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Inside our digestive system, a thin layer of cells forms one of the body’s most important lines of defense. These cells – the epithelial cells – stand between a population of gut bacteria, the microbiota, which form one of the densest microbial ecosystems on the planet, and our sterile inner body. These cells not only prevent the microbes – friendly and disease-causing alike – from crossing into the tissue, they also help maintain the balance of bacteria in the gut. Among these front-line cells are the goblet cells, named for their unique shape, which secrete various substances to repel invaders.
Conventional scientific wisdom has pretty much viewed goblet cells as simple cups that spilled their antibacterial substances into the gut with little plan or design. But recent research led by Weizmann Institute researchers, in collaboration with scientists from the University of British Columbia and Yale University, has revealed for the first time a sophisticated feedback mechanism in the these cells for controlling the secretion of their bacteria-repelling substances. Their findings, which appeared in Cell, show that this mechanism is key to deciphering the complex relationship between the gut bacteria and the body of their host.
It has been known for many decades that goblet cells are important for preventing disease. Comprising between one twentieth and one fifth of the gut epithelial cells, the goblet cells secrete both antibiotic proteins and mucus – a highly effective antibacterial gel that coats the gut lining and prevents microbial penetration. These vital substances are produced within the cell and transported to the cell membrane for release into the gut inside little bubbles known as vesicles. What has not been known, until now, is how the cells know which substance to pack off in the vesicles, and when.
In the present study, research students Christoph Thaiss, Maayan Levy and Meirav Katz in the group of Dr. Eran Elinav of the Weizmann Institute’s Immunology Department, the group of Prof. Bert Finley of the University of British Columbia and the group of Prof. Richard Flavell of Yale University investigated this process in the goblet cells in mice. At the core of the control mechanism they discovered a unique protein cluster called an inflammasome. This cluster monitors the bacterial population: It is created when a precise series of signals is sent around the cell, and it activates the cell’s response to infection. Elinav had, in previous research, discovered the first inflammasome expressed in an epithelial cell, and the present study showed that it is mainly produced in goblet cells. The researchers found that its function is to direct the vesicles: When they created goblet cells lacking inflammasomes, the various antibacterial substances continued to be produced and even packed for shipping in the vesicles; but those vesicles did not release their contents into the gut, and thus the defensive layer did not form.
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Without the antibacterial proteins and mucus secreted by these cells, the intestinal tissue was vulnerable to disease-causing bacteria, which gain entrance by first attaching themselves to the gut lining. But the disruption also affects the overall balance in the population of gut bacteria – the ones that normally do not cause problems. When the body’s defense is weakened, these can reproduce rapidly; and when they, too, come into direct contact with the body’s tissue, they can increase its susceptibility to everything from intestinal inflammation to obesity, diabetes and cancer.
How exactly does the inflammasome affect the vesicle secretion process in the goblet cells? Further investigation revealed that a well-known cellular mechanism called autophagy was at work. Autophagy – literally “self-eating” – is mostly known as a survival mechanism that enables cells to repurpose their non-essential substances in times of starvation or stress. The researchers found that in the goblet cells, the autophagy mechanism directs a sort of “ripening” process the vesicles must undergo before making their way to the cell membrane. In short, autophagy, a cellular survival mechanism, is employed by the inflammasome to regulate the goblet cells’ secretion of various antibacterial substances into the gut.
This study is the first to make the connection between a crucial regulatory mechanism and the body’s plan for managing its relationship with its bacterial population, and it has clarified how disrupting the mechanism can lead to all sorts of ailments. Elinav: “The epithelial cells, particularly the goblet cells, interact directly with the external environment within the gut. The research shows that these cells are an integral part of the innate immune system, an insight that expands our view of biological immunity. As we improve our understanding of the molecular mechanisms our bodies use to control the bacterial population inside us, we will be better able to develop new treatments against some of the more common human multi-factorial diseases.”
Dr. Eran Elinav’s research is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; Yael and Rami Ungar, Israel; the Crown Endowment Fund for Immunological Research; John L. and Vera Schwartz, Pacific Palisades, CA; Alan Markovitz, Canada; Cynthia Adelson, Canada; the estate of Jack Gitlitz; the estate of Lydia Hershkovich; and the European Research Council.
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