Interactions between dietary flavonoids and the gut microbiome: a comprehensive review

Flavonoids are natural polyphenol secondary metabolites that are widely produced in planta. Flavonoids are ubiquities in human dietary intake and exhibit a myriad of health benefits. Flavonoids-induced biological activities are strongly influenced by their in situ availability in the human GI tract, as well as the levels of which are modulated by interaction with the gut bacteria. As such, assessing flavonoids–microbiome interactions is considered a key to understand their physiological activities. Here, we review the interaction between the various classes of dietary flavonoids (flavonols, flavones, flavanones, isoflavones, flavan-3-ols and anthocyanins) and gut microbiota. We aim to provide a holistic overview of the nature and identity of flavonoids on diet and highlight how flavonoids chemical structure, metabolism and impact on humans and their microbiomes are interconnected. Emphasis is placed on how flavonoids and their biotransformation products affect gut microbiota population, influence gut homoeostasis and induce measurable physiological changes and biological benefits.

Bioaccumulation And Biotransformation of BDE-47 Using Zebrafish Eleutheroembryos (Danio Rerio)

Polybrominated diphenyl ethers (PBDEs) industrially used as flame retardants are nowadays considered emerging pollutants as they are endocrine disrupting chemicals (EDCs), persistent in the environment, bioaccumulative and in addition, its hydroxylated (OH-BDEs) and methoxylated (MeO-BDEs) metabolites have similar ecotoxic properties. The aim of this work was to develop an analytical method to be applied in the study of the bioconcentration and biotransformation of BDE-47 due to its bioavailability, toxicity and high persistence and abundance in environmental samples, including humans. So, a dependable ultrasonic extraction process followed to dispersive SPE clean-up step and GC-MS-μECD detection has worked out for the determination of BDE-47 and its main biotransformation products (MeO-BDEs and OH-BDEs), considering the polarity difference. In addition, an alternative method to bioconcentration official guideline OECD 305, developed previously with zebrafish (Danio rerio) eleutheroembryos (i.e., hatched but not yet free feeding embryos) is used, reducing dramatically the animal suffering but also time and reagents. Bioconcentration factors (BCF) were calculated using first order one-compartment toxicokinetic model. The profiles found show rapid absorption in the first hours of larval development and great bioaccumulative with capacity, finding bioconcentration factors (BCF) of 6631 and 44210 at nominal concentrations of 10 and 1 μg·L-1 (< 1% LC50), respectively. Metabolization studies show increasing concentrations of the metabolites BDE-28, 2'-OH-BDE-28 and 5-MeO-BDE-47 throughout the exposure time. The results obtained show the feasibility of the method for bioaccumulation and opens the possibility of metabolic studies with zebrafish eleutheroembryos, which is a very underdeveloped field without official testing or regulation.

Fungal Biotransformation of 2′-Methylflavanone and 2′-Methylflavone as a Method to Obtain Glycosylated Derivatives

Methylated flavonoids are promising pharmaceutical agents due to their improved metabolic stability and increased activity compared to unmethylated forms. The biotransformation in cultures of entomopathogenic filamentous fungi is a valuable method to obtain glycosylated flavones and flavanones with increased aqueous solubility and bioavailability. In the present study, we combined chemical synthesis and biotransformation to obtain methylated and glycosylated flavonoid derivatives. In the first step, we synthesized 2′-methylflavanone and 2′-methylflavone. Afterwards, both compounds were biotransformed in the cultures of two strains of entomopathogenic filamentous fungi Beauveria bassiana KCH J1.5 and Isaria fumosorosea KCH J2. We determined the structures of biotransformation products based on NMR spectroscopy. Biotransformations of 2′-methyflavanone in the culture of B. bassiana KCH J1.5 resulted in three glycosylated flavanones: 2′-methylflavanone 6-O-β-d-(4″-O-methyl)-glucopyranoside, 3′-hydroxy-2′-methylflavanone 6-O-β-d-(4″-O-methyl)-glucopyranoside, and 2-(2′-methylphenyl)-chromane 4-O-β-d-(4″-O-methyl)-glucopyranoside, whereas in the culture of I. fumosorosea KCH J2, two other products were obtained: 2′-methylflavanone 3′-O-β-d-(4″-O-methyl)-glucopyranoside and 2-methylbenzoic acid 4-O-β-d-(4′-O-methyl)-glucopyranoside. 2′-Methylflavone was effectively biotransformed only by I. fumosorosea KCH J2 into three derivatives: 2′-methylflavone 3′-O-β-d-(4″-O-methyl)-glucopyranoside, 2′-methylflavone 4′-O-β-d-(4″-O-methyl)-glucopyranoside, and 2′-methylflavone 5′-O-β-d-(4″-O-methyl)-glucopyranoside. All obtained glycosylated flavonoids have not been described in the literature until now and need further research on their biological activity and pharmacological efficacy as potential drugs.

