07:45am Saturday 11 July 2020

Disease-causing bacterial invaders aided by failure of immune system switch

Cells that lack key inflammasome cannot release the mucus granules (the small circular clusters) that protect intestinal wall from bacteria that cause a host of diseases.

“This gut microbiota has been linked to the inflammation that triggers obesity, diabetes, metabolic disease, and most of chronic health problems of the Western World,” said Yale’s Richard Flavell, Sterling Professor of Immunobiology, Howard Hughes Medical Institute investigator, and co-senior author of the paper appearing Feb. 27 in the journal Cell. “We knew these invaders were causing problems, but we didn’t know how.”

The walls of the intestine are shielded from potentially harmful bacteria by a thin mucus lining, which has been described as the body’s demilitarized zone. The researchers found that production of this mucus lining depends upon a single immune system regulator — the NLRP6 inflammasome — that controls mucus secretion by cells in the wall of the intestine, just like turning on a faucet. In mice lacking the inflammasome, the faucet is closed, there is no mucus shield, and the mice are unable to fend off invaders. As a result, the intestinal wall becomes infected and inflamed, leaving the mice susceptible to conditions as diverse as inflammatory bowel diseases, colon cancer, Type 2 diabetes, obesity, and fatty liver disease. All these conditions stemmed from the bacterial invasion of the intestinal wall.

“The next step is to identify the bacteria in humans, prove that the system works the same way it does in mice, and figure out how to dial up the protective shield,” Flavell said.

Other corresponding authors of the paper were Eran Elinav of the Weizmann Institute of Science, Israel and B. Brett Finlay of UBC.

The research was funded by The Howard Hughes Medical Institute, Canadian Institutes for Health Research (CIHR), The U.S. Department of Defense, Blavatnik Family Foundation, The Leona M. and Harry B. Helmsley Charitable Trust, European Research Council and The Israel Science Foundation.

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Bill Hathaway

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