Toxin provides clues to long-term effects of diarrhea caused by E. coli – health

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Researchers at Washington University School of Medicine in St. Louis have discovered that a toxin produced by the bacterium Escherichia coli (E. coli), long known to bring diarrhea, also has other effects on the human digestive tract.

The toxin, they found, changes gene expression in the cells that line the within of the intestine, inducing them to fabricate a protein that the bacterium then uses to attach to the intestinal wall.

The findings, published November 17 in Proceedings of the National Academy of Sciences, offer a clue to why recurrent but short-lived episodes of diarrhea could lead to long-term nutritional problems.

“There’s more than meets the eye with this toxin. It is basically changing the surface of the gut to benefit itself, probably in the long run to the detriment of the host,” said senior creator James M. Fleckenstein, MD, a professor of medicine and of molecular microbiology.

“Decades ago, people worked out how the toxin causes diarrhea, but until recently, nobody in reality had the tools to delve into what else this toxin might be doing. We’re trying to put together the pieces of the puzzle to learn the way toxin-producing E. coli might be driving malnutrition and other ripple effects of diarrhea,” added Fleckenstein.

Fleckenstein and first creator Alaullah Sheikh, PhD, a postdoctoral researcher, study enterotoxigenic E. coli (ETEC), a toxin-producing strain of E. coli that may be a common cause of severe, watery diarrhea.

The bacterium’s so-called heat-labile toxin causes ion channels on intestinal cells to open, triggering an outpouring of water and electrolytes into the digestive tract — in other words, diarrhea.

Since oral rehydration therapy was once invented in the 1970s, deaths from diarrhea have dropped by more than 80 percent worldwide. While invaluable at helping people live to tell the tale a bout of diarrhea, the therapy does nothing to minimize the number of cases.

Worldwide, young children still develop diarrhea an average of three times a year, with the youngest and poorest children bearing the brunt of the caseload — and of the long-term health consequences.

Fleckenstein and Sheikh speculated that ETEC’s heat-labile toxin might be doing more than just causing acute diarrhea and dehydration. If this is the case, it might provide an explanation for the link between ETEC and malnutrition, stunting and other problems.

To find other ways the toxin affects the intestine, the researchers grew human intestinal cells in a dish and treated the cells with the toxin. They found that the toxin activates a set of genes referred to as CEACAMs. One in specific — CEACAM6 — codes for a protein that is typically in cells of the small gut at low levels.

Further experiments revealed that the toxin causes cells to produce more CEACAM6 protein, which the bacteria then uses to attach to intestinal cells and deliver even more toxin. In addition, the usage of intestinal biopsy specimens from people in Bangladesh infected with ETEC, the researchers showed that CEACAM6 expression increases in the small gut all the way through natural infection.

“CEACAM6 is expressed in what is known as the brush border of the small gut, which is where your whole vitamins and nutrients get absorbed,” Sheikh said.

“This is without doubt one of the first pieces of evidence that ETEC can change the intestinal surface. We don’t yet know the way long that lasts and what that means for people who find themselves infected, but it stands to reason that damage to this a part of the body could impact the ability to take in nutrients,” added Sheikh.

Fleckenstein, Sheikh and colleagues are continuing to study the link between ETEC and malnutrition, stunting and other health consequences.

“We are trying in the lab to understand the role of ETEC and its toxins as they narrate to nondiarrheal effects of ETEC infection, especially in young children in developing countries,” Fleckenstein said.

“There’s numerous work to be done to explore how the toxins might be related to these long-term consequences of diarrhea,” added Fleckenstein.

(This story has been published from a wire agency feed without modifications to the text.)

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