Genetically engineered gut bacteria may open new pathways for targeted nutrition

New research has found that engineering a gut microbe can unlock new natural treatments against diseases. Scientists genetically modified the common gut bacterium Phocaeicola vulgatus. When proliferated in the gut microbiome, it led to reduced oxalate levels, emerging as a potential treatment for kidney stones.

“This research opens up possibilities for precise manipulation of gut microbiome activities, significantly impacting both nutrition science and therapeutic manufacturing,” Weston Whitaker, research scientist at Stanford University, US, tells Nutrition Insight. “By engineering bacteria to perform specific metabolic activities in the gut, we can study gut-host interactions more clearly and potentially deliver targeted nutritional or therapeutic benefits.”

“Additionally, this technology is highly modular, allowing validated components — such as the colonization strategy — to be reused or combined with new therapeutic functions without fundamentally altering the production methods, streamlining development and manufacturing processes.”

Selecting the right bacteria

Researchers chose P. vulgatus for the study as it is one of the most abundant and widespread gut bacteria, says Whitaker. This makes it well-suited for establishing therapeutically effective levels in the gut. He explains how they engineered the bacteria.

“Bacteria naturally perform many beneficial activities in the gut. Through genetic engineering, we can precisely introduce defined functions into these bacteria to treat specific diseases.”

“It also belongs to the Bacteroidaceae family, a group extensively studied in microbiome research, providing us with a robust foundation for engineering. In our research, we genetically modified P. vulgatus by introducing five genes from Oxalobacter, a bacterium that naturally degrades oxalate, helping reduce the risk of hyperoxaluria,” he explains.

Hyperoxaluria occurs when oxalate appears in excess in urine and can cause lower back, side, or groin pain, including during urination. Oxalate, or oxalic acid, is naturally occurring in the body and in many plants.

Whitaker states that genetically editing bacteria allows precise manipulation of the gut microbiome, potentially providing targeted nutritional benefits.“We engineered P. vulgatus to consume and be dependent on porphyran, a seaweed polysaccharide, helping the engineered bacteria establish in the gut, but only in the patient during the treatment period,” adds Whitaker. The bacteria break down oxalate and convert it into formate molecules.

Skeptical about safety?

Some may be skeptical of genetically engineering bacteria and allowing it to alter the microbiome. However, Whitaker emphasizes the importance of using residential bacteria and having regulatory oversight.

“It’s important to carefully consider risks when introducing genetically engineered organisms into the body,” he warns. “Targeting hyperoxaluria as our first application has inherent safety advantages, since the therapeutic activity — removing oxalate — is low risk, given that oxalate has no essential role in human physiology.” 

“Additionally, the genes, bacteria, and metabolic activities we introduced are commonly found in healthy human guts. Our clinical trial supported this safety profile, showing no product-related serious or dose-dependent adverse events.”

According to Whitaker, all therapies involve trade-offs, and sometimes unknowable factors are inevitable during the development phase. However, this is why strict regulatory oversight, such as US FDA frameworks, is necessary to ensure patient safety and effectiveness.

Animal and human trials

His team has successfully carried out the test in animal models and early clinical trials in humans. At the same time, Whitaker notes that introducing genetically engineered bacteria to the microbiome has its own challenges and risks.

P. vulgatus was designed to consume and be dependent on porphyran, a seaweed polysaccharide.“Introducing engineered bacteria into the microbiome requires careful consideration of potential impacts on gut ecology. Our approach intentionally uses bacteria and metabolic activities already common in healthy gut microbiomes, reducing the likelihood of adverse effects,” he comments.

“In our clinical research, we carefully monitored gut microbial diversity and found no negative impact, even in subjects highly colonized by our engineered strain. The overall microbial diversity remained stable and comparable to untreated individuals. However, we are continuing detailed analyses to investigate any subtle changes to better understand the impact on the microbiome.”

The study notes that engineered bacteria show promise in animals but often fail in clinical settings due to inconsistent colonization. It notes that strain stability, biosafety, and competition from native microbes are the main challenges that remain. 

To overcome this problem, the researchers engineered P. vulgatus to consume the seaweed-derived nutrient, porphyran. Their previous studies showed that dietary porphyran prebiotic can enable a controllable environment for porphyran-metabolizing bacteria in the gut to remain stable, which is reversible when needed. 

Bacteria have been lost in many people in industrialized regions and societies.The study in Science notes that microbes in Western people rarely use porphyran, as only approximately 2% naturally carry bacteria that can process it. This enables an “unoccupied ecological niche” where engineered bacteria can survive without competition.

Dietary intervention versus engineering

Whitaker explains why one would opt for genetically engineered bacteria over dietary pathways that alter the microbiome.

“While dietary interventions can support general gut health, they typically rely on existing microbial functions. P. vulgatus does not naturally degrade oxalate, but other natural bacteria do, and their absence can be a risk factor for kidney stones.”

“However, these bacteria have been lost in many people in industrial societies, and reintroducing them effectively into the gut can be unpredictable due to the complexity of gut ecosystems.” 

Whitaker notes that over a decade, clinical trials have tried many times to reintroduce oxalobacter — “the best known oxalate degrader” — but have struggled.

This is why his team decided to take an alternative approach. “Genetic engineering offers a precise, targeted approach to ensure the desired therapeutic function is consistently delivered.”

In other scientific inquiries into kidney health, Gnosis by Lesaffre and its partner Omicron Pharmaceuticals recently published a case study exploring the benefits of K2 supplementation on an individual with calciphylaxis, a condition related to poor kidney function.