No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Tiliae flos metabolites and their beneficial influence on human gut microbiota biodiversity ex vivo
Abstract
Ethnopharmacological relevance
The linden flower (Tiliae flos) has been used for centuries to treat and relieve symptoms of the common cold, throat irritation, and upper respiratory tract disturbances. Traditionally, this herb is administered orally, and thus it undergoes intestinal metabolism. Although it is pharmacopeial plant material, there are no reports about its interaction with human gut microbiota.
Aim of the study
The study aimed to determine the interaction between human gut microbiota and the linden flower extracts, resulting in the biotransformation of the extract's constituents and changes in the microbiota composition.
Material and methods
The linden flower metabolites were obtained by incubation of extract with human faecal slurries from 5 healthy donors. The UHPLC-DAD-MSⁿ analysis determined the composition of raw extract and analysis of microbial metabolites. The intestinal microbiota isolation and sequencing were used to determine changes in microbiota composition. The anti-inflammatory activity was tested using the LPS-stimulated human neutrophils model and ELISA test.
Results
After incubation of linden flower extract with human gut microbiota, twenty metabolites were detected and characterized, and three among them were identified. The extract changed human gut microbiota composition but did not cause dysbiosis (change in the abundance of forty-three genera). Raw extract and their metabolites exhibit different levels of inhibition of cytokines production by LPS-stimulated neutrophils, but the reduction of TNF-α production was observed.
Conclusions
The linden flower extract has a beneficial influence on human gut microbiota because it promotes increasing the abundance of bacteria responsible for SCFAs production. The anti-inflammatory effect might be linked to both microbiota composition changes and direct activity of bioavailable metabolites. Increased abundance of SCFAs producers may inhibit the production of pro-inflammatory cytokines. A low concentration of phenolic compounds in metabolized linden flower extract and responsible for anti-inflammatory properties, and the multitude of biological and chemical particles and their interactions may weaken these properties.
... In recent years, numerous studies confirmed the anti-inflammatory [3], hepatoprotective [5], antinociceptive [6], anxiolytic [7], and antispasmodic properties of Tilia extracts [8]. These properties are frequently associated with the presence of specific flavonols, i.e., phenolic compounds belonging to the broader group of flavonoids acknowledged for their numerous biological properties [9]. In particular, the most active flavonols recognized in TtM flowers are glycosides of quercetin and kaempferol, like tiliroside, isoquercitrin, rutin, and astragalin [4]. ...
... The composition of extracts and their biological activity may depend on the extraction technique and the solvent used [3]. Recent finding also suggest that Tilia flower extracts can positively modulate human gut microbiota and this could contribute to the mentioned anti-inflammatory properties [9]. ...
... These problems could be overcome by using microencapsulation, i.e., the process of entrapping target molecules with one or more wall (or coating) materials to protect them and improve their functionalities. Spray-drying is a largely employed microencapsulation technology by which it is possible to convert liquid extracts into powders with enhanced stability, ease of manipulation and integration into different types of functional foods and supplements [9]. Existing literature on the spray-drying of TtM flower extracts is limited to one study [11] based on maltodextrin 13-17 DE (dextrose equivalents) as the wall material, and no data about the stability over time and the efficacy of the encapsulated bioactive molecules are available. ...
Silver linden ( Tilia tomentosa Moench, TtM ) flowers possess several health-promoting properties, especially at the neurological level, such as intestinal relaxation activity associated with specific flavonols, particularly quercetin and kaempferol derivatives. However, such molecules are susceptible to degradation upon different triggers like heat, light and extreme pH values. To overcome the scarce stability of TtM flowers bioactive molecules and make them suitable for developing functional food and supplements, we applied microencapsulation. Spray-drying microencapsulation of TtM flowers extract was performed using three starch-derived wall materials: maltodextrin 12 DE (MD12) and 19 DE (MD19), and OSA-modified starch (OSA-S). The stability of total phenols, flavanols, and antioxidant capacity was monitored for 70 days under accelerated stress conditions (40 °C/70% RH) by HPLC and spectrophotometric methods, and the intestinal contractile activity was tested in a murine model. In comparison to MD12 and MD19, OSA-S stood out for the higher encapsulation efficiency of quercetin and kaempferol glycosides (+ 36–47% compared to MD12 and + 18–24% compared to MD19) and stability thereof (half-life on average + 30% compared to MD12 and + 51% compared to MD19). The intestinal contractile activity of OAS-S powders resulted comparable to the original extract, indicating that flavonols were biologically active and accessible. Our results underly the potential advantages of OSA-S encapsulated formulation as a functional ingredient for the development of nutraceutical products.
... Flavonoids, phenolic acids, and tannins are abundant in Tilia flowers, while flavonoids have been illustrated as the most important specialized metabolites [3,4]. They have been used in traditional medicine because of their medicinal properties against migraines, feverish colds, and throat irritation [5,6]. ...
Tilia miqueliana is an endemic species belonging to the genus Tilia L. (Tiliaceae) in China, which is known for its fragrant flowers and nectar, but the dynamic changes in metabolites during its growth and development are still unclear. In this study, the metabolic profiles from T. miqueliana flowers at three developmental stages were detected by performing an ultra-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC-ESI-MS/MS)-based widely targeted metabolomic analysis. A total of 1138 metabolites were detected, with 288 Differentially Accumulated Metabolites (DAMs) determined, flavonoids accounting for the largest proportion. The trend analysis showed that DAMs present seven distinctive patterns, and subclass 5 obtained the largest amount with continuously increased relative content during flower development. The Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation and enrichment analysis of DAMs showed different overlap and variability in metabolic pathways, indicating different directions of flavonoids’ metabolic flux in the three developmental stages. A correlation network analysis further revealed five core metabolites that played essential roles in flavonoid biosynthesis. This research provides comprehensive insights into the exploitation and utilization of T. miqueliana as well as a scientific basis for phylogenetic studies of the genus Tilia.
... The utilization of herbal interventions in addressing mood disorders encompasses a multifaceted array of mechanisms [40]. Because of the rich chemical composition of herbs, they can engage with different pathways, offering a wide spectrum of potential effects, with their interplay with the GM community standing out as a noteworthy aspect [41]. ...
Lavender is one of the most popular herbal medicines used to treat mild mood disorders like anxiety and depression. The most cultivated species is Lavandula officinalis, which has a diverse traditional use. This plant is valued for antibacterial, antifungal, hypolipidemic, antioxidant, neuroprotective, anti-aging, diuretic, sedative, hypnotic, anxiolytic and antidepressant properties. However, most often it is used as a water extract for treatment of mild mood disorders (restlessness, insomnia) as additional therapy. Most of the studies were dedicated to the volatile compounds contained in lavender flowers, but few of them were focused on water extract, which contains fewer essential oils, but more polar natural products (polyphenols and other non-volatile compounds). This medicinal plant species is rich in phytochemicals belonging to different chemical groups, including phenolic acids, phenolic aldehydes and flavonoids. Pharmacotherapy of mild mood disorders with infusion of lavender can improve quality of life, so that’s why it needs to be investigated more.
... was confirmed that substances included in the linden extract lead to increased production of SCFA (short-chain fatty acids) and thus inhibit the production of pro-inflammatory cytokines [29]. Special attention is paid to the study of the antioxidant properties of this plant. ...
