Intestinal ammonium production in the rat: The role of the colon, small intestine, and circulating glutamine

Imler, M; Chabrier, G.; Simon, C.; Schlienger, Jean-Louis

doi:10.1007/bf01852088

Cited by 5 publications

(2 citation statements)

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“…Multistep meta bolic pathways can be engineered into bacteria to enhance the con sumption and breakdown of metabolites in the location they are formed. Ammonia (NH 3 ) is a toxic metabolite that is generated in both the small intestine and the colon and enters the portosystemic circulation (10)(11)(12). Elevated circulating ammonia not metabolized to urea by the liver can cross into the brain and induce astrocyte swelling, edema, and neurotoxicity through increased reactive oxy gen species and inflammatory responses (13).…”

Section: Introductionmentioning

confidence: 99%

“…Elevated circulating ammonia not metabolized to urea by the liver can cross into the brain and induce astrocyte swelling, edema, and neurotoxicity through increased reactive oxy gen species and inflammatory responses (13). Similar quantities of ammonia are generated in the small and large intestine (10), but the mechanisms of ammonia generation differ. Small intestinal ammo nia arises from the deamidation of glutamine within intestinal epi thelial cells (14,15), whereas bacterial degradation of protein and microbial urease activity generates ammonia in the colon (16,17).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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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Section: Introductionmentioning

confidence: 99%