Gout, chronic kidney disease, type 2 diabetes, and cardiovascular disease are all linked to elevated levels of uric acid (UA) in the blood. Even with improved methods of treatment, gout still receives less-than-ideal attention. In healthy people, the kidneys metabolize and eliminate roughly 70% of the UA in circulation, while the intestines handle 30%. New research points to the gut microbiome’s ability to play a role in UA breakdown. Furthermore, gout patients have been observed to have a notable gut dysbiosis associated with dysregulated host urate degradation. Based on these results, researchers designed a synthetic biotic to break down UA in the digestive system. The SYN-GOUT strain of Escherichia coli Nissle 1917 has been genetically edited to overexpress a urate transporter and to express bacterial and fungal urate oxidase enzymes. Allantoin is a purine derivative that is water-soluble and easily removed since the strain converts UA to 5-hydroxyisourate. Over the course of 120 minutes in vitro, SYN-GOUT efficiently digested ~2 mM UA, leading to a rise in the concentration of its metabolite allantoin. Under hypoxic (2-7% oxygen) circumstances similar to the gastrointestinal system, an activity assay showed that SYN-GOUT efficiently consumed UA. A tiny amount of tagged UA (1,3-15N2) given intraperitoneally to mice resulted in the emergence of 1,3-15N2-UA in the small intestine, suggesting the presence of an enterorecirculation loop. Finally, SYN-activity GOUT’s in vivo was demonstrated by a more than 2-fold reduction in urine UA production after a single dose in non-human primates (NHPs). SYN-GOUT is an innovative Synthetic Biotic because it can efficiently absorb UA in vitro while maintaining activity in low-oxygen environments. SYN-GOUT reduced urine UA levels in NHPs and was well tolerated and safe to use in vivo. SYN-GOUT may be able to reduce systemic UA levels because it consumes UA within the GI tract, which is supported by the observation that a pool of UA circulates between the systemic and GI compartments. It follows that SYN-GOUT has the potential to be a viable option for the treatment of gout, particularly in people with impaired kidney function.
Source: asn-online.org/education/kidneyweek/2022/program-abstract.aspx?controlId=3766374
