Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice

Abstract

Tetrahydrobiopterin (BH4) is a cofactor of a number of regulatory enzymes. Although there are no known BH4 exogenous sources, the tissue content of this biopterin increases with age in GTP cyclohydrolase 1-deficient hyperphenylalaninemia-1 (hph-1) mice. Since certain bacteria are known to generate BH4, we hypothesize that generation of this biopterin by the intestinal microbiota contributes to its tissue increase in hph-1 adult mice. The goal of this study was to comparatively evaluate hph-1 mice and wild-type C57Bl/6 controls for the presence of intestinal BH4-producing bacteria. Newborn and adult mice fecal material was screened for 6-pyruvoyltetrahydropterin synthase (PTPS-2) an enzyme only present in BH4-generating bacteria. Adult, but not newborn, wild-type control and hph-1 mouse fecal material contained PTPS-2 mRNA indicative of the presence of BH4-generating bacteria. Utilizing chemostat-cultured human fecal bacteria, we identified the PTPS-2-producing bacteria as belonging to the Actinobacteria phylum. We further confirmed that at least two PTPS-2-producing species, Aldercreutzia equolifaciens and Microbacterium schleiferi, generate BH4 and are present in hph-1 fecal material. In conclusion, intestinal Actinobacteria generate BH4. This finding has important translational significance, since manipulation of the intestinal flora in individuals with congenital biopterin deficiency may allow for an increase in total body BH4 content.

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina

“…Retinal tissues (pool of five retinas per sample, n = 3 per group) were collected from WT mice and hph-1 mice at postnatal day 7, 14, and 22. Determination of BH4 in retinal tissues was performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) as previously described [ 32 ]. Briefly, analysis was performed on an AB Sciex 5500QTRAP mass spectrometer (Foster City, CA, USA) coupled with a Shimadzu Nexera ultrahigh pressure liquid chromatograph system (Kyoto, Japan).…”

Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease

“…Interestingly, BH 4 supplementation (10 mg/kg/day) significantly decreased various types of congenital heart defects in the embryos of pregestational diabetic mice ( 42 ), suggesting the importance of sufficient antioxidant and anti-inflammatory compounds during pregnancy. There are currently no known food sources of BH 4 although intestinal microbiota may be a source ( 48 ), suggesting future research may show low levels of BH 4 producing bacteria in CVD patients or in other chronic conditions/diseases.…”

“…Another interesting approach is to enhance the production or delivery of BH 4 , a key molecule in maintaining eNOS coupling. Apart from de novo intracellular synthesis, certain intestinal microbiota may provide a unique exogenous source ( 48 ). This suggests there could be a gut microflora–antioxidant connection (from fruit and vegetable intake or individual antioxidant molecules); however, little is known about how the microbiome effects CVD and this field is still in its infancy ( 102 ).…”

The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?

“…In rodents, BH 4 production is age-dependent and is related to the presence of Actinobacteria in the bowel, especially Adlercreutzia equolifaciens and Microbacterium schleiferi . These same species have been identified in the human gut microbiome ( Belik et al , 2017 ). Very little is known about the determinants of responsiveness to BH 4 therapy and its effects on cerebral activity and cognition, but these effects are known to be multifactorial, as they vary across individuals with the same genotype ( Pérez et al , 2005 ).…”