Engineered Probiotics kill H. pylori, a cancer-causing bacterium - Drug Discovery News

Peptic ulcers and the accompanying intense stomach pain don't come from eating too much spicy food, but actually are caused by an overgrowth of a species of bacteria in the stomach that can potentially lead to gastric cancer. Gastric cancer is the fifth deadliest cancer worldwide,  and researchers attribute 75 percent of cases to a typically harmless gut bacteria named Helicobacter pylori (1,2). 

While there are substantial studies dedicated to understanding the virulence of this pathogen and its association with gastric cancers, little has been done to address the larger problem: Antibiotics fail to get rid of H. pylori, and when taken, they often have negative side effects such as killing all of the gut bacteria, good and bad (3). Now, a team of researchers led by Chris Kearney at Baylor University has developed a tool to help answer this growing problem.

To create something specifically targeting H. pylori is an intriguing idea. 
– Ivo Gomperts Boneca, Pasteur Institute

Antimicrobial peptides (AMP), small peptides that disrupt bacterial membranes, effectively eliminate H. pylori in vitro. "The big problem with AMP is that they are just peptides. So, if you tried to give them topically or orally, they would be going to a place that naturally degrades them, and so we had to give them some form of protection," said Kearney. "Probiotics were an answer to deliver these AMP on site in the stomach, without them degrading, and it happened to be cheaper in manufacturing."

In a recent study, Kearney and his collaborators created an AMP delivery system using the typical yogurt inhabitant Lactococcus lactis (4). This engineered probiotic secretes AMP that selectively eradicated H. pylori in mice without harming the rest of the gastric microflora.

"To create something specifically targeting H. pylori is an intriguing idea," said Ivo Gomperts Boneca, a microbiologist from the Pasteur Institute, who was not involved in this study. 

The researchers engineered L. lactis to secrete nonspecific AMP and AMP specific for a protein on the surface of H. pylori. The engineered bacteria carried out this function only after reaching the acidic pH found in the stomach.

Researchers in Chris Kearney's team developed a probiotic targeted to kill only H. pylori in the gut. From left to right: Toslim Mahmud, Chris Kearney, Mikaeel Young, Ankan Choudhury, and Patrick Ortiz.

Credit: Chris Kearney

Working with young mice, the team introduced natural gut flora from healthy mouse donors. They then orally administered H. pylori to establish an infection. Five days later, the researchers treated the mice with the engineered L. lactis probiotic. Compared to the nonspecific AMP, the specific AMP produced an 83-fold reduction in off-target toxicity, suggesting that other species of bacteria would remain unharmed by this treatment. By examining the mucus contents of the gastric organs, the team found that after five days, the H. pylori infection reduced to near eradication, regardless of the type of AMP used. 

When treated with standard antibiotics, the microflora decreased steadily over time to 26 percent on day 10 of the study. Comparatively, the treatment with either the specific or nonspecific AMP led to a balanced gut microflora. 

Boneca would like to learn where the engineered L. lactis localizes in the mouse gut. "I am skeptical of the translation between mice and humans," he added, mentioning that mice have a special section of the stomach that humans lack. This region could provide a space for the L. lactis to grow and secrete more AMP, potentially leading to the observed benefits that may not be seen in humans. He is also interested in the long-term effects of extended probiotic-induced AMP secretion on the entire GI tract. 

Kearney's team is currently investigating the use of this probiotic AMP platform for treating other gut pathogens, expanding their repertoire to create an elegant system that can deliver effective AMP to places once thought to be unsuitable. 

References

1. WCRF International. Stomach cancer statistics.
2. Herrera, V. & Parsonnet, J. Helicobacter pylori and gastric adenocarcinoma. Clinical Microbiology and Infection  15, 971–976 (2009).
3. Park, J. Y. et al. Helicobacter pylori Clarithromycin Resistance and Treatment Failure Are Common in the USA. Dig Dis Sci  61, 2373–2380 (2016).
4. Choudhury, A. et al. Control of Helicobacter pylori with engineered probiotics secreting selective guided antimicrobial peptides. Microbiology Spectrum  11, e02014-23 (2023).

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