Understanding the foundations of ulcerative colitis, a condition affection millions worldwide, has proven elusive. Now, researchers at the Medical University of Graz and the University of Graz have shed light on the role of gut bacteria and their antibody-coated vesicles (extracellular sacs) in spiking the chronic inflammation in the colon linked to the condition.
Analyzing colonic fluid from 74 volunteers, a Nature Communications study reveals that nano-scale extracellular vesicles (BEVs) that gut microbes shed become coated with patients’ own IgA antibodies. These IgA-BEV complexes subsequently bind the CD89 receptor on infiltrating immune cells. This in turn triggers a release of inflammatory cytokines and exacerbates disease in a human-CD89 mouse model.
The work shifts attention from whole-bacteria to their antibody-coated parcels, reviving interest in CD89 blockade or B-cell–directed approaches that earlier trials had shelved.
The research could have drug discovery ramifications. From the paper’s abstract: “Considering the inflammatory potency of IgA-coated BEVs reported here, we propose that adaptive B cell immune processes warrant renewed attention in drug development strategies.”
The bacterial extracellular vesicles (BEVs) are miniscule, only a few nanometers in size, and contain a range of bacterial elements including pro-inflammatory substances such as lipopolysaccharide (LPS), proteins or pieces of DNA.
“BEVs can be thought of as a molecular communication system: With their help, bacteria influence their environment—and also the human immune system,” said Christoph Högenauer, a Med Uni Graz gastroenterologist, in a news release.
While the ulcerative colitis therapeutic armamentarium includes a growing numer of FDA-approved drugs targeting pathways like TNF, integrins, interleukins (IL-12/23, IL-23p19), JAK signaling, and S1P modulation, the recent discovery by Austrian researchers represents a distinct mechanism. The researchers’ identification of IgA-coated bacterial vesicles as a central inflammatory driver acting through the CD89 receptor could open the door for new therapeutic possibilities. This could involve direct CD89 blockade or, as the researchers propose, a re-evaluation of “adaptive B cell immune processes” for future drug development.
Filed Under: Gastroenterology
