Investigators at UMC Utrecht and Utrecht University have found that ADP-heptose, a pro-inflammatory metabolite that is secreted by bacterium Campylobacter jejuni, is responsible for gut inflammation after food poisoning, resulting in diarrhea. This finding contributes to the pathogenesis of C. jejuni infections and may provide clues for a preventive therapy of food poisoning.

The Gram-negative bacterium Campylobacter jejuni is a major cause of foodborne disease in humans. After infection, C. jejuni rapidly colonizes the mucus layer of the small and large intestine and induces a potent pro-inflammatory response characterized by the production of a large repertoire of cytokines, chemokines, and innate effector molecules, resulting in (bloody) diarrhea. However, the molecular virulence mechanisms by which C. jejuni causes enteritis are still largely unknown. Therefore, researchers at University Medical Center (UMC) Utrecht and Utrecht University jointly started an in vitro study into the drivers of the inflammatory response in the gastrointestinal tract due to food poisoning caused by the bacterial pathogen C. jejuni.

Immune response after C. jejuni infection

Once ingested, C. jejuni crosses the mucus layer and colonizes the bottom of the crypts of the colon. This is believed to be followed by breaching of the epithelial layer and triggering of immune responses that lead to a massive neutrophil influx with crypt abscess formation, which likely explains an important part of the acute inflammatory pathology observed during C. jejuni infection. A key feature in the pathogenesis therefore appears to be the interaction with immune receptors on epithelial and innate immune cells and the subsequent induction of a potent innate immune response.

Drivers of inflammation

In this study, the investigators showed for the first time that C. jejuni releases a potent pro-inflammatory compound into its environment, which activates a pro-inflammatory response including the induction of several cytokines and chemokines. This response was dependent on a functional intracellular alpha kinase 1 (ALPK1) receptor. Chemical characterization, inactivation of the heptose-biosynthesis pathway by gene deletion and in vitro engineering identified the released factor as ADP-heptose. During experimental C. jejuni infection of intestinal cells, the pro-inflammatory master regulator of immune and inflammatory genes NF-ĸB was potently activated by release of heptose metabolites.

Principal investigator Marcel de Zoete, PhD (Department of Medical Microbiology, UMC Utrecht) concludes: “These new findings classify ADP-heptose as a major virulence factor of C. jejuni that may play an important role during Campylobacter infection in humans. This significantly contributes to our knowledge of the pathogenesis of C. jejuni infections and provides novel clues for a targeted preventive therapy for food poisoning.”

Marcel de Zoete, PhD

Foodborne diseases

Foodborne diseases are caused by contamination of food (e.g. with bacteria or viruses) and encompass a wide range of illnesses ranging from diarrhea to cancer. Diseases causing diarrhea are a major problem in all countries of the world, though the burden is carried disproportionately by low- and middle-income countries and by children under 5 years of age. This growing public health problem causes considerable socioeconomic impact through strains on healthcare systems, lost productivity, and harming tourism and trade. The WHO estimates that 1 in 10 people worldwide fall ill from food poisoning each year.

Publication

Cui J, Duizer C, Bouwman LI, van Rooijen KS, Voogdt CGP, van Putten JPM, de Zoete MR. The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal cells. PLoS Pathogens 17(8): e1009787