Characterization of Phase I Hepatic Metabolites of Anti-Premature Ejaculation Drug Dapoxetine by UHPLC-ESI-Q-TOF

Determination of the metabolism pathway of xenobiotics undergoing the hepatic pass is a crucial aspect in drug development since the presence of toxic biotransformation products may result in significant side effects during the therapy. In this study, the complete hepatic metabolism pathway of dapoxetine established according to the human liver microsome assay with the use of a high-resolution LC–MS system was described. Eleven biotransformation products of dapoxetine, including eight metabolites not reported in the literature so far, were detected and identified. N-dealkylation, hydroxylation, N-oxidation and dearylation were found to be the main metabolic reactions for the investigated xenobiotic. In silico analysis of toxicity revealed that the reaction of didesmethylation may contribute to the increased carcinogenic potential of dapoxetine metabolites. On the other hand, N-oxidation and aromatic hydroxylation biotransformation reactions possibly lead to the formation of mutagenic compounds.

Fungal biotransformation of limonene and pinene as a biotechnological approach for production of aroma compounds

The number of aroma compounds obtained by biotechnological process has increased tremendously in recent years and, as a result, are now being extensively employed in order to make products more attractive for consumers. In the present review, we inten to assess the wide range of reactions are catalyzed by fungal strains in regards to biotransformation of limonene and pinene for the aroma compounds production, their production rates/maximum concentrations and their biological potential. We comprehensively summarized in this review available data (2000–2021) regarding fungal biotransformation of limonene and pinene as biotechnological processes. Over the past years, has been paid to the biotransformation processes due to mild and environmentally friendly conditions applied. This review has shown that reports on the application of the fungi as a promising source of biocatalysts, mainly for stereoselective reactions such as hydroxylation and epoxidation. Studies have demonstrated the existence of promising monoterpenes used as substrates, which could be important from an industrial standpoint since this increases their importance as starting materials for obtaining aromatic molecules new. Moreover, biological (e.g.,antioxidant, anticancer) activities attributed to some monoterpene biotransformation products are increasingly being reported, indicating that their applications may transcend food, cosmetic and pharmaceutical industry.

Identification and Toxicity Prediction of Biotransformation Molecules of Organophosphate Flame Retardants by Microbial Reactions in a Wastewater Treatment Plant

Organophosphate flame retardants (OPFRs) are substances added to plastics, textiles, and furniture, and are used as alternatives to brominated flame retardants. As the use of OPFRs increases in the manufacturing industry, the concentration in the aquatic environment is also increasing. In this study, OPFRs introduced into a wastewater treatment plant (WWTP) were identified, and the toxicity of biotransformation molecules generated by the biological reaction was predicted. Tris(2-butoxyethyl) phosphate, tris(2-butoxyethyl) phosphate, and triphenyl phosphate were selected as research analytes. Chemicals were analyzed using high-resolution mass spectrometry, and toxicity was predicted according to the structure. As a result, tris(1-chloro-2-propyl) phosphate showed the highest concentration, and the removal rate of OPFRs in the WWTP was 0–57%. A total of 15 biotransformation products were produced by microorganisms in the WWTP. Most of the biotransformation products were predicted to be less toxic than the parent compound, but some were highly toxic. These biotransformation products, as well as OPFRs, could flow into the water from the WWTP and affect the aquatic ecosystem.

