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      Role of tryptophan-metabolizing microbiota in mice diarrhea caused by Folium sennae extracts

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          Abstract

          Background

          Although reports have provided evidence that diarrhea caused by Folium sennae can result in intestinal microbiota diversity disorder, the intestinal bacterial characteristic and specific mechanism are still unknown. The objective of our study was to investigate the mechanism of diarrhea caused by Folium sennae, which was associated with intestinal bacterial characteristic reshaping and metabolic abnormality.

          Results

          For the intervention of Folium sennae extracts, Chao1 index and Shannon index were statistical decreased. The Beta diversity clusters of mice interfered by Folium sennae extracts were distinctly separated from control group. Combining PPI network analysis, cytochrome P450 enzymes metabolism was the main signaling pathway of diarrhea caused by Folium sennae. Moreover, 10 bacterial flora communities had statistical significant difference with Folium sennae intervention: the abundance of Paraprevotella, Streptococcus, Epulopiscium, Sutterella and Mycoplasma increased significantly; and the abundance of Adlercreutzia, Lactobacillus, Dehalobacterium, Dorea and Oscillospira reduced significantly. Seven of the 10 intestinal microbiota communities were related to the synthesis of tryptophan derivatives, which affected the transformation of aminotryptophan into L-tryptophan, leading to abnormal tryptophan metabolism in the host.

          Conclusions

          Folium sennae targeted cytochrome P450 3A4 to alter intestinal bacterial characteristic and intervene the tryptophan metabolism of intestinal microbiota, such as Streptococcus, Sutterella and Dorea, which could be the intestinal microecological mechanism of diarrhea caused by Folium sennae extracts.

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          Most cited references37

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          The Virtual Metabolic Human database: integrating human and gut microbiome metabolism with nutrition and disease

          Abstract A multitude of factors contribute to complex diseases and can be measured with ‘omics’ methods. Databases facilitate data interpretation for underlying mechanisms. Here, we describe the Virtual Metabolic Human (VMH, www.vmh.life) database encapsulating current knowledge of human metabolism within five interlinked resources ‘Human metabolism’, ‘Gut microbiome’, ‘Disease’, ‘Nutrition’, and ‘ReconMaps’. The VMH captures 5180 unique metabolites, 17 730 unique reactions, 3695 human genes, 255 Mendelian diseases, 818 microbes, 632 685 microbial genes and 8790 food items. The VMH’s unique features are (i) the hosting of the metabolic reconstructions of human and gut microbes amenable for metabolic modeling; (ii) seven human metabolic maps for data visualization; (iii) a nutrition designer; (iv) a user-friendly webpage and application-programming interface to access its content; (v) user feedback option for community engagement and (vi) the connection of its entities to 57 other web resources. The VMH represents a novel, interdisciplinary database for data interpretation and hypothesis generation to the biomedical community.
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            ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: An updated review

            ATP citrate lyase (ACLY) is an important enzyme linking carbohydrate to lipid metabolism by generating acetyl-CoA from citrate for fatty acid and cholesterol biosynthesis. Mendelian randomization of large human cohorts has validated ACLY as a promising target for low-density-lipoprotein-cholesterol (LDL-C) lowering and cardiovascular protection. Among current ACLY inhibitors, Bempedoic acid (ETC-1002) is a first-in-class, prodrug-based direct competitive inhibitor of ACLY which regulates lipid metabolism by upregulating hepatic LDL receptor (LDLr) expression and activity. ACLY deficiency in hepatocytes protects from hepatic steatosis and dyslipidemia. In addition, pharmacological inhibition of ACLY by bempedoic acid, prevents dyslipidemia and attenuates atherosclerosis in hypercholesterolemic ApoE-/- mice, LDLr-/- mice, and LDLr-/- miniature pigs. Convincing data from clinical trials have revealed that bempedoic acid significantly lowers LDL-C as monotherapy, combination therapy, and add-on with statin therapy in statin-intolerant patients. More recently, a phase 3 CLEAR Harmony clinical trial ("Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol") has shown that bempedoic acid reduces the level of LDL-C in hypercholesterolemic patients receiving guideline-recommended statin therapy with a good safety profile. Hereby, we provide a updated review of the expression, regulation, genetics, functions of ACLY in lipid metabolism and atherosclerosis, and highlight the therapeutic potential of ACLY inhibitors (such as bempedoic acid, SB-204990, and other naturally-occuring inhibitors) to treat atherosclerotic cardiovascular diseases. It must be pointed out that long-term large-scale clinical trials in high-risk patients, are warranted to validate whether ACLY represent a promising therapeutic target for pharmaceutic intervention of dyslipidemia and atherosclerosis; and assess the safety and efficacy profile of ACLY inhibitors in improving cardiovascular outcome of patients.
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              Effects of Serotonin and Slow-release 5-HTP on Gastrointestinal Motility in a Mouse Model of Depression

              Mood disorders and constipation are often comorbid yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Defects in neuron production of 5-HT might therefore result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%–80% decrease in levels of 5-HT in central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT–dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamineevoked release of endogenous 5-HT. In live mice we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximo-distal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice, compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.
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                Author and article information

                Contributors
                xiaonenqun@sohu.com
                tanzhjin@sohu.com
                Journal
                BMC Microbiol
                BMC Microbiol
                BMC Microbiology
                BioMed Central (London )
                1471-2180
                29 June 2020
                29 June 2020
                2020
                : 20
                : 185
                Affiliations
                [1 ]GRID grid.488482.a, ISNI 0000 0004 1765 5169, School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, ; Changsha, Hunan China
                [2 ]Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Changsha, Hunan China
                [3 ]GRID grid.488482.a, ISNI 0000 0004 1765 5169, Hunan University of Chinese Medicine, ; Changsha, Hunan China
                Author information
                http://orcid.org/0000-0003-3193-073X
                Article
                1864
                10.1186/s12866-020-01864-x
                7325056
                32600333
                4989850f-c85a-4d08-9f9d-cde8195d62e7
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 28 January 2020
                : 18 June 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81874460
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Microbiology & Virology
                diarrhea,intestinal microbiota,cytochrome p450,tryptophan metabolism,folium sennae

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