Engineered gut bacteria designed to treat kidney stones successfully colonized the gut microbiome and reduced oxalate levels in animal models and early clinical trials in humans, researchers report. The findings offer a promising, yet still imperfect, step toward microbial therapies. Efforts to manipulate the gut microbiome using engineered bacteria for therapeutic purposes have shown promise in animals, but often fail in clinical settings due to being hindered by inconsistent colonization. To overcome this challenge, Weston Whitaker and colleagues focused on Phocaeicola vulgatus, a common gut bacterium, and engineered it to consume the seaweed-derived nutrient, porphyran. Their previous work showed that adjusting dietary levels of a porphyran prebiotic can create a controllable niche that enables stable and tunable colonization of porphyran-metabolizing bacteria in the gut, which can be reversed when needed. Porphyran is rarely utilized by microbes in Western populations – only about 2% naturally carry bacteria with this capability, thus creating a largely unoccupied ecological niche for an engineered strain to thrive without competition. To evaluate whether this setup could be used to deliver microbial therapeutics, Whitaker et al. engineered a porphyran-metabolizing strain of P. vulgatus to break down oxalate (a cause of recurrent kidney stones) by introducing a specialized transporter and a metabolic pathway that converts oxalate into formate. In animal models and a phase 1/2a clinical trial in healthy humans, the authors show that engineered gut bacteria can safely and effectively colonize the gut and deliver therapeutic effects by reducing oxalate levels. However, some individuals developed persistent colonization due to genetic mutations, and notable horizontal gene transfer events compromised the strain’s therapeutic function. While the approach showed modest, early signs of reducing oxalate levels, challenges remain, Whitaker et al. note, including strain stability, biosafety, and competition from native microbes.
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