The use of natural ingredients in recent years has been of great importance in many industries and medicine. In biomedical applications, hydrogel materials also play a significant role. In view of this, the aim of this study was to synthesize and characterize hydrogel materials enriched with broadleaf linden hydrolate. An important aspect was to carry out a series of syntheses with varying types and amounts of crosslinking agents so as to test the possibility of synthesizing materials with controlled properties. The obtained hydrogels were subjected to detailed physicochemical analysis. The results of the tests confirmed the relationship between the selected properties and the type of crosslinking agent used. A crosslinking agent with a lower molar mass (575 g/mol) results in a material with a compact and strongly crosslinked structure, which is characterized by high surface roughness. The use of a crosslinking agent with a molecular weight of 700 g/mol resulted in a material with a looser-packed polymer network capable of absorbing larger amounts of liquids. The work also proved that regardless of the type of crosslinking agent used, the addition of linden hydrolate provides antioxidant properties, which is particularly important in view of the target biomedical application of such materials.
... In recent years, considerable attention has been paid to the role of microbiota, mainly from the gut, in the biotransformation of ingested substances (Dadi et al., 2020). Nowadays, scientific databases are rich in research on the biotransformation by gut microbiota (Kruk et al., 2022;Popowski et al., 2021), but little is known about the influence of the skin microbiome on the chemical composition of externally applied preparations. As the mechanisms behind the pharmacological effects of extracts are not well understood, there is an expectation that the interaction between the extract's chemical composition and the human microbiota may play a role in their therapeutic effects towards dermatologic conditions. ...
Ethnopharmacological relevance:
Comfrey root (Symphytum officinale L., Boraginaceae) has been used in folk medicine for a long time to treat different diseases. It is recommended for swellings, phlebitis, contusions, gastro-duodenal ulcers, respiratory diseases, and metrorrhagia. Currently, preparations from S. officinale are only topically used due to its wound-healing effects, and for reducing inflammation and the treatment of broken bones, tendon damage, painful joints and muscles. Although it is a widespread plant material, little is known about the interaction of externally applied preparations of comfrey with the human skin microbiome.
Aim of the study:
The study aims to determine the interaction between human skin microbiota and the comfrey root extracts, by monitoring the biotransformation of the constituents present in the extract and evaluating changes in the population of the skin microbiota in an ex vivo setting.
Material and methods:
The comfrey root extract was incubated with the human skin microbiota from ten healthy donors. The UHPLC-DAD-MSn analysis determined the composition of the raw extract and the microbial metabolites. Bacterial genomic DNA was extracted and examined by amplification sequencing of the 16S rDNA to determine changes in the bacterial composition.
Results:
The hydroethanolic extract of comfrey root primarily consists of phenolic acids, pyrrolizidine alkaloids, and their derivatives, and lignans. The natural products present in the extract underwent biodegradation by the skin microbiota, leading to the formation of smaller molecules. It was observed that the skin microbial metabolism primarily focused on modifying the derivatives of pyrrolizidine alkaloids. It resulted in the production of deacetylated and deesterificated compounds. However, it did not lead to the conversion of these compounds into free alkaloids.
Conclusions:
The microbiota-triggered biotransformation of the comfrey root extract was observed. A few N-oxides were metabolized to deacetylated and deesterificated forms in ex vivo conditions. It suggests that the intermittent external applications of comfrey preparations perchance are unlikely to pose a substantial risk. While it even may serve as a potential factor influencing the extract activity in treating skin diseases.
... However, nowadays, many investigations on microbiota residing in the gut have been described. For instance, human and swine microbiota transformed natural products in the goldenrod infusion into smaller molecules, mainly phenylpropanoid acid derivatives [20].Twenty metabolites were detected and characterized after incubating the linden flower extract with human gut microbiota [21]. All changes in the chemical composition of the raw plant material caused by the interaction with microbiota can lead to potentially active compounds responsible for their bioactivity in vivo. ...
Skin disorders of different etiology, such as dermatitis, atopic dermatitis, eczema, psoriasis, wounds, burns, and others, are widely spread in the population. In severe cases, they require the topical application of drugs, such as antibiotics, steroids, and calcineurin inhibitors. With milder symptoms, which do not require acute pharmacological interventions, medications, dietary supplements, and cosmetic products of plant material origin are gaining greater popularity among professionals and patients. They are applied in various pharmaceutical forms, such as raw infusions, tinctures, creams, and ointments. Although plant-based formulations have been used by humankind since ancient times, it is often unclear what the mechanisms of the observed beneficial effects are. Recent advances in the contribution of the skin microbiota in maintaining skin homeostasis can shed new light on understanding the activity of topically applied plant-based products. Although the influence of various plants on skin-related ailments are well documented in vivo and in vitro, little is known about the interaction with the network of the skin microbial ecosystem. The review aims to summarize the hitherto scientific data on plant-based topical preparations used in Poland and Ukraine and indicate future directions of the studies respecting recent developments in understanding the etiology of skin diseases. The current knowledge on investigations of interactions of plant materials/extracts with skin microbiome was reviewed for the first time.
The study addresses the utilization of food waste by-products from faba bean (Vicia faba L.) pods (FBP) as an alternative feed supplement to promote sustainable piglet growth by reducing antimicrobial use. Objectives include evaluation of FBP in terms of nutritional components (proximate composition, fibres, minerals), phytochemical composition (total phenols, HPLC-MS profiling), and in vitro biological activities. Air-dried FBP from the cultivar ‘Bizon’ contained high levels of crude protein (144 g/kg), dietary fibre (413 g/kg), potassium (27.8 g/kg), and iron (126 mg/kg). Phytochemical analysis of methanolic extract from FBP revealed significant levels of polyphenols, including vestitol, piscidic acid, hydroxyeucomic acid, quercetin, and kaempferol glycosides with no detectable tannins. The extract showed negligible activity against porcine digestive enzymes (α-amylase, lipase, and trypsin) (IC50 > 4 mg/mL) and demonstrated a dose-dependent antibacterial activity against Escherichia coli and Salmonella enterica in concentrations of 1–8 mg/mL. The extract had low cytotoxicity (IC50 = 432.6 µg/mL) against IPEC-J2 – cells derived from porcine jejunal epithelium. The results indicate that FBP ‘Bizon’ is a valuable source of bioactive compounds with antibacterial properties, without adverse effects on porcine enzymes or IPEC-J2 cells, supporting its potential as a sustainable feed in piglet nutrition, in line with circular economy concepts.
Introduction
For centuries, various species from the genus Alchemilla have been utilized in traditional medicine worldwide. Among them, Alchemilla vulgaris L. (Rosaceae) stands out as a promising herbal drug candidate due to its phytochemicals displaying anti-inflammatory and antioxidant properties.
Methods
In our study, we investigated the interaction between the human gut microbiota and lady’s mantle herb extract (AV) following the biotransformation of the extract’s constituents and their impact on colorectal cancer cells (HT-29) and normal CCD 841 CoN epithelial cells. The A. vulgaris herb metabolites were obtained by incubating the extract (AV) with human fecal slurries from three healthy donors (D1, D2, and D3).
Results
After incubating the AV extract with the human gut microbiota (AVD1-AVD3 samples), thirty-three metabolites were detected and characterized by LC-MS. Among them, one was identified as urolithin C. The AV and AVD1-AVD3 extracts and their metabolites exhibit various levels of antiproliferative and cytotoxic activities against cancer cells. Their biological effect might be linked to the changes and direct activity of bioavailable metabolites. Samples from AVD1, AVD2, and AVD3 increase the lactate dehydrogenase (LDH) released from damaged colon cancer cells in a dose-dependent manner. At 250 μg/mL, AVD1, AVD2, and AVD3 elevated the LDH level by 12.6%, 25.3%, and 30.0%, respectively. The biotransformed samples also showed significantly higher antiproliferative activity than the AV extract. The most active sample from donor 3 (AVD3) reached IC50 = 471 μg/mL.
