety and efficacy of probiotics than either animal models or cell cultures.
“[M]any human intestinal pathogens cannot be adequately modeled in cell culture or experimental animals, such as mice, and it is not clear whether information from these surrogate infection models is reliable enough to guide medical practice. Stem cell-derived human tissues, such as [human intestinal organoids], provide a powerful alternative to traditional experimental approaches.”
However, they caution that while Nissle may be effective in preventing infection, it may not be safe to use as a treatment for existing E. coli O157:H7 infections. They say that their work suggests that, in common with some antibiotics, Nissle may provoke increased production of Shiga toxin.