An anticonvulsive drug, valproic acid (valproate), has effects on the biosynthesis of fatty acids and polyketides in microorganisms

Abstract

Valproic acid or valproate (VpA) is an anticonvulsive drug used for treatments of epilepsy, bipolar disorder, and migraine headaches. VpA is also an epigenetic modulator, inhibiting histone deacetylase, and it has been subjected to clinical study for cancer treatment. During the investigation of VpA on a metabolite profile in a fungus, we found that VPA has significant effects on the production of some fatty acids. Further exploration of VPA on fatty acid profiles of microorganisms, fungi, yeast, and bacteria, as well as representative gut microbiome, revealed that VpA could enhance or reduce the production of some fatty acids. VpA was found to induce the production of trans-9-elaidic acid, a fatty acid that was previously reported to have cellular effects in human macrophages. VPA could also inhibit the production of some polyketides produced by a model fungus. the present work suggests that the induction or inhibition of fatty acid biosynthesis by VPA (100 µM) in gut microbiome could give effects to patients treated with VPA because high doses of VPA oral administration (up to 600 mg to 900 mg) are used by patients; the concentration of VPA in the human gut may reach a concentration of 100 µM, which may give effects to gut microorganisms. Valproic acid (VPA) or valproate, an anticonvulsive drug, has been used as drug for the treatment of epilepsy, bipolar disorder, and for the prevention of migraine headaches. VPA has side effects, for example, hepatic steatogenesis in rats 1 , and negative influence on hepatic carbohydrate and lipid metabolism 2. There were a number of fatal cases of hyperammonemia for patients treated with VPA 3. In mitochondria, VPA undergoes fatty acid β-oxidation pathway, causing toxicity due to interference with mitochondrial β-oxidation, and many serious inborn errors of metabolism are caused by VPA treatment 4. VPA interferes with carnitine palmitoyl-transferase I, a key enzyme in mitochondrial fatty acid β-oxidation, and thus inducing hepatotoxicity and weight gain for patients under VPA therapy 5. VPA could inhibit N-acetyl glutamate synthetase, and thus inhibiting urea synthesis 6,7. VPA was found to induce abnormal autism-like behaviors in mice 8. Recently, a number of research groups paid attention on the risk of VPA on autism spectrum disorders 9-14. The discovery that VPA is an inhibitor of histone deacetylase, a promising anticancer drug target, has stimulated the scientific community worldwide to investigate the detailed mechanisms of VPA in various aspects 15,16. Recently, drug repurposing of VPA has been intensively explored for the treatment of various diseases, for example, the treatment of breast cancer 17 , colon cancer associated with diabetes mellitus 18 , diffuse intrinsic pontine glioma 19 , high-fat diet-induced hypertension 20 ,

Comparing the Gut Microbiome in Autism and Preclinical Models: A Systematic Review

“…In addition to genetic influences, environmental factors can modify microbial profiles and could contribute to the etiology of complex disorders. Several medications, including the antiepileptic drug, valproate, modify gut microbial function including fatty acid production (Poolchanuan et al, 2020). It has also been shown that the risk of ASD diagnosis is increased in infants born to mothers prescribed valproate (Christensen et al, 2013).…”

Flow cytometric resolution of yeast is affected by enzymatic treatment and culture media

“…Naturally, the altered protein proportion was potentially attributed to the varied metabolism of yeast cells when grown in the different media [ 17 ], and the absence or presence of a certain compound in media would possibly lead to such an alteration in the resolution [ 18 ]. Although other ingredients in the cell wall could cause fluctuant resolution [ 19 ], further investigations are needed to determine the exact components that influence the cytometric resolution of the yeast cell cycle.…”

Gastrointestinal Microbiome: Novel Paradigm Proposed in the Treatment of Autism Spectrum Disorder Associated Social Behavioral Symptoms in Two Rodent Models

“…Moreover, as different gut microbial community was found in ASD patients in contrast to the healthy individuals, researchers attempted to modify the gut microbiome via probiotics and some results indicate bene cial effects on both behavioral and GI manifestations of ASD [46][47][48][49] . In addition, VPA rat model not just imitate ASD symptoms, it also has a transgenerational impact on the gut microbiota [50][51][52] .…”