Discussion
The differences in anticancer effect might be linked to the changes and direct activity of bioavailable metabolites. The non-transformed AV extract affected neither normal nor cancer colon cells, indicating the beneficial effect of the biotransformation procedure on the anticancer properties of the evaluated extracts. The above results clearly indicate that microbial metabolism is a crucial factor that is potent in altering the biological activity of lady’s mantle extract.
Background. The article reviews literature data on the peculiarities of changes in the health status of children after acute respiratory viral infections (ARVI) of various etiologies and the development of post-viral asthenic syndrome accompanied by physical, cognitive, emotional, and psychological symptoms that significantly impair the quality of life. The purpose of the study is to summarize the literature data on the features, mechanisms of development of changes in the health status of children after ARVI, and methods to correct these disorders, in particular by prescribing herbal remedies. Materials and methods. Bibliographic and information-analytical research methods were used. A theoretical analysis of scientific data from the search databases PubMed, Web of Science, Scopus, Google Scholar, and British Medical Journal for the last 10 years was carried out on the possibility of using, efficacy, safety, and properties of oregano, thyme, rose, small-leaved linden, hibiscus sabdariffa, calendula officinalis, black currant. Results. According to the literature review, the incidence of post-viral asthenic syndrome in children is 36.8 %, with cognitive-emotional changes (84 %), sleep disturbances (74 %), decreased appetite (64 %), and headaches (52 %) dominating in the clinical picture. The persistence of these manifestations hinders the adequate restoration of the child’s adaptive capacity and the fight against hypoxia, acidosis, metabolic disorders due to ARVI, and post-viral asthenic syndrome. This determines the urgency of finding appropriate methods of correction with etiopathogenetic (inhibition of oxidative stress, reduction of acidosis and hypoxia, restoration of liver function), immunoregulatory (improvement of the immune system), and symptomatic (improvement of appetite) effects. The analysis of scientific data on the properties of oregano, thyme, rose, small-leaved linden, hibiscus sabdariffa, calendula officinalis, black currant made it possible to verify the possibility of using this combination to correct the clinical manifestations of post-viral asthenic syndrome in children and restore their health after ARVI. Conclusions. Phytocombination of oregano, thyme, rose, small-leaved linden, hibiscus sabdariffa, calendula officinalis, black currant can be recommended for the restoration of children’s health after ARVI, influenza, COVID-19, adenovirus infection, and children with clinical manifestations of post-viral asthenic syndrome due to the properties that provide antioxidant, anti-inflammatory, antiviral effects, a positive impact on the gastrointestinal tract, nervous and immune systems.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. It severely affects the quality of life of victims. The prevalence of AD has been increasing in recent years. Therefore, it is of great importance to elucidate the pathogenic mechanism of AD and search for effective therapeutic approaches. Gut microbiota dysbiosis, an altered state of gut microbiota, has been well known for its involvement in the pathogenesis of AD. Much effort has been made in searching for approaches capable of modulating the composition of gut microbiota in recent years. Herbal medicines have attracted extensive attention in recent decades for the prevention and treatment of AD. Here, we gave an overview of the recent research progress on the modulatory effects of herbal medicines and herbal formulae on gut microbiota as well as the possible beneficial effects on AD, which may provide new insights into the discovery of anti-AD agents and their therapeutic potential for AD through modulating the composition of gut microbiota.
Respiratory syncytial virus (RSV) infection is a constant threat to the health of young children, and this is mainly attributed to the lack of effective prevention strategies. This study aimed to determine whether Lactobacillus ( L. ) mucosae , a potential probiotic, could protect against respiratory viral infection in a mouse model. Naive 3–4-week-old BALB/c mice were orally administered with three L. mucosae strains (2.5 × 10 ⁸ CFU/mouse) 7 days before RSV infection (10 ⁵ TCID 50 /mouse). Results showed that all three strains inhibited RSV replication and reduced the proportions of inflammatory cells, including granulocytes and monocytes in the blood. The L. mucosae M104R01L3 treatment maintained stable weight in mice and increased interferon (IFN)-β and tumor necrosis factor (TNF)-α levels. The L. mucosae DCC1HL5 treatment increased interleukin (IL)-1β and IL-10 levels. Moreover, the M104R01L3 and DCC1HL5 strains increased the proportions of Akkermansia , Alistipes , and Anaeroplasma which contributed to the advantageous modulation of the gut microbiota. Besides, L. mucosae affected the gut levels of short-chain fatty acids (SCFAs) that are important for the antiviral response. L. mucosae 1,025 increased acetate, propionate, and butyrate levels, whereas L. mucosae M104R01L3 increased the level of acetate in the gut. L. mucosae M104R01L3 may protect against viral infection by upregulating the IFN-β levels in the lungs and its antiviral effect may be related to the increase of acetate levels in the gut. In conclusion, the three L. mucosae strains exerted antiviral effects against RSV infection by differentially regulating immune responses and intestinal micro-ecological balance. This study can provide a reference for studying the mechanisms underlying the antiviral effects of L. mucosae .
Simple Summary: Flavonoid's consumption is reported to impact GI cancer progression positively. As 90% of flavonoids consumed, undergo metabolism and conversion by the human gut microbi-ome, understanding their enzymatic bioconversion and metabolism could advance the current knowledge of their anticancer activities. While it is reported that specific flavonoids target cancer-related pathways such as apoptosis, inflammation and cellular proliferation, efforts are required to assess the possibility of combining those specific flavonoids together or with current treatment such as chemotherapy and evaluate their effect on the pathogenesis of GI cancer. Additionally, Studies aimed to standardize flavonoids administered concentration, purification and isolation methods are required. Abstract: Gastrointestinal (GI) cancer is a prevalent global health disease with a massive burden on health care providers. Internal and external factors such as obesity, smoking, diet (red meat), low socioeconomic status and infection with Helicobacter pylori are the critical risk factors of GI cancers. Flavonoids are natural phenolic compounds found abundantly in fruits and vegetables. Upon in-gestion, 90% of flavonoids consumed require further enzymatic metabolism by the gut microbiome to enhance their bioavailability and absorption. Several epidemiological studies reported that consumption of flavonoids and their enzymatic conversion by gut microbes is strongly associated with the reduced risk of GI cancer development. This review summarizes the current knowledge on the enzymatic conversion of flavonoids by the human gut microbiome. It also addresses the underlying anti-GI cancer effects on metabolic pathways such as apoptosis and cellular proliferation. Overall, metabolites produced from flavonoid's enzymatic conversion illustrate anti-GI cancer effects, but the mechanisms of action need further clarification.
The human intestine contains an intricate community of microorganisms, referred to as the gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, medicines and environmental factors, particularly diet. Growing evidence supports the involvement of GM dysbiosis in gastrointestinal (GI) and extraintestinal metabolic diseases. The beneficial effects of dietary polyphenols in preventing metabolic diseases have been subjected to intense investigation over the last twenty years. As our understanding of the role of the gut microbiota advances and our knowledge of the antioxidant and anti-inflammatory functions of polyphenols accumulates, there emerges a need to examine the prebiotic role of dietary polyphenols. This review firstly overviews the importance of the GM in health and disease and then reviews the role of dietary polyphenols on the modulation of the gut microbiota, their metabolites and how they impact on host health benefits. Inter-dependence between the gut microbiota and polyphenol metabolites and the vital balance between the two in maintaining the host gut homeostasis are also discussed.
