Toward Oral Supplementation of Diamine Oxidase for the Treatment of Histamine Intolerance

Abstract

A new diamine oxidase (DAO-1) was discovered recently in the yeast Yarrowia lipolytica PO1f and investigated for its histamine degradation capability under simulated intestinal conditions. DAO-1 was formulated together with catalase as a sucrose-based tablet. The latter (9 × 7 mm; 400 mg) contained 690 nkat of DAO-1 activity, which was obtained from a bioreactor cultivation of a genetically modified Y. lipolytica with optimized downstream processing. The DAO-1 tablet was tested in a histamine bioconversion experiment under simulated intestinal conditions in the presence of food constituents, whereby about 30% of the histamine was degraded in 90 min. This amount might already be sufficient to help people with histamine intolerance. Furthermore, it was found that the stability of DAO-1 in a simulated intestinal fluid is influenced distinctively by the presence of a food matrix, indicating that the amount and type of food consumed affect the oral supplementation with DAO. This study showed for the first time that a microbial DAO could have the potential for the treatment of histamine intolerance by oral supplementation.

Recent advances in the application of microbial diamine oxidases and other histamine-oxidizing enzymes

“…The latter contains monobasic potassium phosphate, sodium hydroxide and the enzyme preparation ‘pancreatin.’ Pancreatin is a mixture of different enzyme activities, such as amylases, lipases and peptidases (Salhi et al 2020 ). The latter cause a rapid degradation of microbial and animal HOX, which further highlights the need for the administration of high activities to compensate for activity losses (Kettner et al 2020 , 2022 ). The half-life period of free pig DAO in a simulated intestinal fluid was 19 min (Kettner et al 2020 ).…”

“…The half-life period of free pig DAO in a simulated intestinal fluid was 19 min (Kettner et al 2020 ). It was shown with a microbial DAO in a simulated intestinal fluid, that the amount and type of food consumed has a distinct effect on the stability of a supplemented DAO, extending its half-life period to at least 30 min (Kettner et al 2022 ). In contrast, a vegetal DAO from pea ( L. sativus ) showed a high stability in a simulated intestinal fluid with a half-life period of around 16 h (Blemur et al 2016 ).…”

“…The application of microbial HOX as a dietary adjuvant for the histamine degradation in the human intestine was investigated with the DAO from Y. lipolytica PO1f (Kettner et al 2022 ). Here, the DAO was prepared as a sucrose-based tablet and it reduced high amounts of histamine under simulated intestinal conditions.…”

“…Thereby, one nkat was defined as the amount of enzyme that converts 1 nmol histamine per second at 37 °C, which corresponds to 0.06 Enzyme Units (µmol histamine per minute). Furthermore, much higher activities of at least 690 nkat might be required when used under actual simulated intestinal conditions (Kettner et al 2022 ). To obtain this DAO activity, around 1.4 kg pig kidneys would be required for the extraction and partial purification (Kettner et al 2020 ).…”

“…To put this into perspective, the DAO extraction and partial purification from around 80 kg pig kidneys would be necessary to obtain the DAO amount required for 1 L of this tuna soup (Kettner et al 2020 ). In contrast, this DAO activity is obtainable by the disruption and purification of around 2 kg wet yeast mass of a genetically modified Yarrowia lipolytica PO1f strain that produces a microbial DAO (Kettner et al 2022 ). However, the activity of 42 µkat/L used by Naila et al is not an appropriate amount at all when a true application in industry would be considered.…”