Reacción a "Gut bacteria engineered as a possible treatment for kidney stones"

Hyperoxaluria promotes kidney stone formation and, in severe cases, can cause acute kidney failure and chronic kidney disease requiring dialysis. Causes include a diet high in oxalate, intestinal surgeries (including bariatric surgery used for weight loss), and hereditary defects in oxalate metabolism. The latter are the most serious.

Interestingly, people who are very health-conscious can develop this problem if, instead of eating vegetables, they juice them, which allows them to ingest enormous amounts that they wouldn’t consume by chewing. There are multiple reported cases of acute kidney failure under these circumstances (references 1, 2, 3, 4).

The work is based on solid data and methods, including studies in mice with diet- or surgery-induced hyperoxaluria, healthy volunteers, and patients with surgery-induced hyperoxaluria—in other words, animal models and people in whom intestinal oxalate absorption causes hyperoxaluria.

Throughout the process, they identify different barriers they manage to overcome. Unfortunately, despite this, they found additional barriers in patients, partly due to the excess intestinal oxalate targeted by the treatment. Therefore, clinical application will require future studies.

Nevertheless, beyond the specific problem they tried to solve, they have demonstrated the feasibility of a new method with possible therapeutic applications for other metabolic diseases: the genetic modification of gut microbiota bacteria to achieve two goals: a) to establish and maintain a colony of the desired intestinal bacteria by making it dependent on a specific nutrient—allowing it to be eliminated by stopping that nutrient—and b) to endow that colony with specific metabolic properties of therapeutic interest. These properties can be used either to destroy unwanted metabolites (like oxalate) or to produce desired ones.

For example, some gut bacteria produce vitamin K and anti-inflammatory products such as short-chain fatty acids that have gerosuppressive properties [editor’s note: they inhibit cellular senescence processes] by stimulating the production of the anti-aging protein Klotho in the kidneys. Similarly, some toxins that accumulate in kidney disease are generated by gut microbiota, so modifying it could prevent toxin production. While dialysis is universally accessible in Europe, that’s not the case in most countries, and intestinal destruction of uremic toxins could help people without access to dialysis.

The idea of modifying gut microbiota to reduce oxaluria is not new. In the past, clinical trials were conducted using Oxalobacter formigenes, a bacterium that breaks down oxalate by feeding on it and also secretes factors that stimulate intestinal cells to secrete oxalate into the gut. The results were inconclusive. The current study shows that it is possible to create new bacteria that destroy oxalate and to control their persistence by making them dependent on an orally administered nutrient that can be withdrawn when we want to eliminate them.

On this basis, further work can refine the system. A frequent issue among people interested in microbiota and its benefits is that they take probiotics (bacteria) to maintain gut health, but then don’t feed them (i.e., they don’t eat enough fruits and vegetables, which are essential for a healthy microbiota), so these probiotic supplements starve. This study introduces the innovation of making therapeutic bacteria dependent on a specific food, which allows them to survive as long as desired.

The main limitation of the study is that the intervention was less effective in patients than in healthy individuals, illustrating the challenges of manipulating an already altered microbiota living in a suboptimal environment.

Secondly, this is a proof of concept. There were a limited number of participants and short-term follow-up. Despite that, a potential biosafety issue was already identified due to gene exchange between bacteria. Therefore, it is necessary to address these issues before progressing further.

What relevance does this have for clinical practice in Spain?

In the short term, none. In the medium term, there are multiple potential applications—if the identified problems are corrected—from the treatment of hyperoxaluria itself to the treatment of other metabolic diseases, and to promoting the production of anti-inflammatory and gerosuppressive molecules by the microbiota.

What are the obstacles to applying this in clinical practice?

The authors clearly identify the barriers. Following this proof of concept, it’s necessary to understand and address the factors that reduced the intervention’s effectiveness in patients, even though it was effective in healthy volunteers.