The widely accepted strategy to justify the use of medicinal plant extracts in diseases with inflammatory background is their examination on in vitro models using immune cells. It is also a key initial step of research for active principles, which could be then isolated and tested on more advanced models, becoming new pharmacologically active lead molecules. The crucial aspect which has not been so far addressed in this context, is the presence of pyrogens in plant preparations. The aim of this study was the examination of pyrogens interference with in vitro evaluation of anti-inflammatory activity of plant extracts using human primary neutrophils model together with introduction of effective method of interfering factors elimination. The obtained results showed that chosen plant extracts contained pyrogens, which were responsible for concentration-dependent stimulation of pro-inflammatory cytokines production by human neutrophils in vitro in the same extent as LPS did. The ultrafiltration method was successfully applied for pyrogens elimination, which effectiveness was confirmed using LAL test. The determined interference of pyrogens implies the necessity of their consideration and removal when in vitro studies include direct addition of plant extracts to the cell culture, what can be obtained by ultrafiltration, which does not affect extract composition.
The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays.
In recent years, many xenobiotics derived from natural products have been shown to undergo extensive metabolism by gut microbiota. Ellagitannins, which are high molecular polyphenols, are metabolized to dibenzo[b,d]pyran-6-one derivatives- urolithins. These compounds, in contrast with their parental compounds, have good bioavailability and are found in plasma and urine at micromolar concentrations. In vivo studies conducted for ellagitannin-containing natural products indicate their beneficial health effects towards inflammation and cancer, which are associated with the formation of urolithins. However, the great majority of in vitro experiments that have revealed the molecular mechanisms responsible for the observed effects were conducted for urolithin aglycones. These studies are thus incongruent with the results of pharmacokinetic studies that clearly indicate that glucuronide conjugates are the dominant metabolites present in plasma, tissue and urine. The aim of this study was to isolate and structurally characterize urolithin conjugates from the urine of a volunteer who ingested ellagitannin-rich natural products and to evaluate the potential role of β-glucuronidases-triggered cleavage in urolithin disposition. Glucuronides of urolithin A, iso-urolithin A and urolithin B were isolated and shown to be cleaved by the β-glucuronidases released by neutrophils from azurophilic granules upon f-MLP stimulation as well as by E. coli standard strains and clinical isolates from patients with urinary tract infections. These results justify the hypothesis that the selective activation of urolithin glucuronides by β-glucuronidase, which are present at high concentrations at inflammation and infection sites and in the microenvironments of solid tumors, could locally increase the concentration of bioactive urolithin aglycones.
Background
VSEARCH is an open source and free of charge multithreaded 64-bit tool for processing and preparing metagenomics, genomics and population genomics nucleotide sequence data. It is designed as an alternative to the widely used USEARCH tool (Edgar, 2010) for which the source code is not publicly available, algorithm details are only rudimentarily described, and only a memory-confined 32-bit version is freely available for academic use.
Methods
When searching nucleotide sequences, VSEARCH uses a fast heuristic based on words shared by the query and target sequences in order to quickly identify similar sequences, a similar strategy is probably used in USEARCH. VSEARCH then performs optimal global sequence alignment of the query against potential target sequences, using full dynamic programming instead of the seed-and-extend heuristic used by USEARCH. Pairwise alignments are computed in parallel using vectorisation and multiple threads.
Results
VSEARCH includes most commands for analysing nucleotide sequences available in USEARCH version 7 and several of those available in USEARCH version 8, including searching (exact or based on global alignment), clustering by similarity (using length pre-sorting, abundance pre-sorting or a user-defined order), chimera detection (reference-based or de novo), dereplication (full length or prefix), pairwise alignment, reverse complementation, sorting, and subsampling. VSEARCH also includes commands for FASTQ file processing, i.e., format detection, filtering, read quality statistics, and merging of paired reads. Furthermore, VSEARCH extends functionality with several new commands and improvements, including shuffling, rereplication, masking of low-complexity sequences with the well-known DUST algorithm, a choice among different similarity definitions, and FASTQ file format conversion. VSEARCH is here shown to be more accurate than USEARCH when performing searching, clustering, chimera detection and subsampling, while on a par with USEARCH for paired-ends read merging. VSEARCH is slower than USEARCH when performing clustering and chimera detection, but significantly faster when performing paired-end reads merging and dereplication. VSEARCH is available at https://github.com/torognes/vsearch under either the BSD 2-clause license or the GNU General Public License version 3.0.
Discussion
VSEARCH has been shown to be a fast, accurate and full-fledged alternative to USEARCH. A free and open-source versatile tool for sequence analysis is now available to the metagenomics community.
Urolithins are dibenzo[b,d]pyran-6-one derivatives that are produced by the human gut microbiota from ellagitannins and ellagic acid. These metabolites are much better absorbed than their precursors and have been suggested to be responsible for the health effects attributed to ellagitannins and ellagic acid that occur in food products as berries and nuts. In the present review, the role and potential of urolithins in human health are critically reviewed, and a perspective of the research approach needed to demonstrate these health effects is presented, based on the existing knowledge. The analytical methods available for urolithin analysis, their occurrence in different tissues and biological fluids and their metabolism by human gut microbiota are considered. In addition, the inter-individual variability observed for the production of urolithins (metabotypes), and its relationship with health status and dysbiosis are also reviewed. The potential mechanisms of action of urolithins are also critically discussed paying attention to the concentration and the type of metabolites used in the in vitro and in vivo assays and the physiological significance of the results obtained. The gut microbiota metabolism of ellagic acid to urolithins and that of daidzein to equol, their individual variations and the effects on health are also compared. This article is protected by copyright. All rights reserved.
Molecular microbial ecology investigations often employ large marker gene datasets, for example, ribosomal RNAs, to represent the occurrence of single-cell genomes in microbial communities. Massively parallel DNA sequencing technologies enable extensive surveys of marker gene libraries that sometimes include nearly identical sequences. Computational approaches that rely on pairwise sequence alignments for similarity assessment and de novo clustering with de facto similarity thresholds to partition high-throughput sequencing datasets constrain fine-scale resolution descriptions of microbial communities. Minimum Entropy Decomposition (MED) provides a computationally efficient means to partition marker gene datasets into 'MED nodes', which represent homogeneous operational taxonomic units. By employing Shannon entropy, MED uses only the information-rich nucleotide positions across reads and iteratively partitions large datasets while omitting stochastic variation. When applied to analyses of microbiomes from two deep-sea cryptic sponges Hexadella dedritifera and Hexadella cf. dedritifera, MED resolved a key Gammaproteobacteria cluster into multiple MED nodes that are specific to different sponges, and revealed that these closely related sympatric sponge species maintain distinct microbial communities. MED analysis of a previously published human oral microbiome dataset also revealed that taxa separated by less than 1% sequence variation distributed to distinct niches in the oral cavity. The information theory-guided decomposition process behind the MED algorithm enables sensitive discrimination of closely related organisms in marker gene amplicon datasets without relying on extensive computational heuristics and user supervision.The ISME Journal advance online publication, 17 October 2014; doi:10.1038/ismej.2014.195.
There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.
Bacteria comprise the most diverse domain of life on Earth, where they occupy nearly every possible ecological niche and play key roles in biological and chemical processes. Studying the composition and ecology of bacterial ecosystems and understanding their function are of prime importance. High-throughput sequencing technologies enable nearly comprehensive descriptions of bacterial diversity through 16S ribosomal RNA gene amplicons. Analyses of these communities generally rely upon taxonomic assignments through reference data bases or clustering approaches using de facto sequence similarity thresholds to identify operational taxonomic units. However, these methods often fail to resolve ecologically meaningful differences between closely related organisms in complex microbial data sets.
