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June 15, 2017

Diarrhea Starts with Inflammatory Signal, Ends with Pathogen Clearance

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    Diarrhea may serve as a host defense mechanism when it is driven by an immune mechanism in which interleukin-22 upregulates claudin-2 and promotes pathogen clearance. In the absence of claudin-2, clearance of Citrobacter rodentium is impaired, and bacteria invade the normally protected colonic crypt lumen. (Red) C. rodentium; (green) F-actin; (blue) DNA. [Turner Lab, BWH]

    Diarrhea is a purge with a purpose, insists a team of scientists at Brigham and Women’s Hospital (BWH). In support of this assertion, the scientists point to a new finding—at diarrhea’s base there is an immune mechanism that causes paracellular loosening. This mechanism, the scientists add, appears to promote pathogen clearance and limit disease severity.

    "The hypothesis that diarrhea clears intestinal pathogens has been debated for centuries," said Jerrold Turner, M.D., Ph.D., of the BWH departments of pathology and medicine. "Its impact on the progression of intestinal infections remains poorly understood. We sought to define the role of diarrhea and to see if preventing it might actually delay pathogen clearance and prolong disease."

    To conduct their investigation, Dr. Turner and colleagues studied mice that were infected with Citrobacter rodentium. (For mice, this is the equivalent of an Escherichia coli infection.) After just two days of infection, the mice showed an increase in the permeability of the intestinal barrier, well before they experienced inflammation and epithelial damage. Also, the scientists noticed that claudin-2, a molecule previously implicated in diarrhea, interacted with interleukin-22 (IL-22).

    The details of the scientists’ work appeared June 14 in the journal Cell Host & Microbe, in an article entitled “IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance.” This article defines the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense.

    “Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2,” wrote the article’s authors. “Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity.”

    Although other investigators have proposed developing new therapeutics to inhibit claudin-2, Dr. Turner and colleagues explain that the activation of this pathway may be critical for combating an infection, particularly in the early stages of a disease.

    “Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux,” the authors of the current study concluded. “Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.”

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