Genetically Enhanced Microorganisms Could Optimize the Microbiota

Genetically modified enterobacteria can effectively degrade compounds linked to kidney stones. This innovative approach to regulating gut microbiota could extend beyond just treating kidney stones, opening pathways for new therapies for various conditions, such as inflammatory bowel disease and colon cancer.

“The gut microbiota significantly influences our health and presents an exciting opportunity for intervention,” says Weston Whitaker from Stanford University in California. However, prior efforts in this area have encountered challenges. Bacteria, whether they are naturally occurring probiotics or genetically engineered strains, often struggle to colonize the large intestine because they must compete with the existing microbial flora.

In an innovative twist, Whitaker and his team decided to genetically modify bacteria that are already prevalent in most people’s intestines, specifically Phocaeicola vulgatus. “We aimed for a strain that would assimilate well into the gut environment,” he explains.

The research team made three key genetic modifications. The first enabled the bacteria to break down a compound called oxalates, which is known to contribute to kidney stones. The second modification allowed them to digest porphyran, a carbohydrate found in red seaweed, providing a competitive edge since most gut microbes do not utilize porphyran. The final adjustments made the bacteria dependent on porphyran for survival, allowing researchers to manage microbial growth effectively.

The researchers conducted a study involving 12 rats on a high-oxalate diet over four days, half of which were treated with genetically modified bacteria that could process oxalate. All rats received porphyran in their daily diet. After six days, those receiving the engineered bacteria had an average of 47% less oxalate in their urine compared to the control group.

The team also examined nine engineered microorganisms in cases of intestinal hyperoxaluria, a condition where excessive oxalate absorption leads to recurrent kidney stones. All subjects consumed 10 grams of porphyran daily for 28 days. On average, participants with the condition but without treatment displayed 27% more oxalate in their urine compared to those receiving the modified strains.

While this reduction in oxalate was not statistically significant, likely due to the small sample size, Whitaker notes that existing clinical trials indicate a 20% decrease in oxalate is sufficient to alleviate symptoms. Therefore, there remains hope for bacteria to help prevent kidney stones.

No serious side effects were reported among participants; however, those treated with genetically modified gut microorganisms were more prone to mild gastrointestinal issues such as abdominal discomfort and diarrhea.

A significant concern emerged from the genetic analysis of the gut microbiota of human subjects, conducted eight weeks post-supplementation, which revealed that only four individuals retained the engineered bacteria capable of digesting porphyran. This suggests that the modified bacteria exchanged genetic material with the resident gut microorganisms. Although this shouldn’t pose safety risks for participants, Whitaker emphasizes the necessity for further investigation in this area.

“This [approach] represents a major breakthrough,” states Christophe Thaiss at Stanford University, who was not involved in the study. He highlights the potential for designing intestinal microorganisms with therapeutic properties that can be reliably integrated into the gut, offering strategies to address various medical conditions.

“We understand that our gut microbiota is linked to many diseases, including diabetes, heart disease, and cancer,” Whitaker observes. “However, the specific relationship between the microbiota and disease causation or prevention remains unclear,” he adds, emphasizing the need for further exploration into this approach.