In this paper, we describe oligotyping, a novel supervised computational method that allows researchers to investigate the diversity of closely related but distinct bacterial organisms in final operational taxonomic units identified in environmental data sets through 16S ribosomal RNA gene data by the canonical approaches.
Our analysis of two data sets from two different environments demonstrates the capacity of oligotyping at discriminating distinct microbial populations of ecological importance.
Oligotyping can resolve the distribution of closely related organisms across environments and unveil previously overlooked ecological patterns for microbial communities. The URL http://oligotyping.org offers an open-source software pipeline for oligotyping.
Short-chain fatty acids (SCFAs), produced at relatively high levels by anaerobic bacteria in bacterial vaginosis (BV), are believed to be anti-inflammatory. BV, a common alteration in the genital microbiota associated with increased susceptibility to HIV infection, is characterized by increased levels of both pro-inflammatory cytokines and SCFAs. We investigated how SCFAs alone or together with Toll-like receptor (TLR) ligands affected pro-inflammatory cytokine secretion.
Cytokines were measured by ELISA. Flow was used for phenotyping and reactive oxygen species (ROS) measurement.
Short-chain fatty acids, at 20 mM, induced interleukin (IL)-8, IL-6, and IL-1β release, while lower levels (0.02-2 mM) did not induce cytokine secretion. Levels >20 mM were toxic to cells. Interestingly, lower levels of SCFAs significantly enhanced TLR2 ligand- and TLR7 ligand-induced production of IL-8 and TNFα in a time- and dose-dependent manner, but had little effect on lipopolysaccharide-induced cytokine release. SCFAs mediated their effects on pro-inflammatory cytokine production at least in part by inducing the generation of ROS.
Our data suggest that SCFAs, especially when combined with specific TLR ligands, contribute to a pro-inflammatory milieu in the lower genital tract and help further our understanding of how BV affects susceptibility to microbial infections.
Chimeric DNA sequences often form during polymerase chain reaction amplification, especially when sequencing single regions (e.g. 16S rRNA or fungal Internal Transcribed Spacer) to assess diversity or compare populations. Undetected chimeras may be misinterpreted as novel species, causing inflated estimates of diversity and spurious inferences of differences between populations. Detection and removal of chimeras is therefore of critical importance in such experiments.
We describe UCHIME, a new program that detects chimeric sequences with two or more segments. UCHIME either uses a database of chimera-free sequences or detects chimeras de novo by exploiting abundance data. UCHIME has better sensitivity than ChimeraSlayer (previously the most sensitive database method), especially with short, noisy sequences. In testing on artificial bacterial communities with known composition, UCHIME de novo sensitivity is shown to be comparable to Perseus. UCHIME is >100× faster than Perseus and >1000× faster than ChimeraSlayer.
robert@drive5.com
Source, binaries and data: http://drive5.com/uchime.
Supplementary data are available at Bioinformatics online.
Acetate is normally regarded as an endproduct of anaerobic fermentation, but butyrate-producing bacteria found in the human colon can be net utilisers of acetate. The butyrate formed provides a fuel for epithelial cells of the large intestine and influences colonic health. [1-(13)C]Acetate was used to investigate the contribution of exogenous acetate to butyrate formation. Faecalibacterium prausnitzii and Roseburia spp. grown in the presence of 60 mm-acetate and 10 mm-glucose derived 85-90 % butyrate-C from external acetate. This was due to rapid interchange between extracellular acetate and intracellular acetyl-CoA, plus net acetate uptake. In contrast, a Coprococcus-related strain that is a net acetate producer derived only 28 % butyrate-C from external acetate. Different carbohydrate-derived energy sources affected butyrate formation by mixed human faecal bacteria growing in continuous or batch cultures. The ranking order of butyrate production rates was amylopectin > oat xylan > shredded wheat > inulin > pectin (continuous cultures), and inulin > amylopectin > oat xylan > shredded wheat > pectin (batch cultures). The contribution of external acetate to butyrate formation in these experiments ranged from 56 (pectin) to 90 % (xylan) in continuous cultures, and from 72 to 91 % in the batch cultures. This is consistent with a major role for bacteria related to F. prausnitzii and Roseburia spp. in butyrate formation from a range of substrates that are fermented in the large intestine. Variations in the dominant metabolic type of butyrate producer between individuals or with variations in diet are not ruled out, however, and could influence butyrate supply in the large intestine.
Ethnopharmacological relevance
Solidago virgaurea L. (also known as European goldenrod) is a pharmacopoeial plant material popularly used by patients in the form of an infusion. It was traditionally used in Europe and North America for the treatment of urinary tract conditions. It is also reported as a topical agent for skin disorders.
Aim of the study
Gut microbiota metabolism plays a crucial role in the bioavailability of natural products contained in plant extracts taken orally. The aim of the current study was to establish the biotransformation of compounds contained in an infusion from goldenrod using human and piglet fecal microbiota in vitro. The permeability of unmetabolized natural products and gut microbiota metabolites was evaluated using a Caco-2 cell model. Preliminary anti-inflammatory assays of raw extract using human neutrophils were also established.
Material and methods
An infusion was prepared from Solidaginis virgaureae herba commercially available on the market. The characterization of the raw extract was performed by UHPLC-DAD-MS method. The infusion was incubated with human or swine fecal samples in anaerobic conditions. Metabolism products were analyzed and identified by UHPLC-DAD-MS technique. The permeability of the natural products contained in the raw infusion and after metabolism was checked by UHPLC method. The influence of raw extracts on proinflammatory functions of human neutrophils after LPS stimulation was established by flow cytometry and ELISA.
Results
The experiments showed that goldenrod infusion contains mainly caffeoylquinic acid derivatives, flavonoids, and some phenylpropanoids. Natural products present in the extract were transformed by human and swine microbiota to smaller molecules mainly phenylpropanoid acid derivatives. The permeability assays showed that most of the parental compound present in the infusion cannot cross the gut epithelial barrier. In contrast, metabolites were able to cross the Caco-2 monolayer. Depending on the structure, different possible mechanisms of transport were observed. The infusion did not significantly influence the proinflammatory functions of human neutrophils.
Conclusions
Following oral administration of goldenrod infusion, phytochemicals are prone to undergoing metabolism by gut microbiota to smaller phenylpropionic acid derivatives that can be bioavailable after crossing the gut epithelial barrier to be further metabolized and distributed. Detected metabolites should be considered as potentially active compounds responsible for the bioactivity of the raw plant material in vivo.
Linden trees are a source of food products called lime flowers (Tiliae flos), traditionally used in the form of infusion for the treatment of feverish colds and coughs. Lime flowers should include flowers of Tilia cordata Mill., T.x europaea L., and T.platyphyllos Scop. or a mixture of these. The aim of current research was to establish a fast, sensitive HPTLC (high-performance thin-layer chromatography) method that would allow the differentiation of material obtained from five species of lime occurring in Europe. The fingerprints for distinguishing these species were established, as well as a key for identification based on a visual evaluation of chromatograms. The results obtained were also subjected to chemometric analyses. It was shown that each species contains characteristic compounds i.e. linarin that can be used for their identification. The method developed can, in theory, be introduced for the quality control or authentication of linden flowers on the European market.
Ethnopharmacological relevance
Herbal medicine in Russia has a long history starting with handwritten herbalist manuscripts from the Middle Ages to the officinal Pharmacopoeia of the 21st century. The "herbophilious" Russian population has accumulated a lot of knowledge about the beneficial effects of local medicinal plants. Yet, for a long time, Russian traditional and officinal herbal medicine was not well known to the international audience. In our previous comprehensive review, we discussed the pharmacological effects of specific plants included in the 11th edition of the Pharmacopoeia of the USSR, which was also for a while used in Russia. The 14th edition of the Russian Federation’s State Pharmacopoeia was implemented in 2018.
