The human gut is a smorgasbord of bacteria—some good and some bad. While the friendly bacteria play crucial roles in digestion and stimulation of immune responses, the unwelcome invaders can lead to a host of problems, from gastrointestinal distress to mental health disorders. Helicobacter pylori is one such bacterium that resides in the stomach lining of half the world’s population and can provoke the formation of gastric ulcers and tumors.1 It can also modify the resident intestinal microbiota and alter the production of essential bacterial metabolites.
Until now, H. pylori was mostly known for being injurious to humans. But it might get an image makeover! In a new study published in Science Advances, researchers have shown that the bacterium releases a protein that can inhibit the formation of abnormal protein clusters associated with conditions like type 2 diabetes and some neurodegenerative disorders.2 The molecule’s broad-spectrum activity against diverse misfolded proteins could potentially be used for therapeutics in the future.
H. pylori mounts its attack by injecting a part of the cytotoxin-associated gene A protein (CagA) into neighboring cells, disrupting their growth, motility, and integrity.3 The process leaves behind the N-terminus of the protein (CagAN), which researchers have detected in the serum of individuals infected with H. pylori and in vesicles traveling between tissues. These observations suggest that CagAN could have a systemic impact beyond the infection site. Gefei Chen, a protein biochemist at Karolinska Institute, wanted to understand the broader effects of this H. pylori protein.
He set out to investigate whether CagAN interacted with molecules in its vicinity, such as those present on other bacteria. Gut microbes like Escherichia coli and Pseudomonas species form biofilms that protect them from host immune cells, antibiotics, and other bacteria. These biofilms contain bacterially-secreted proteins arranged in an ordered fiber, giving rise to an amyloid state of proteins.4 Despite this shield, H. pylori harms them.
Chen and his colleagues wanted to know if CagAN makes the biofilm-protected bacteria susceptible to H. pylori’s attack. They exposed Pseudomonas bacteria to recombinant CagAN and observed that the protein drastically inhibited biofilm formation in the normal bacteria, as well as in Pseudomonas variants that produced high levels of amyloid fibrils. The treatment reduced the amyloid content in the bacteria, extended the time needed to form the aggregates, and diminished bacterial mortality.
Although amyloids help bacteria survive, their accumulation in mammalian organs can be deleterious. Pathogenic aggregates of different proteins lead to disorders like type 2 diabetes, Alzheimer’s disease, and Parkinson’s disease.5 So, Chen and his team tested the effect of CagAN on proteins implicated in these diseases: amyloid β isoforms and tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, and islet amyloid polypeptide in type 2 diabetes. The protein efficiently inhibited amyloid cluster formation for all the targets, exhibiting its ability to act on proteins of varying sizes and charges.
To understand the mechanism of inhibition, Chen and his team analyzed the protein’s domains and their interactions with the targets using AlphaFold3. Domain II emerged as a strong binding partner for the amyloid aggregates. On experimentally testing the effects of the recombinantly expressed domain II, the team observed potent inhibition of amyloid β fiber formation.
Drug-resistant bacterial infections and human amyloid disorders are a huge burden to public health. Chen and his team speculate that these findings could serve as a stepping stone for developing new therapeutics to combat these diseases.
- Iino C, Shimoyama T. Impact of Helicobacter pylori infection on gut microbiota. World J Gastroenterol. 2021;27(37):6224-6230.
- Jin Z, et al. Helicobacter pylori CagA protein is a potent and broad-spectrum amyloid inhibitor. Sci Adv. 2025.
- Odenbreit S, et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287(5457):1497-1500.
- Levkovich SA, et al. Two decades of studying functional amyloids in microorganisms. Trends Microbiol. 2021;29(3):251-265.
- Chiti F, Dobson CM. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu Rev Biochem. 2017;86:27-68.