New Cardenolides from Biotransformation of Gitoxigenin by the Endophytic Fungus Alternaria eureka 1E1BL1: Characterization and Cytotoxic Activities

Microbial biotransformation is an important tool in drug discovery and for metabolism studies. To expand our bioactive natural product library via modification and to identify possible mammalian metabolites, a cytotoxic cardenolide (gitoxigenin) was biotransformed using the endophytic fungus Alternaria eureka 1E1BL1. Initially, oleandrin was isolated from the dried leaves of Nerium oleander L. and subjected to an acid-catalysed hydrolysis to obtain the substrate gitoxigenin (yield; ~25%). After 21 days of incubation, five new cardenolides 1, 3, 4, 6, and 8 and three previously- identified compounds 2, 5 and 7 were isolated using chromatographic methods. Structural elucidations were accomplished through 1D/2D NMR, HR-ESI-MS and FT-IR analysis. A. eureka catalyzed oxygenation, oxidation, epimerization and dimethyl acetal formation reactions on the substrate. Cytotoxicity of the metabolites were evaluated using MTT cell viability method, whereas doxorubicin and oleandrin were used as positive controls. Biotransformation products displayed less cytotoxicity than the substrate. The new metabolite 8 exhibited the highest activity with IC50 values of 8.25, 1.95 and 3.4 µM against A549, PANC-1 and MIA PaCa-2 cells, respectively, without causing toxicity on healthy cell lines (MRC-5 and HEK-293) up to concentration of 10 µM. Our results suggest that A. eureka is an effective biocatalyst for modifying cardenolide-type secondary metabolites.

Bioreduction of the Chalcones by Fungus Scedosporium apiospermum EJCP13

Biotransformations are chemical reactions carried out by microorganisms on organic substrates. Biotransformations can be regio-, chemo-, stereo- and enantio-selective. Bioreductions are of great interest to the food and pharmaceutical industries as they help to reduce costs and impacts on the environment. In this work, the following biotransformations of chalcones were performed: (2E)-1-(4-hydroxy-phenyl)-3-(2-methoxy-phenyl)-prop-2-en-1-one (1), (2E)-1-(4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-prop-2-en-1-one (2), and (2E)-1-(4-hydroxy-phenyl)-3-phenyl-prop-2-en-1-one (3) by the fungus Scedosporium aspiospermum, leading to formation through chemo-selective reduction of dihydrochalcones 1-(4-hydroxy-phenyl)-3-(2-methoxy-phenyl)-propan-1-one (4), 1-(4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propan-1-one (5), and 1-(4-hydroxy-phenyl)-3-phenyl-propan-1-one (6). Compounds 1-6 had their antimicrobial activities tested and were observed better activity to the biotransformation products compared with substrates. This is the first report of chemo-selective bioreduction by fungi of the genus Scedosporium in biotransformation reactions. Resumen. Las biotransformaciones son reacciones químicas llevadas a cabo por microorganismos sobre sustratos orgánicos. Las biotransformaciones pueden ser regio-, quimio-, estereo- y enantio-selectivas. Las biorreducciones son de gran interés para la industria alimentaria y farmacéutica, ya que ayudan a reducir costes e impactos sobre el medio ambiente. En este trabajo se realizaron las siguientes biotransformaciones de las chalconas: (2E)-1-(4-hidroxi-fenil)-3-(2-metoxi-fenil)-prop-2-en-1-ona (1), ( 2E)-1-(4-hidroxi-fenil)-3-(4-metoxi-fenil)-prop-2-en-1-ona (2) y (2E)-1-(4-hidroxi-fenil)-3-fenil-prop-2-en-1-ona (3) por el hongo Scedosporium aspiospermum, que conduce a la formación mediante reducción quimio-selectiva de dihidrocalconas 1-(4-hidroxi-fenil)-3-(2-metoxi-fenil)-propan-1-ona (4), 1-(4-hidroxi-fenil)-3-(4-metoxi-fenil)-propan-1-ona (5) y 1-(4-hidroxi-fenil)-3-fenil-propan-1-ona (6). Se ensayaron las actividades antimicrobianas de los compuestos 1-6 y se observó una mejor actividad para los productos de biotransformación en comparación con los sustratos. Este es el primer informe de biorreducción quimio-selectiva por hongos del género Scedosporium en reacciones de biotransformación.