Aim of the review
The aims of the present review are: (i) to trace the evolution of medicinal plant handling from handwritten herbalist manuscripts to Pharmacopoeias; (ii) to describe the modern situation with regulatory documents for herbal medicinal products and their updated classification; (iii) to summarize and discuss the pharmacology, safety, and clinical data for new plants, which are included in the new edition of the Pharmacopoeia.
Methods
New medicinal plants included in the 14th edition of the Russian Federation’s State Pharmacopoeia were selected. We carefully searched the scientific literature for data related to traditional use, pharmacological, clinical application, and safety. The information was collected from local libraries in Saint-Petersburg, the online databases E-library.ru, Scopus, Web of Science, and the search engine Google scholar.
Results
Investigating the evolution of all medicinal plants referred to in the Russian Pharmacopoeias led us to the identification of ten medicinal plants that were present in all editions of civilian Russian Pharmacopoeias starting from 1778. In the 14th edition of the modern Russian Pharmacopoeia, medicinal plants are described in 107 monographs. Altogether, 25 new monographs were included in the 14th edition, and one monograph was excluded in comparison to the 11th edition. Some of the included plants are not endemic to Russia and do not have a history of traditional use, or on the other hand, are widely used in Western medicine. For 15 plants, we described the specificity of their application in Russian traditional medicine along with the claimed dosages and indications in officinal medicine. The pharmacology, safety, and clinical data are summarized and assessed for nine plants, underlining their therapeutic potential and significance for global phytopharmacotherapy.
Conclusions
In this review, we highlight the therapeutical potential of new plants included in the modern edition of the Russian Pharmacopoeia. We hope that these plants will play an imperative role in drug development and will have a priority for future detailed research.
Excessive use of antibiotics has led to the emergence of multidrug-resistant bacteria that are a serious threat to human health. There is a need to develop efficient antibacterial agents to address this problem. Tannins are high molecular weight (MW) polyphenols (500−30,000 Da), distributed throughout the plant kingdom. Tannins are one of the major compounds in plants with potential health benefits. This review addresses the antibacterial and antivirulence effects of different types of tannins and highlights the underlying antibacterial mechanisms of action. Furthermore, an overview of the antibacterial effects of emerging tannin-loaded nanoparticles/hydrogels is presented. Tannins have been found to inhibit bacterial growth using different mechanisms of action including iron chelation, inhibition of cell wall synthesis, disruption of the cell membrane, and inhibition of fatty acid biosynthetic pathways. Tannins can act as quorum sensing inhibitors and attenuate the gene expression of several virulence factors such as biofilms, enzymes, adhesins, motility, and toxins. Also, tannin-loaded nanoparticles/hydrogels show good antibacterial effects. Overall, tannins may be promising antibacterial and antivirulence agents for preventing bacterial infections.
Lime flowers are traditionally used as medicinal plants. According to the Pharmacopeia Europaea, only three species of Tilia are admitted as source species. However, so far, no methods enabling the discrimination between these three species and other species of Tilia occurring in Europe have been established. It is also not clear whether the chemical composition of extracts from lime flowers differs between source species. Here, we describe a comprehensive validated UHPLC-DAD-MS/MS method to distinguish the five most important Tilia species in Europe based on phytochemical analyses of extracts prepared from their flowers. Forty-two phenolics were detected in the analyzed extracts and twenty-one of them were quantified using a validated method. A chemometric analysis revealed significant differences between the investigated species. Based on the chemical profile of their extracts, we provide a dichotomous key for the identification of Tiliae flos source species.
Linden tea has been used in Serbian folk medicine for centuries to induce sweating for colds, relieve throat irritation and cough, reduce blood pressure, as well as a diuretic, spasmolytic, and as a sedative. The main aim of this study was to determine the comprehensive metabolite profile, free radical scavenging activity, and antimicrobial activities against 23 human and plant pathogens of both commercial and field-collected linden tea samples from Serbia. Developed high-performance thin-layer chromatography (HPTLC) method allowed identification of eight major metabolites in investigated samples, while forty-six metabolites were tentatively identified using high resolution mass spectrometry (HRMS): 14 phenolic acids and their derivatives, 15 glycosides, 9 flavonoids, and 8 procyanidins. Both commercial and field-collected linden tea samples showed similar total phenolic content and radical scavenging activity. Seven compounds such as p-hydroxybenzoic acid 4-Ohexoside, caffeic acid cinnamyl ester, pinocembrin, galangin, luteolin 7-O-glucuronide (and its isomer), isorhamnetin hexosyl hexoside were found in Tilia samples for the first time. Radical reagent 2,2-Diphenyl-1-picrylhydrazyl· (DPPH·) was used in DPPH-HPTLC assay which identified chlorogenic acid, caffeic acid, astragalin, quercitrin, tiliroside, and rutin as compounds that exhibit radical scavenging activity. Tilia samples showed inhibitory effect overwhelming only on Gram-positive bacteria, especially on Bacillus subtilis with the lowest MIC values observed, as well as towards Staphylococcus aureus and oral cavity isolates of Streptococcus pyogenes and Streptococcus mutans. Vaginal isolate of Candida glabrata showed more susceptibility than Candida albicans isolate. Generally, extract from Tilia cordata Miller (L4) showed the highest antimicrobial activity against the most of the tested pathogens, among all field-collected Tilia samples.
The substantial discrepancy between the strong effects of functional foods and various drugs, especially traditional Chinese medicines (TCMs), and the poor bioavailability of these substances remains a perplexing problem. Understanding the gut microbiota, which acts as an effective bioreactor in the human intestinal tract, provides an opportunity for the redefinition of bioavailability. Here, we discuss four different pathways associated with the role of the gut microbiota in the transformation of parent compounds to beneficial or detrimental small molecules, which can enter the body’s circulatory system and be available to target cells, tissues, and organs. We further describe and propose effective strategies for improving bioavailability and alleviating side effects with the help of the gut microbiota. This review also broadens our perspectives for the discovery of new medicinal components.
Covering: 1958 to June 2018 Phenyl-γ-valerolactones (PVLs) and their related phenylvaleric acids (PVAs) are the main metabolites of flavan-3-ols, the major class of flavonoids in the human diet. Despite their presumed importance, these gut microbiota-derived compounds have, to date, in terms of biological activity, been considered subordinate to their parent dietary compounds, the flavan-3-ol monomers and proanthocyanidins. In this review, the role and prospects of PVLs and PVAs as key metabolites in the understanding of the health features of flavan-3-ols have been critically assessed. Among the topics covered, are proposals for a standardised nomenclature for PVLs and PVAs. The formation, bioavailability and pharmacokinetics of PVLs and PVAs from different types of flavan-3-ols are discussed, taking into account in vitro and animal studies, as well as inter-individual differences and the existence of putative flavan-3-ol metabotypes. Synthetic strategies used for the preparation of PVLs are considered and the methodologies for their identification and quantification assessed. Metabolomic approaches unravelling the role of PVLs and PVAs as biomarkers of intake are also described. Finally, the biological activity of these microbial catabolites in different experimental models is summarised. Knowledge gaps and future research are considered in this key area of dietary (poly)phenol research.
