苯丙氨酸
粪便
大肠杆菌
酶
生物
苯丙酮尿症
尿
拉伤
医学
药理学
基因
生物化学
氨基酸
化学
微生物学
内科学
作者
Vincent M. Isabella,Binh Ha,Mary Joan Castillo,David Lubkowicz,Sarah E. Rowe,Yves Millet,Cami Anderson,Ning Li,Adam Fisher,Kip A. West,Philippa J. Reeder,Munira Momin,Christopher G Bergeron,Sarah E. Guilmain,Paul Miller,Caroline Kurtz,Dean Falb
摘要
Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pahenu2/enu2 PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.
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