Research ArticleMetabolism

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

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Science Translational Medicine  16 Jan 2019:
Vol. 11, Issue 475, eaau7975
DOI: 10.1126/scitranslmed.aau7975

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An anti-ammonia probiotic

Hyperammonemia, or excess blood ammonia, is a serious condition that can result in brain damage and death. In pursuit of a potential therapeutic, Kurtz et al. modified the metabolism of a probiotic E. coli strain to overproduce arginine, thereby sequestering some of the ammonia produced by gut bacteria into the amino acid molecules. The engineered strain, called SYNB1020, lowered blood ammonia, increased survival in mouse hyperammonemia models, and showed repeat-dose tolerability in nonhuman primates. A phase 1 dose-escalation study in healthy human volunteers resulted in no serious adverse events and indicated that the bacterium was metabolically active in vivo, suggesting that SYNB1020 warrants further clinical development.

Abstract

The intestine is a major source of systemic ammonia (NH3); thus, capturing part of gut NH3 may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Escherichia coli Nissle 1917 to create strain SYNB1020 that converts NH3 to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. SYNB1020 produced l-arg and consumed NH3 in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase–deficient spfash mice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 1012 colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma 15N-nitrate (highest dose versus placebo, P = 0.0015), and urinary 15N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.

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