The discourse about whether “insulin resistance leads to obesity” or “obesity leads to insulin resistance” has been a long- lasting debate. There is now convincing evidence that in most cases, obesity itself deteriorates insulin sensitivity in proportion to the degree and the duration of the obesity. The location of the excess fat in obese individuals is an important determinant of the magnitude of insulin resistance. In this chapter, we review (1) the evidence that lead researchers to conclude that obesity is a condition leading to insulin resistance and eventually to type 2 diabetes mellitus (T2DM); (2) the methods used to measure insulin sensitivity in the clinic; (3) the physiological mechanisms by which an expanded fat mass leads to insulin resistance; and (4) the molecular mechanisms underlying impaired insulin signaling.
Scope
Several studies have demonstrated that flavan‐3‐ol/procyanidins are associated with biological functions in the prevention of various chronic diseases including obesity and diabetes. Knowledge of their mechanisms including bioavailability has significantly progressed in the last decade. However, the differences of the metabolic signatures among flavan‐3‐ol/procyanidins remain ambiguous.
Methods and results
We analyzed the metabolites in urine over time after acute administration of three typical flavan‐3‐ol/procyanidins (epicatechin, epigallocatechin gallate, and procyanidin dimer) in view of the chemical structure by HPLC‐quadrupole TOF/MS. We observed several bile acid and amino acid derivatives including tryptophan and tyrosine as well as flavan‐3‐ol/procyanidin conjugates and phenolic acid degradation products generated by the gut microbiota in rat urine.
Conclusion
Multivariate statistical analyses suggest that the exogenous and endogenous metabolites of flavan‐3‐ol/procyanidins greatly differ, although the chemical structures of three typical flavan‐3‐ol/procyanidins, (epi)catechin (EPC), EGCG, and procyanidin dimer (PC) are similar. Thus, metabolomic differences likely affect their biological functions and health benefits.
This article is protected by copyright. All rights reserved
Gut bacterial consortium is essential for the homeostasis of the immune system in mammals. A significant role in maintaining this balance play short-chain fatty acids (SCFA), bacterial metabolites resulting from fermentation of dietary oligosaccharides. The most significant are butyric, propionic and acetic acids present in the microbiome in a specified mole ratio, but these proportions may change due to diet, age, diseases, and other factors.
SCFA are the type of messengers between microbiota and immune system. They are responsible for maintaining the balance in the pro- and anti-inflammatory reaction through the set of free fatty acid receptors (GPR). Short chain fatty acids may induce regulatory T-cells (Treg) by an bakteinhibition
of histone deacetylase enzyme; the biggest inhibitory potential has butyric acid,
causing proliferation and an increase of the functional capabilities of Treg cells.
Manipulation of the gut microbiome composition and SCFA level constitutes a promising tool
supporting treatment of chronic gastrointestinal diseases associated with an inflammation
or caused by dysbiosis due to intensive use of antibiotics.
Linden flower is a wildly used plant material among patients in the treatment of common cold symptoms and mucosa inflammations. However, the structure and bioactivity of flavan-3-ol derivatives present in infusions from flowers of Tilia cordata have not been studied so far. The aim of current study was to isolate and identify main procyanidins present in the flowers of small-leaved lime and to evaluate their influence on the inflammatory response of human neutrophils ex vivo. The chemical structure of isolated compounds was established by 1D and 2D NMR experiments. The bioactivity of obtained compounds was tested in human neutrophils model. Cytotoxicity and influence of compounds on apoptosis was established by flow cytometry. The levels of produced cytokines were established ELISA after stimulation with lipopolysaccharide (LPS). The inhibition of the production of reactive oxygen species was checked by luminol dependent chemiluminescence method after N-formylmethionyl-leucyl-phenylalanine (f-MLP) induction. The phytochemical work resulted in the isolation of 10 compounds. Compounds were identified as oligomeric procyanidins and their precursor epicatechin. The potential anti-inflammatory activity of compounds was evaluated in the concentration range 5-20 μM. All compounds were able to decrease the production of ROS from f-MLP-stimulated neutrophils. Most of compounds were able to inhibit the LPS-induced release of IL-8. Some trimeric and tetrameric derivatives were also able to decrease the production of MIP-1β. Obtained results partially support the traditional usage of infusion from lime flowers in the treatment of symptoms of inflammation and irritation of mucosa in common cold, pharyngitis and tonsillitis.
Silver linden flowers contain different pectins (PSI-PSIII) with immunomodulating properties. PSI is a low-esterified pectic polysaccharide with predominant homogalacturonan region, followed by rhamnogalacturonan I (RGI) with arabinogalactan II and RGII (traces) domains. PSII and PSIII are unusual glucuronidated RGI polymers. PSIII is a unique high molecular weight RGI, having almost completely O-3 glucuronidated GalA units with >30% O-3 acetylation at the Rha units. Linden pectins induced reactive oxygen species (ROS) and NO generation from non-stimulated whole blood phagocytes and macrophages, resp., but suppressed OZP-(opsonized zymosan particles)-activated ROS generation, LPS-induced iNOS expression and NO production. This dual mode of action suggests their anti-inflammatory activity, which is known for silver linden extracts. PSI expressed the highest complement fixation and macrophage-stimulating activities and was active on intestinal Peyer’s patch cells. PSIII was active on non-stimulated neutrophils, as it induced ß2-integrin expression, revealing that acetylated and highly glucuronidated RGI exhibits immunomodulating properties via phagocytes.
Ellagitannin-rich plant materials are used as popular remedies in the treatment of various inflammatory diseases. Urolithins are gut microbiota metabolites of ellagitannins and are considered responsible for in vivo health effects. Various natural products have been studied that are known sources of urolithins. However, few studies have focused on the metabolism of ellagitannin molecules. The aim of the study was to examine the metabolic fate of select ellagitannins using ex vivo cultures of human gut microbiota. Fifteen monomeric and dimeric ellagitannins, 1-O-galloyl-4,6-(S)-HHDP-β-d-glucose (2), pedunculagin (3), potentillin (4), casuarictin (5), coriariin B (6), vescalagin (7), castalagin (8), stachyurin (9), casuarinin (10), stenophyllinin A (11), stenophyllanin A (12), salicarinin A (13), gemin A (14), agrimoniin (15), and oenothein B (16), and ellagic acid (1) were studied. The formation of the metabolites in ex vivo human microbiota cultures was monitored using UHPLC-DAD-MS/MS. Ellagitannins possessing hexahydroxydiphenoyl moieties were metabolized to 6H-dibenzo[b,d]pyran-6-one derivatives, i.e., urolithins. The observed differences in amounts of produced urolithins indicated that the individual microbiota composition and type of ingested ellagitannins could determine the rate of urolithin production. When the oral ingestion of natural products containing ellagitannins with hexahydroxydiphenoyl groups is considered, the formation of urolithins and their bioactivity should be addressed.
Procyanidins (PAs) are polyphenols in plant food that have many health benefits, including cancer prevention, cardiovascular protection and diabetes prevention. PAs have been known to have low oral bioavilability. In this review, we summarize the published results on the ADME (absorption, distribution, metabolism and excretion) of PAs in vivo and in vitro. After oral administration, in the stomach the decomposition of PAs is highly dependent on the pH value of gastric juice, which is also affected by food intake. In the small intestine, PA polymers and oligomers with DP > 4 are not directly absorbed in vivo, but minor PA monomers and dimers could be detected in the plasma. Methylated and glucuronidated PA dimers and monomers are the main metabolites of PAs in plasma. In the colon, PAs are catabolized by colonic microflora into a series of low molecular weight phenolic acids, such as phenyl valerolactone, phenylacetic acids and phenylpropionic acids. We reviewed the degradation of PAs in gastric digestion, the absorption of PAs in the small intestine and the metabolic pathway of PAs by colonic microflora. To clearly explain the in vivo pharmacokinetics of PAs, a systematic comparative analysis on previously published data on PAs was conducted.
Ellagitannin-rich food products and medicinal plant materials were shown to have beneficial effects towards intestinal inflammation. Due to the questionable bioavailability of ellagitannins their gut microbiota metabolites-urolithins have come to be regarded as potential factors responsible for biological activities observed in vivo. The aim of the study was to determine the influence of the three most abundant bioavailable ellagitannin gut microbiota metabolites-urolithins A, B and C on inflammatory responses in RAW 264.7 murine macrophages, which are involved in the pathogenesis of intestine inflammation.
Urolithins A, B and C decreased NO production via inhibition of the iNOS protein and mRNA expression. They decreased the expression of IL-1β, TNF-α and IL-6 mRNA in LPS challenged RAW 264.7 murine macrophages. A clear inhibition of NF-κB p65 nuclear translocation and p50 DNA binding activity was associated with the observed anti-inflammatory activities of urolithins. Among the tested compounds urolithin A had the strongest anti-inflammatory activity.
The anti-inflammatory effects of urolithins at concentrations that are physiologically relevant for gut tissues (≥40 μM), as revealed in this study, support the data from in vivo studies showing the beneficial effects of ellagitannin-rich products towards intestinal inflammation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
The mammalian intestine is colonized by trillions of microorganisms, most of which are bacteria that have co-evolved with the host in a symbiotic relationship. The collection of microbial populations that reside on and in the host is commonly referred to as the microbiota. A principal function of the microbiota is to protect the intestine against colonization by exogenous pathogens and potentially harmful indigenous microorganisms via several mechanisms, which include direct competition for limited nutrients and the modulation of host immune responses. Conversely, pathogens have developed strategies to promote their replication in the presence of competing microbiota. Breakdown of the normal microbial community increases the risk of pathogen infection, the overgrowth of harmful pathobionts and inflammatory disease. Understanding the interaction of the microbiota with pathogens and the host might provide new insights into the pathogenesis of disease, as well as novel avenues for preventing and treating intestinal and systemic disorders.
The catabolism by human faecal microbiota of (-)-epicatechin (1) (2, 3-cis stereochemistry) and its dimer pure procyanidin B2 (2), has been compared using a static in vitro culture model. The catabolites were characterised by LC-MS(n), UV absorption and relative retention time, and quantified relative to standards. No more than approximately 10% of procyanidin B2 (2) was converted to epicatechin (1) by scission of the interflavan bond. Five phenolic acid catabolites (M(r)<290) were unique to 2, and ten phenolic acid catabolites (M(r)<290) were common to both substrates. The dominant catabolites (> or =24 h incubation) were 5-(3'-hydroxy phenyl) valeric acid (9), 3-(3'-hydroxyphenyl) propionic acid (10) and phenyl acetic acid (12) (maximum yields 27.4+/-4.2, 38.2+/-4.2, 22.7+/-2.9%, respectively, from 1 and 9.4+/-1.2, 52.8+/-2.1, 28.8+/-1.6%, respectively, from 2). Substrate 2 was degraded twice as rapidly as 1. Evidence is presented for the production of previously unreported catabolites of 2 that retain the flavanol A-ring and the C4-->C8 interflavan bond. It was confirmed that catabolism favoured removal of the 4'-hydroxyl rather than the 3'-hydroxyl group and that both beta-oxidation and alpha-oxidation occurred.
Silver linden, Tilia argentea Desf. ex DC (Tiliaceae) leaves are used in the treatment of common cold and bronchitis. In order to evaluate this information, antinociceptive and anti-inflammatory activities of the two main flavonoid glycosides: kaempferol-3,7-O-alpha-dirhamnoside and quercetin-3,7-O-alpha-dirhamnoside isolated from the leaves, were investigated. For the antinociceptive activity, p-benzoquinone-induced writhing test and for the anti-inflammatory activity, carrageenan-induced hind paw edema model in mice were used. Both compounds were shown to possess potent antinociceptive and anti-inflammatory activity at 50 mg/kg dose, per os, without inducing any apparent acute toxicity as well as gastric damage.
The aerial parts of Tilia americana var. mexicana (Schltdl) Hardin (Tiliaceae) have been widely used in Mexican traditional medicine to relieve sleeplessness, headache, and nervous excitement. The anxiolytic effect of four extracts and several flavonoid fractions from the bracts of Tilia americana subsp.mexicana, var. mexicana (Schltdl) Hardin or Tilia mexicana (Tiliaceae) was studied. Administration of 100mg/kg of n-hexane, ethyl acetate, and aqueous extracts to elevated plus-maze (EPM)-exposed mice displayed no anxiolytic effect; however, identical doses of methanol extract was able to increase the time percentage that mice spent in the EPM's open arms, as well as the percentage of crossings in the EPM's arms. The dose-response curve produced by methanol extract showed anxiolytic activity since 25mg/kg; animals showed no motor activity alteration in the open field test (OFT). Methanol extract was subjected to a bioassay-guided fractionation to obtain four ascendant polarity fractions (F1-F4) which were administrated at 100mg/kg. Data results indicate that F1 displayed the main anxiolytic effect. The purification of F1 produced a rich flavonoid anxiolytic mixture (F1C). This fraction was purified by RP-18 open chromatographic column to obtain four polar descent fractions: F1C(1), F1C(2), F1C(3), and F1C(4), respectively. Tiliroside was the major ingredient from the active fraction. High performance liquid chromatography analysis indicated that F1C was constituted principally of tiliroside, quercetin, quercitrin, kaempherol, and their glycosides. These results supported the use of Tilia americana in Mexican traditional medicine as well as the anxiolytic effect of a rich flavonoid fraction without affect motor activity.
Bioavailability and metabolism of flavonoids
- M Akhlaghi
- S Foshati
Akhlaghi, M., Foshati, S., 2017. Bioavailability and metabolism of flavonoids. Int. J.
Nutr. Sci. 2, 180-184. https://doi.org/10.30906/0869-2092-2011-74-6-33-40.
Linder flower -Tiliae flos
- M Blumenthal
- W Busse
- A Goldberg
- J Gruenwald
- T Hall
- C W Riggins
- R S Rister
Blumenthal, M., Busse, W., Goldberg, A., Gruenwald, J., Hall, T., Riggins, C.W., Rister, R.
S., 1998b. Linder flower -Tiliae flos. In: The Complete German Commission E
Monographs. American Botanical Council, Austin Texas, p. 163.
Committee on Herbal Medicinal Products (HMPC), 2012. Assessment Report on Tilia
Cordata Miller, Tilia Platyphyllos Scop., Tilia x vulgaris Heyne or Their Mixtures,
Flos.
Pharmacological properties of linden flower (Tiliae inflorescentia)
- Krajewska
Plants havings wound healing property: a review
- P Nasa
- H Kumar
Nasa, P., Kumar, H., 2020. Plants havings wound healing property: a review.
J. Pharmaceut. Sci. Res. 12, 1071-1075.
Herbal drugs used in respiratory system diseases
- Szumny
Pharmacological properties of linden flower
- J Krajewska
Krajewska, J., 2014. Pharmacological properties of linden flower (Tiliae inflorescentia).
Farmakoterapia 24, 41-45.
Herbal drugs used in respiratory system diseases
- D Szumny
- E Szypuła
- M Szydłowski
- E Chlebda
- M Skrzypiec-Spring
- A Szumny
Szumny, D., Szypuła, E., Szydłowski, M., Chlebda, E., Skrzypiec-Spring, M., Szumny, A.,
2007. Herbal drugs used in respiratory system diseases. Dent. Med. Probl 44,
507-515.